Computational STAT4 rSNP Analysis, Transcriptional Factor Binding Sites and Disease

The Janus Kinase-Signal Transducers and Activators of Transcription (JAK-STAT) pathways play a critical role in immune, neuronal, hematopoietic and hepatic systems ¹. JAK-STAT is a principal signal transduction pathway in cytokine and growth factor signaling as well as regulating various cellular processes such as cell proliferation, differentiation migration and survival ². JAK-STAT provides the principle intracellular signaling mechanism required for a wide array of cytokines ^{3, 4}. The STAT portion of the signaling cascade has seven mammalian family members which are STAT1, 2, 3, 4, 5a, 5b and 6 ^{3, 4}. These STATs bind thousands of transcriptional factor binding sites (TFBS) in the genome and regulate the transcription of many protein-coding genes, miRNAs and long noncoding RNAs ⁴. The STAT 4 gene which is important for signaling by interleukins (IL-12 and IL-23) and type 1 interferons ⁴ has been found to have several simple nucleotide polymorphisms (SNPs) associated with human disease ^{5, 6, 7, 8, 9, 10, 11, 12}. STAT4 transduces IL-12, IL-23 and type 1 interferon-mediated signals into helper T (Th) cells (Th1 and Th17) differentiation, monocyte activation, and interferon-gamma production ^{12, 13}. The STAT4-dependent cytokine regulation is found in the pathogenesis of autoimmune disease ^{14, 15} such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) ^{16, 17}.

The STAT4 gene maps to human chromosome 2q32.3 and is about 143 kb in size. The coding region consists of 22 exons with a large 70 kb intron between exons 2 and 3. Several SNPs in the gene have been significantly association with Behcet’s Disease ¹⁸, diabetes risk ¹¹, hepatitis B virus-related hepatocellular carcinoma ^{6, 10, 19, 20}, inflammatory bowel disease ²¹, juvenile idiopathic arthritis ²², primary biliary cirrhosis and Crohn's disease ²³, severe renal insufficiency in lupus nephritis ⁸, systemic lupus erythematosus ⁵ and ulcerative colitis ²⁴ (Table 1). The rs7574865 STAT4 SNP has been found to be significantly associated with diabetes ¹¹, hepatitis B virus-related hepatocellular carcinoma ^{6, 10, 19, 20}, inflammatory bowel disease ²¹, juvenile idiopathic arthritis ²², primary biliary cirrhosis and Crohn's disease ²³, severe renal insufficiency in lupus nephritis ⁸, systemic lupus erythematosus ⁵ and ulcerative colitis ²⁴. The rs11889341 STAT4 SNP has been found to be significantly associated with diabetes ¹¹, hepatitis B virus (HBV) infection, HBV-related cirrgisus and hepatocellular carcinoma ²³, severe renal insufficiency in lupus nephritis ⁸, and systemic lupus erythematosus ⁵. The rs8179673 STAT4 SNP has been found to be significantly associated with diabetes ¹¹, hepatitis B virus (HBV) infection, HBV-related cirrgisus and hepatocellular carcinoma ²³ and systemic lupus erythematosus ⁵. The rs7582694 STAT4 SNP has been found to be significantly associated with hepatitis B virus (HBV) infection, HBV-related cirrgisus and hepatocellular carcinoma ²³ and severe renal insufficiency in lupus nephritis ⁸. The rs7574070 and rs7572482 STAT4 SNPs have been found to be significantly associated with Behcet’s disease ¹⁸. The rs7572482 STAT4 SNP is located in the promoter region while the remaining SNPs are located in the large 70 kb intron between exon 2 and 3. The reports listed above indicate that these SNPs are in strong linkage disequilibrium (LD) with each other.

Table 1. STAT4 SNPs and disease. The SNPs have been found to be significantly associated with these diseases. The SNPs are located in STAT4 intron 3. MAF is the minor allele frequency. LD is linkage disequilibrium.

Disease	SNP	Chr 2 Pos	Alleles	MAF	Risk Allele	LD	Study Group	Reference
Behcet's	rs7574070	191145762	A/C	C=0.47		Yes	Chinese	7
	rs7572482	191150346	A/G	A=0.47		Yes
Diabetes	rs11889341	191079016	C/T	T=0.34		Yes	Asian, Caucasian	11
	rs7574865	191099907	G/T	T=0.25		Yes
	rs8179673	191104615	T/C	C=0.26		Yes
	rs10181656	191105153	C/G	G=0.26		Yes
Hepatitis B virus-related hepatocellular carcinoma	rs7574865	191099907	G/T	T=0.25	G		Chinese	6
HBV infection, HBV-related cirrgisus and hepatocellular carcinoma	rs7574865 rs7582694 rs11889341 rs8179673	191099907 191105394 191079016 191104615	G/T G/C C/T T/C	T=0.25 C=0.33 T=0.34 C=0.26	G G C T	Yes Yes Yes Yes
							Chinese	10
HBV viral clearance	rs7574865	191099907	G/T	T=0.25	G		Tibetan, Uygur	19
Hepatocellular carcinoma	rs7574865	191099907	G/T	T=0.25	G		Korean	20
Inflammatiory bowel disease	rs7574865	191099907	G/T	T=0.25	G		Chinese, Causcians	21
Juvenil Idiopathic arthritis	rs7574865	191099907	G/T	T=0.25	T		Han Chinese	22
Primary biliary cirrhosis and Crohn's disease	rs7574865	191099907	G/T	T=0.25	T		Japanese	23
Severe renal insufficiency in lupus nephritis	rs11889341 rs7574865 rs7568275 rs7582694	191079016 191099907 191101726 191105394	C/T G/T C/G G/C	T=0.28 T=0.23 G=0.28 C=0.22		Yes Yes Yes Yes	Swedish	8
Systemic Lupus Erythematosus	rs11889341 rs7574865 rs8179673 rs10181656	191079016 191099907 191104615 191105153	C/T G/T T/C C/G	T=0.28 T=0.23 C=0.26 G=0.26		Yes Yes Yes Yes	European descent	5
Ulcerative colitis	rs7574865	191099907	G/T	T=0.25	T		European descent	24

Single nucleotide changes that affect gene expression by impacting gene regulatory sequences such as promoters, enhances, and silencers are known as regulatory SNPs (rSNPs) ^{25, 26, 27, 28}. A rSNPs within a transcriptional factor binding site (TFBS) can change a transcriptional factor’s (TF) ability to bind its TFBS ^{29, 30, 31, 32} in which case the TF would be unable to effectively regulate its target gene ^{33, 34, 35, 36, 37}. This concept is examined for the above STAT4 rSNPs and their allelic association with TFBS, where computation analyses ^{38, 39, 40, 41} was used to identify TFBS alterations created by the STAT4 rSNPs. Recent reports have also introduced the concept of modeling of epigenetic modifications to transcriptional factor binding sites in the control of gene expression ^{42, 43}. In this report, the rSNP associations with changes in potential TFBS are discussed with their possible relationship to these diseases in humans.

The JASPAR CORE database ^{44, 45} and ConSite ⁴⁶ were used to identify the potential STAT4 TFBS in this study. JASPAR is a database of transcription factor DNA-binding preferences used for scanning genomic sequences where ConSite is a web-based tool for finding cis-regulatory elements in genomic sequences. The TFBS and rSNP location within the binding sites have previously been discussed ⁴⁷. The Vector NTI Advance 11.5 computer program (Invitrogen, Life Technologies) was used to locate theTFBS in theSTAT4 gene (NCBI Ref Seq NM_003151) from 4 kb upstream of the transcriptional start site to 8.3 kb past the 3’UTR which represents a total of 130.9 kb. The JASPAR CORE database was also used to calculate each nucleotide occurrence (%) within the TFBS, where upper case lettering indicate that the nucleotide occurs 90% or greater and lower case less than 90%. The occurrence of each SNP allele in the TFBS is also computed from the database (Table 2 & Appendix).

Table 2. The STAT4 SNPs that were examined in this study where the minor allele is in red. Also listed are the transcriptional factors (TF), their potential binding sites (TFBS) containing these SNPs and DNA strand orientation. TFs in red differ between the SNP alleles. Where upper case nucleotide designates the 90% conserved BS region and red is the SNP location of the alleles in the TFBS. Below the TFBS is the nucleotide occurrence (%) obtained from the Jaspar Core database. Also listed are the number (#) of binding sites in the gene for the given TF. Note: TFs can bind to more than one nucleotide sequence.

SNP	Allele			TFs		Protein name				# of Sites					TFBS	Strand
rs7574865	G			EN1		Engrailed homeobox 1				1					gaatagtggtt	plus
															g=20%
				FOXA1		Forkhead box A1				1					ccacTaTTcaCattt	minus
															c=0%
				FOXA2		Forkhead box A2				1					TaTTcACatttt	minus
															c=0.1%
				FOXL1		Forkhead box L1				8					tgtgaATA	plus
															g=17%
				HLTF		Helicase-like transcription factor				1					tcaCaTtttg	minus
															c=20%
				MAX		MYC Associated Factor X				3					attCACaTtt	minus
															C=100%
				RUNX2		Runt-related transcription factor 2				1					gtgaataGTGGttat	plus
															g=40%
				SOX17		SRY (sex determining region Y)-box 17				2					cacATTtTg	minus
															c=29%
				ZNF354C		Zinc finger protein 354C				81					attCAC	minus
															C=100%
	T			ARID3A		AT rich interactive domain 3A				81					ATtAAc	minus
	0.25					(BRIGHT-like)									A=100%
				EN1		Engrailed homeobox 1				1					taatagtggtt	plus
															t=30%
				FOXA1		Forkhead box A1				1					ccacTaTTaaCattt	minus
															a=0%
				HLTF		Helicase-like transcription factor				1					taaCaTtttg		minus
															a=34%
				NKX2-5		Natural killer 3 homeobox 2				23					ttAAtag		plus
															t=76%
				NR1HE: RXRa		Nuclear Receptor Subfamily 1, Group H, Member 3				1					TaaccactatTaacatttt		minus
						Retinoid X receptor, alpha									a=44%
				PDX1		Pancreatic and duodenal homeobox 1				158					tTAATa		plus
															T=100%
				PRRX2		Paired related homeobox 2				518					tATTA		minus
															A=98%
				RUNX2		Runt-related transcription factor 2				1					gttaataGTGGttat		plus
															t=38%
				SOX5		SRY (sex determining region Y)-box 5				42					AaTGTTa		plus
															T=91%
				SOX17		SRY (sex determining region Y)-box 17				4					aacATTtTg		minus
															a=23%
				SRY		Sex determining region Y				4					attaACAtt		minus
															a=64%
rs11889341	C			AR		Androgen Receptor				1					aaGaAtAagatGttc		minus
															G=100%
				CEBPb		CCAAT/enhancer binding protein (C/EBP), beta				1					tcTTttaccAc		plus
															c=6%
				FOXL1		Forkhead box L1				24					aaagaATA		minus
															g=26%
				HLTF		Helicase-like transcription factor				2					attCtTttac		plus
															C=100%
				NR3C1		Nuclear Receptor Subfamily 3, Group C, Member 1				1					agaataagatGTtCa		minus
						(Glucocorticoid Receptor)									g=80%
				SOX3		SRY (sex determining region Y)-box 3				1					ttaTTcTttt		plus
															c=7%
					SOX5	SRY (sex determining region Y)-box 5			73						aTTcTTt					plus
															c=0%
					SOX6	SRY (sex determining region Y)-box 56			6						ttaTTcTttt					plus
															c=0%
					SRY	Sex determining region Y			9						taaaAgAAa					minus
															g=0%
					ZNF263	Zinc finger protein 263			1						agaGcAgtggtaaaagaataa					minus
															g=75%
	T				CDX2	Caudal type homeobox 2			13						tggtaAaaAAa					minus
	0.34														A=100%
					FOXA1	Forkhead box A1			1						atctTaTTtttttac					plus
															t=0%
					FOXD1	Forkhead Box D1			14						gTAAAaAa					minus
															A=100%
					FOXD3	Forkhead box D3			29						tctTaTTttttt					plus
															t=68%
					FOXI1	Forkhead box I1			29						tctTaTTTtttt					plus
															T=100%
					FOXL1	Forkhead box L1			59						aaaaaATA					minus
															a=57%
					FOXO1	Forkhead Box O1			13						attTtTTtacc					plus
															T=100%
					FOXO1	Forkhead Box O1			2						tctTaTTtttt					plus
															t=88%
					FOXO3	Forkhead Box O3			9						ggtAAAaA					plus
															A=92%
					FOXP1	Forkhead box P1			1						cagtggtAAAaAaat					minus
															A=100%
					FOXP2	Forkhead box P2			13					tggTAAAaAaa						minus
														A=100%
					GATA1	GATA binding protein 1			2					atcTTATtttt						plus
														t=88%
					GATA1	GATA binding protein 1			10					tttTTAccact						plus
														t=51%
					GATA2	GATA binding protein 2			2					atttttTTAcCact						plus
														t=54%
					GATA2	GATA binding protein 2			1					aacatcTTATtttt						plus
														t=72%
					GATA3	GATA Binding Protein 3			24					AaATAAga						minus
														A=100%
					GATA4	GATA binding protein 4			2					tcTTATttttt						plus
														t=79%
					HLTF	Helicase-like transcription factor			1					catCtTattt						plus
														t=25%
					MEF2C	Myocyte Enhancer Factor 2C			1					ggtaaaaAAATAaga						minus
														A=95%
					MEF2C	Myocyte Enhancer Factor 2C			1					gtggtaaAAAaAtaa						minus
														A=97%
					NR3C1	Nuclear Receptor Subfamily 3, Group C, Member 1			1					aaaataagatGTtCa						minus
						(Glucocorticoid Receptor)								a=15%
					SOX5	SRY (sex determining region Y)-box 5			164					aTTtTTt						plus
														t=0%
					SOX6	SRY (sex determining region Y)-box 56			8					ttaTTtTttt						plus
														t=0%
					SRY	Sex determining region Y			19					taaaAaAAt						minus
														a=0%
					SRY	Sex determining region Y			4					gtaaAaAAa						minus
														A=100%
					ZNF263	Zinc finger protein 263			1					agaGcAgtggtaaaaaaataa						minus
														a=19%
rs8179673		T			ARID3A	AT rich interactive domain 3A			397					AatAAa						plus
						(BRIGHT-like)								t=63%
					ARID3A	AT rich interactive domain 3A			227					ATttAa						minus
						(BRIGHT-like)								A=100%
					EN1	Engrailed homeobox 1			1					aaataaaggtc						plus
														t=80%
					FOXA1	Forkhead box A1			1					ccTTTaTTtaatata						minus
														a=27%
					FOXL1	Forkhead box L1			25					attaaATA						plus
														T=91%
					FOXL1	Forkhead box L1			23					atttaATA						minus
														a=30%
					GATA3	GATA Binding Protein 3			27					AaATAAag						plus
														T=100%
					HOXA5	Hoxa5			27					ctttatTt						minus
														a=88%
					LHX3	LIM homeobox 3			3					atATTAAaTaaag						minus
														T=95%
					NFIL3	Nuclear factor, interleukin 3 regulated			2					TTAttTAAtat						minus
														A=96%
					NKX3-1	NK3 homeobox 1			72					tTAtTTA						minus
														A=100%
					RORA_1	RAR-related orphan receptor A			11					ataaaGGTCc						plus
														t=60%
					RXRa	Retinoid X receptor, alpha			5					taaAGgtCcat						plus
														t=5%
					SOX2	SRY (sex determining region Y)-box 2			11					CCtTTaTt						minus
														a=0%
					SOX3	SRY (sex determining region Y)-box 3			1					cctTTaTtta						minus
														a=0%
					SOX6	SRY (sex determining region Y)-box 6			1					cctTTaTtta						minus
														a=0%
					SOX10	SRY (sex determining region Y)-box 10			142					cttTaT						minus
														a=0%
					SRY	Sex determining region Y			9					ttaaAtAAa						plus
														t=7%
					TBP	TATA Box Binding Protein			1					gtATAtAttaaataa						plus
														t=16%
		C			BRCA1	breast cancer 1, early onset			39					acAaagg						plus
		0.26												c=81%
					FOXA1	Forkhead box A1			1					ccTTTgTTtaatata						minus
														g=9%
					FOXA2	Forkhead box A2			1					TgTTtaatatat						minus
														g=72%
					FOXA2	Forkhead box A2			1					TaTggACctttg						minus
														g=36%
					FOXD1	Forkhead Box D1			6					tTAAACAa						plus
														C=90%
					FOXH1	Forkhead Box H1			1					tatAtTaaACa					plus
														C=100%
					FOXO1	Forkhead Box O1			1					cttTGTTtaat					minus
														G=100%
					FOXP1	Forkhead box P1			1					atatattAAAcAaag					plus
														c=89%
					FOXP2	Forkhead box P2			1					tatTAAACAaa					plus
														C=99%
					FOXQ1	Forkhead box Q1			1					ctttGTTTAat					minus
														G=100%
					HLTF	Helicase-like transcription factor			1					gacCtTtgtt					minus
														g=17%
					HNF1A	Hepatocyte Nuclear Factor 1 homeobox A			1					gtTTAaTatatact					minus
														g=67%
					HNF4A	Hepatocyte Nuclear Factor 4, Alpha			1					tggacctttgtttaa					minus
														g=12%
					HNF4G	Hepatocyte Nuclear Factor 4, Gamma			1					attaaaCAaAGgtcc					plus
														C=93%
					JUN::FOS	Jun Proto-Oncogene			48					TtAaacA					plus
						FBJ Murine Osteosarcoma Viral Oncogene Homolog								c=83%
					RXRa	Retinoid X receptor, alpha			1					caaAGgtCcat					plus
														c=85%
					SPX2	SRY (sex determining region Y)-box 2			2					CCtTgGTc					minus
														G=100%
					SOX3	SRY (sex determining region Y)-box 3			1					cctTTGTttA					minus
														G=93%
					SOX5	SRY (sex determining region Y)-box 5			134				tTTGTTt						minus
													G=96%
					SOX6	SRY (sex determining region Y)-box 56			1				cCtTTGTtta						minus
													G=100%
					SOX9	SRY (sex determining region Y)-box 9			4				cctTtGttt						minus
													G=95%
					SOX10	SRY (sex determining region Y)-box 10			141				cttTgT						minus
													g=86%
					SRY	Sex determining region Y			4				ttaaACAAa						plus
													C=93%
					TBP	TATA Box Binding Protein			1				gtATAtAttaaacaa						plus
													c=30%
rs7582694		G			BATF::JUN	Basic leucine zipper transcription factor,			1				tctaTGtgTcA						minus
						ATF-like Jun proto-oncogene							c=5%
					CEBPa	CCAAT/enhancer binding protein (C/EBP), alpha			1				gTTgCatactc						minus
													c=32%
					FOSL2	FOS-Like Antigen 2			1				ctaTGtgTCAt						minus
													c=19%
					FOXC1	Forkhead box C1			3				atagaGTA						plus
													g=25%
					HLTF	Helicase-like transcription factor			1				acaCaTagag						plus
													g=37%
					HLF	Hepatic Leukemia Factor			1				ggTtgcatactc						minus
													c=28%
					JUN(var.2)	Jun Proto-Oncogene			2				actctaTGtgTCAt						minus
													c=10%
					JUNB	Jun B Proto-Oncogene			1				ctaTGtgTCAt						minus
													c=20%
					MAX	MYC Associated Factor X			1				tgaCACaTag						plus
													g=29%
					SOX3	SRY (sex determining region Y)-box 3			2				tctaTGTgtc						minus
													c=75%
					SOX10	SRY (sex determining region Y)-box 10			77				ctaTgT						minus
													c=86%
					T	T, Brachyury Homolog			1				cTAtGTGTcAt						minus
													c=70%
		C			BATF: JUN	Basic leucine zipper transcription factor,			2				tgtaTGtgTcA						minus
		0.33				ATF-like Jun proto-oncogene							g=27%
					BH1HE40	Basic Helix-Loop-Helix Family, Member E40			2				gaCACaTacag						plus
													c=75%
					CEBPa	CCAAT/enhancer binding protein (C/EBP), alpha			1				gTTgCatactg						minus
													g=6%
					FOSL2	FOS-Like Antigen 2			1				gtaTGtgTCAt						minus
													g=39%
					FOXC1	Forkhead box C1			7				atacaGTA						plus
													c=25%
					FOXC1	Forkhead box C1			10				atactGTA						minus
													G=100%
					HLF	Hepatic Leukemia Factor			1				ggTtgcatactg						minus
													g=17%
					HIF1a: ARNT	Hypoxia Inducible Factor 1, Alpha Subunit			11				gtatGTGt						minus
						Aryl Hydrocarbon Receptor Nuclear Translocator							g=47%
					JUN(var.2)	Jun Proto-Oncogene			1				actgtaTGtgTCAt						minus
													g=32%
					JUNB		Jun B Proto-Oncogene	1					gtaTGtgTCAt					minus
													g=24%
rs7574070		A			CEBPB		CCAAT/enhancer binding protein (C/EBP), beta	1					aaTgtCtccAt					plus
													A=100%
					MZF1_1-4		Myeloid Zinc Finger 1	112					tGGaGA					minus
													t=40%
					NFE2L1::MafG		Nuclear Factor, Erythroid 2-Like 1	123					caTGAa					plus
							V-Maf Avian Musculoaponeurotic						a=85%
							Fibrosarcoma Oncogene Homolog G
					PAX2		Paired box gene 2	3					cttCatgg					minus
													t=35%
					RFX1		Regulatory Factor X, 1	1					ttcttCatgGagAC					minus
							(Influences HLA Class II Expression)						t=84%
					RFX5		Regulatory factor X, 5 (influences HLA	1					cttCatgGagACatt					minus
							class II expression)						t=78%
					STAT3		Signal transducer and activator of	1					cTtCatGgAga					minus
							transcription 3 (acute-phase response factor)						t=30%
					STAT5A::STAT5B		Signal transducer and activator of	1					gtcTCcatGAA					plus
							transcription 5A and transcription 5B						a=43%
					THAP1		THAP domain containing,	3					tctCCatga					plus
							apoptosis associated protein 1						a=29%
					ZNF354C		Zinc finger protein 354C	87					ctCCAt					plus
													A=100%
		C			EBF1		Early B-cell factor 1	7					ttCttcaGgGa					minus
		0.47											G=97%
					ELK1		ELK1, member of ETS oncogene family	2					ctccctGAag					plus
													c=86%
					STAT1		Signal Transducer And Activator	6					cTTCagGGAga					minus
							Of Transcription 1, 91kDa						G=96%
					STAT3		Signal transducer and activator of	3					cTtCagGgAga					minus
							transcription 3 (acute-phase response factor)						g=45%
					STAT4		Signal Transducer And Activator Of Transcription 4	1					cTtcaggGAgacat					minus
													g=43%
					STAT5A::STAT5B		Signal transducer and activator of	4					gtcTCcctGAA					plus
							transcription 5A and transcription 5B						c=37%
					TFAP2C		Transcription factor AP-2 gamma	1					ccattCttcAGggag					minus
							(activating enhancer binding protein 2 gamma)						G=99%
					THAP1		THAP domain containing,	3					tctCCctga					plus
							apoptosis associated protein 1						c=68%
rs7572482		A			ARID3A		AT rich interactive domain 3A	237					ATgAAa					plus
							(BRIGHT-like)						A=100%
					EBF1		Early B-cell factor 1	2					ttCtCatGaaa					plus
													a=27%
					EBF1		Early B-cell factor 1	1					ttttCatGaGa					minus
													t=37%
					FOS		FBJ Murine Osteosarcoma Viral Oncogene Homolog	1					tcTttcTCAtg					plus
													A=100%
					NFE2L1::MafG		Nuclear Factor, Erythroid 2-Like 1	79					caTGAg					minus
							V-Maf Avian Musculoaponeurotic						T=100%
							Fibrosarcoma Oncogene Homolog G
					NFE2L1::MafG		Nuclear Factor, Erythroid 2-Like 1	123					caTGAa					plus
							V-Maf Avian Musculoaponeurotic						a=85%
							Fibrosarcoma Oncogene Homolog G
					POU5F1::SOX2	POU Class 5 Homeobox 1		1					ctTTctcATGaaaac					plus
						SRY (Sex Determining Region Y)-Box 2							A=90%
					RFX1	Regulatory Factor X, 1		1					tttctCatgaaaAC					plus
						(Influences HLA Class II Expression)							a=59%
					SPIB	Spi-B transcription factor (Spi-1/PU.1 related)		52					tgaGaAA					minus
													t=37%
					SOX3	SRY (sex determining region Y)-box 3		1					tctTTcTcat					plus
													a=1%
					STAT3	Signal transducer and activator of		1					tTcatgagAAa					minus
						transcription 3 (acute-phase response factor)							t=60%
					STAT4	Signal Transducer And Activator Of Transcription 4		1					tTcatgaGAAagaa					minus
													t=35%
					STAT6	Signal Transducer And Activator Of Transcription 6		1					tctTTCtcaaGAAaa					plus
						Interleukin-4 Induced							a=18%
					STAT6	Signal Transducer And Activator Of Transcription 6		1					gttTTCatgaGAAag					minus
						Interleukin-4 Induced							t=51%
					STAT5A::STAT5B	Signal transducer and activator of		1					ttTctcatGAA					plus
						transcription 5A and transcription 5B							a=43%
					STAT5A::STAT5B	Signal transducer and activator of		1					gtTTtcatGAg					minus
						transcription 5A and transcription 5B							t=5%
		G			ARNT	Aryl Hydrocarbon Receptor Nuclear Translocator		14					cACGaG					minus
		0.47											C=100%
					ARNT	Aryl Hydrocarbon Receptor Nuclear Translocator		14					ctCGTG					plus
													G=100%
					ARNT::AHR	Aryl Hydrocarbon Receptor Nuclear Translocator		14					ctCGTG					plus
						Aryl Hydrocarbon Receptor							G=96%
					SOX3	SRY (sex determining region Y)-box 3		10					tctTTcTcgt					plus
													g=1%
					SPI1	Spleen focus forming virus (SFFV)		1				acgagaaaGAAgtag						minus
						proviral integration oncogene spi1						c=12%
					STAT3	Signal transducer and activator of		3				tTcacgagAAa						minus
						transcription 3 (acute-phase response factor)						c=36%
					STAT4	Signal Transducer And Activator Of Transcription 4		1				tTcacgaGAAagaa						minus
												c=52%
					STAT6	Signal Transducer And Activator Of Transcription 6		3				tctTTCtcgaGAAaa						plus
						Interleukin-4 Induced						g=65%
					STAT6	Signal Transducer And Activator Of Transcription 6		1				gttTTCacgaGAAag						minus
						Interleukin-4 Induced						c=37%
					ZBTB33	Zinc Finger And BTB Domain Containing 33		1				ttCtCGtGaaaactg						plus
												G=100%
rs7568275		C			FOXA1	Forkhead box A1		1				gtaaTaTTaactgaa						minus
												g=6%
					FOXI1	Forkhead box I1		3				ataTgTTcagtt						plus
												c=0%
					FOXL1	Forkhead box L1		10				tgaacATA						minus
												g=9%
					HLTF	Helicase-like transcription factor		8				gaaCaTataa						minus
												g=20%
					NKX2-5	NK2 Homeobox 5		19				ttAActg						minus
												g=65%
					SRF	Serum Response Factor		1				actgaaCatAtaaaGtaa						minus
						(C-Fos Serum Response Element-Binding						g=0.44
						Transcription Factor)
		G			BATF: JUN	Basic leucine zipper transcription factor,		2				atgtTGAgTtA						plus
		0.28				ATF-like Jun proto-oncogene						G=99%
					BATF::JUN	Basic leucine zipper transcription factor,		1				atatTaAcTcA						minus
						ATF-like Jun proto-oncogene						c=82%
					BRCA1	Breast Cancer 1, Early Onset		43				tcAacat						minus
												c=81%
					FOXA1	Forkhead box A1		1				gtaaTaTTaactcaa						minus
												c=33%
					FOXA1	Forkhead box A1		1				tataTgTTgagttaa						plus
												g=13%
					FOXA2	Forkhead box A2		1				TgTTgAgttaat						plus
												g=22%
					FOXA2	Forkhead box A2		1				TaTTaActcaac						minus
												c=33%
					Foxd3	Forkhead box D3		1				ataTgTTgagtt						plus
												g=21%
					FOXD3	Forkhead box D3		1				taaTaTTaactc						minus
												c=26%
					FOXH1	Forkhead Box H1		2				ttaAcTcaACa						minus
												c=70%
					FOXI1	Forkhead box I1		1				ataTgTTgagtt						plus
												g=0%
					FOXL1	Forkhead box L1		16				tcaacATA						minus
												c=17%
					HLTF	Helicase-like transcription factor		1				caaCaTataa						minus
												c=17%
					JUN::FOS	Jun Proto-Oncogene		17				TaActcA						minus
						FBJ Murine Osteosarcoma Viral Oncogene Homolog						c=83%
			MAFF			V-Maf Avian Musculoaponeurotic		1				attaacTCAacAtataaa						minus
						Fibrosarcoma Oncogene Homolog F						C=94%
			MAFK			V-Maf Avian Musculoaponeurotic		1				ttaacTCAaCAtata						minus
						Fibrosarcoma Oncogene Homolog K						C=96%
			ZNF354C			Zinc finger protein 354C		58				ctCCAc						minus
												C=100%
rs10181656		C	AR			Androgen Receptor		1				tgGtACAagggGtga						minus
												G=95%
			E2F6			E2F transcription factor 6		3				ggGtGaGAaga						minus
												G=100%
			GATA1			GATA binding protein 1		4				ctcTTcTCacc						plus
												c=22%
			GATA2			GATA binding protein 2		1				caactcTTcTCacc						plus
												c=40%
			GATA4			GATA binding protein 4		3				tcTTcTCaccc						plus
												c=45%
			HLTF			Helicase-like transcription factor		7				cccCtTgtac						plus
												c=17%
			KLF5			Kruppel-like factor 5 (intestinal)		1				ttctCaCCCc						plus
												C=100%
			MZF1_1-4			Myeloid Zinc Finger 1		58				gGGtGA						minus
												G=90%
			MZF1_5-13			Myeloid Zinc Finger 1		1				caAgGgtga						minus
												g=88%
			NR1H3: RXRa			Nuclear Receptor Subfamily 1, Group H, Member 3		1				TcaccccttgTaccactac						plus
						Retinoid X receptor, alpha						c=77%
			MAFF			V-Maf Avian Musculoaponeurotic		1				attaacTCAacAtataaa						minus
						Fibrosarcoma Oncogene Homolog F						C=94%
			MAFK			V-Maf Avian Musculoaponeurotic		1				ttaacTCAaCAtata						minus
						Fibrosarcoma Oncogene Homolog K						C=96%
			ZNF354C			Zinc finger protein 354C		58				ctCCAc						minus
												C=100%
rs10181656		C	AR			Androgen Receptor		1				tgGtACAagggGtga						minus
												G=95%
			E2F6			E2F transcription factor 6		3				ggGtGaGAaga						minus
												G=100%
			GATA1			GATA binding protein 1		4				ctcTTcTCacc						plus
												c=22%
			GATA2			GATA binding protein 2		1				caactcTTcTCacc						plus
												c=40%
			GATA4			GATA binding protein 4		3				tcTTcTCaccc						plus
												c=45%
			HLTF			Helicase-like transcription factor		7				cccCtTgtac						plus
												c=17%
			KLF5			Kruppel-like factor 5 (intestinal)		1				ttctCaCCCc						plus
												C=100%
			MZF1_1-4			Myeloid Zinc Finger 1		58				gGGtGA						minus
												G=90%
			MZF1_5-13			Myeloid Zinc Finger 1		1				caAgGgtga						minus
												g=88%
			NR1H3: RXRa			Nuclear Receptor Subfamily 1, Group H, Member 3		1				TcaccccttgTaccactac						plus
						Retinoid X receptor, alpha						c=77%
			SP1			Specificity Protein 1		1			ttCtcacCcct							plus
											C=80%
			SREBF1			Sterol regulatory element binding		2			cTCAcccctt							plus
						transcription factor 1					c=88%
			SREBF2			Sterol regulatory element binding		2			aaGgggTGAg							minus
						transcription factor 2					g=77%
			ZNF263			Zinc finger protein 263		1			agtGgtacaaggggtgagaag							minus
											g=59%
		G	BRCA1			Breast cancer 1, early onset		12			tcAgccc							plus
		0.26									g=9%
			GATA1			GATA binding protein 1		1			ctcTTcTCagc							plus
											g=34%
			GATA2			GATA binding protein 2		1			caactcTTcTCagc							plus
											g=45%
			GATA4			GATA binding protein 4		1			tcTTcTCagcc							plus
											g=34%
			HLTF			Helicase-like transcription factor		1			gccCtTgtac							plus
											g=20%
			HNF4G			Hepatocyte Nuclear Factor 4, Gamma		1			gtggtaCAagGgctg							minus
											c=46%
			KLF5			Kruppel-like factor 5 (intestinal)		1			tctCagCCCt							plus
											g=38%
			MAFB			v-maf musculoaponeurotic fibrosarcoma		15			Gctgagaa							minus
						oncogene homolog B (avian)					c=80%
			SP1			Specificity Protein 1		1			tctcagCcctt							plus
											g=43%
			SREBF1			Sterol regulatory element binding		1			cTCAgccctt							plus
						transcription factor 1					g=12%
			STAT3			Signal transducer and activator of		1			gggCtgagAAg							minus
						transcription 3 (acute-phase response factor)					C=91%
			THAP1			THAP domain containing,		2			cagCCcttg							plus
						apoptosis associated protein 1					g=6%

Genome-wide association studies (GWAS) over the last decade have identified nearly 6,500 disease or trait-predisposing SNPs where only 7% of these are located in protein-coding regions of the genome ^{48, 49} and the remaining 93% are located within non-coding areas ^{50, 51} such as regulatory or intergenic regions. SNPs which occur in the putative regulatory region of a gene where a single base change in the DNA sequence of a potential TFBS may affect the process of gene expression are drawing more attention ^{25, 27, 52}. A SNP in a TFBS can have multiple consequences. Often the SNP does not change the TFBS interaction nor does it alter gene expression since a transcriptional factor (TF) will usually recognize a number of different binding sites in the gene. In some cases the SNP may increase or decrease the TF binding which results in allele-specific gene expression. In rare cases, a SNP may eliminate the natural binding site or generate a new binding site. In which cases the gene is no longer regulated by the original TF. Therefore, functional rSNPs in TFBS may result in differences in gene expression, phenotypes and susceptibility to environmental exposure ⁵². Examples of rSNPs associated with disease susceptibility are numerous and several reviews have been published.^{52, 53, 54, 55}.

The rs7574865 rSNP STAT4-G allele ^{G (+ strand) or C (} located in the unique MAX and ZNF354C TFBS have a 100% occurrence in humans while the unique FOXL1 TFBS has a 17% occurrence (Table 2). Since these binding sites (BS) occur multiple times in the gene, the rSNP G allele should not have much of an impact gene regulation (Table 2). The minor rs7574865 rSNP STAT4-T allele ^{T (+ strand) or A (} located in the unique ARID3A, FOXQ1 and PDX1 TFBS have a 100% occurrence in humans while the NR1HE::RXRa TFBS has a 44% occurrence (Figure 1, Table 2). Since all the unique BS for this allele occur multiple times in this gene, it would not be expected that these TFBS would have much of an effect on STAT4 regulation except for the NR1HE:: RXRa BS which occurs only once in the gene (Table 2) and is a key regulator of macrophage function, controlling transcriptional programs involved in lipid homeostasis and inflammation (Appendix). Since NR1HE:: RXRa protein duplex is part of the NR1 subfamily of the retinoid nuclear receptor superfamily, the presence of its TFBS created by the minor T allele could in part be responsible for the diseases listed in Table 1, that are significantly associated with this rSNP.

The rs11889341 rSNP STAT4-C allele [C (+ strand) or G (- strand) located in the unique AR TFBS has a 100% occurrence in humans and occurs only once in the gene (Figure 2, Table 2). The androgen receptor is a steroid-hormone activated transcription factor which stimulates transcription of androgen responsive genes that are expressed in bone marrow, mammary gland, prostate, testicular and muscle tissues. The absence of this TFBS created by the minor STAT4-T allele should have a major effect relating to the diseases listed in Table 1. The minor rs11889341 rSNP STAT4-T allele ^{T (+ strand) or A (} located in the unique CDX2, FOXOD1, FOXI1, FOXO1, FOXP1, FOXP2 and GATA3 TFBS have a 100% occurrence in humans. These TFBS occur multiple times in the gene so they would not be expected to have much impact on the regulation of the gene, except for the FOXP1 TFBS which occurs only once in the gene (Table 2). Although FOXP1 is a member of the subfamily P of the forkhead box (FOX) transcription factors which play important roles in the regulation of tissue- and cell type-specific gene transcription during both development and adulthood, it is doubtful that the presence of this TFBS only with the minor T allele would have much impact on the regulation of the gene since there are other family members TFBS represented with the minor allele (Table 2). The SNP T allele is also located in the two unique MEF2C TFBS which have a 95 and 97% occurrence in humans and each occurs only once in the gene (Table 2). The MEF2C TF controls cardiac morphogenesis and myogenesis, and is also involved in vascular development and consequently the presence or absence of this TFBS should have an impact on the diseases listed in Table 1.

The rs8179673 rSNP STAT4-T allele ^{T (+ strand) or A (} located in the unique ARID3A, GATA3 and NKX3-1 TFBSs have a 100% occurrence in humans while the LHX3 and NFIL3 TFBS have a 95 and 96% occurrence (Table 2). Since these TFBS occur more than once in the gene, it is doubtful that these BS would have much impact on the regulation of the gene. The minor rs8179673 rSNP STAT4-C allele ^{C (+ strand) or G (} located in the unique FOXH1, FOXO1, FOXQ1, SOX2 and SOX6 TFBS have a 100% occurrence in humans while the HNF1a and HNF4g TFBS have a 67 and 93% occurrence, respectively (Table 2). All of these TFBS occur only once in the gene (Table 2). However, the FOXH1, FOXO1, FOXQ1, SOX2 and SOX6 TFBS are involved with transcription machinery and are represented in families consisting of multiple members. Therefore, it is unlikely that the presence or absence of one family member would have much impact on gene regulation especially since there are TFBS for multiple family members represented by the minor C allele (Table 2, Appendix). The unique HNF1a and HNF4g TFBS which also occur only once in the gene are BS for the HNF1a and HNF4g transcriptional activators that regulates the tissue specific expression of multiple genes, especially in pancreatic islet cells and in liver (Table 2, Appendix).

The rs7574070 rSNP STAT4-A allele ^{A (+ strand) or T (} located in the unique CEBPb and ZNF354C TFBS have a 100% occurrence in humans while the RFX1 and RFX5 TFBS have a 84 and 78% occurrence, respectively (Table 2). The CEBPb, RFX1 and RFX5 TFBS occur only once in the gene while the ZNF354C TFBS occurs 87 times in the gene (Table 2); consequently, only the CEBPb, RFX1 and RFX5 TFBS might have an impact on gene regulation. The CEBPb TF is an important transcriptional activator regulating the expression of genes involved in immune and inflammatory responses; consequently, the loss of the BS with the minor C allele could have an impact on Behcet’s disease (Table 1). The RFX1 & 5 TFs are important regulatory factors essential for MHC class II gene expression and the loss of these BS with the presence of the minor C allele could also have an impact on Behcet’s disease (Table 1). The rs7574070 rSNP STAT4-C allele ^{C (+ strand) or G (} located in the unique STAT4 and THAP2C TFBS have a 43 and 99% occurrence in humans and occur only once in the gene (Table 2). The STAT4 TF is important in regulating genes associated with systemic lupus erythematosus and rheumatoid arthritis (Appendix); consequently, the occurrence of this TFBS only with the minor C allele could have an impact on Behcet’s disease (Table 1). The THAP2C TF is involved with a large spectrum of important biological functions (Appendix) and also contribute to Behcet’s disease when the TFBS is only represented in the minor C allele (Table 2, Appendix).

The rs7572482 rSNP STAT4-A allele ^{A (+ strand) or T (} located in the unique ARID3A, FOS, NFE2L1::MAFG and POU5F1::SOX2 TFBS have a 100% occurrence in humans except for the POU5F1::SOX2 TFBS for which it has a 90% occurrence (Table 2). The ARID3A and NFE2L1::MAFG TFBS occur multiple times in the gene while the FOS and POU5F1::SOX2 TFBS only occurs once (Table 2). The FOS TF is a regulator of cell proliferation, differentiation and transformation while the POU5F1::SOX2 TFs play a key role in embryonic development and stem cell pluripotency (Appendix) which could have an impact on Behcet’s disease (Table 1). The rs7572482 rSNP STAT4-G allele ^{G (+ strand) or C (} located in the unique ARNT, ARNT::AHR and ZBTB33 TFBS have a 100% occurrence in humans except for the ARNT::AHR TFBS for which it has a 96% occurrence (Table 2). The ARNT and ARNT::AHR TFBS occur 14 times in the STAT4 gene while the ZBTB33 TFBS only occurs once. The ZBTB33 TF is a transcriptional regulator involved with zinc finger motifs and may contribute to the repression of target genes of the Wnt signaling pathway (Appendix). Similar logic can be used to evaluate the potential TFBS within the other STAT4 rSNPs found in the Table 1 & Table 2.

Human diseases or conditions can be associated with rSNPs of the STAT4 gene as illustrated above. What a change in the rSNP alleles can do, is to alter the DNA landscape around the SNP for potential TFs to attach and regulate a gene. As an example, the potential TFBS associated with the rs7574865 rSNP STAT4-T allele from Table 2 are illustrated in Figure 1 as well as the rs11889341 common rSNP STAT4-C allele illustrated in Figure 2. As can be seen in Table 2, these potential TFBS change when an individual carries the alternate allele. The importance of this has been illustrated in Figure 2 with the AR TFBS where the common C allele has this function and the minor T allele does not. The AR TF is a steroid-hormone activated transcription factor which stimulates transcription of androgen responsive genes. A second example would be the HNF1a and HNF4g TFBS where the minor rs8179673 T allele has this function while the common allele does not. This TF regulates the tissue specific expression of multiple genes, especially in pancreatic islet and liver cells. A third example found with the rs7574070 common rSNP STAT4-A allele and not for the minor C allele is for the RFX1 & 5 TFBS whose TFs are important regulatory factors essential for MHC class II gene expression. Other examples can be found in Table 2.

SNPs that alter the TFBS are not only found in the promoter regions but in the introns, exons and the UTRs of a gene. The nucleus of the cell is where epigenetic alterations occur and TFs operate to convert chromosomes into single stranded DNA for mRNA transcription while it is the cytoplasm where mRNA is processed by separating exons and introns for protein translation. Consequently, it doesn’t matter where TFs bind the DNA in the nucleus because it is only there that TFs function. The SNPs outlined in this report should be considered as rSNPs since they change the DNA landscape for TF binding and have been associated with disease. In this report, examples have been described to illustrate that a change in rSNP alleles in the STAT4 gene can provide different TFBS which in turn are also associated with disease in humans. The potential alterations in TFBS obtained by computational analyses need to be verified by future protein/DNA electrophoretic mobility gel shift assays and gene expression studies.

Appendix. Transcriptional factor (TF) discriptions.

Appendix. Transcriptional factor (TF) discriptions .
TFs			TF discription
AR			The protein functions as a steroid-hormone activated transcription factor. Upon binding the hormone ligand, the receptor dissociates from accessory proteins, translocates into the nucleus, dimerizes, and then stimulates transcription of androgen responsive genes. They are expressed in bone marrow, mammary gland, prostate, testicular and muscle tissues where they exist as dimers coupled to Hsp90 and HMGB proteins.
ARID3A			Transcription factor which may be involved in the control of cell cycle progression by the RB1/E2F1 pathway and in B-cell differentiation
ARNT			This gene encodes a protein containing a basic helix-loop-helix domain and two characteristic PAS domains along with a PAC domain. The encoded protein binds to ligand-bound aryl hydrocarbon receptor and aids in the movement   of this complex to the nucleus, where it promotes the expression of genes involved in xenobiotic metabolism.
ARNT::AHR			The dimer alters transcription of target genes. Involved in the induction of several enzymes that participate in xenobiotic metabolism.
BATF::JUN			The protein encoded by this gene is a nuclear basic leucine zipper protein that belongs to the AP-1/ATF superfamily of transcription factors. The leucine zipper of this protein mediates dimerization with members of the Jun family of proteins. This protein is thought to be a negative regulator of AP-1/ATF transcriptional events.
Bhlhe40			This gene encodes a basic helix-loop-helix protein expressed in various tissues. The encoded protein can interact with ARNTL or compete for E-box binding sites in the promoter of PER1 and repress CLOCK/ARNTL's transactivation of PER1. Transcriptional repressor involved in the regulation of the circadian rhythm by negatively regulating the activity of the clock genes and clock-controlled genes.
BRCA1			This gene encodes a nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor.
CDX2			This gene is a member of the caudal-related homeobox transcription factor gene family. The encoded protein is a major regulator of intestine-specific genes involved in cell growth an differentiation. major regulator of intestine-specific genes involved in cell growth an differentiation.
CEBPA			C/EBP is a DNA-binding protein that recognizes two different motifs: the CCAAT homology common to many promoters and the enhanced core homology common to many enhancers
CEBPB			Important transcriptional activator regulating the expression of genes involved in immune and inflammatory responses. Binds to regulatory regions of several acute-phase and cytokines genes and probably plays a role in the regulation of acute-phase reaction, inflammation and hemopoiesis.
CRX			The protein encoded by this gene is a photoreceptor-specific transcription factor which plays a role in the differentiation of photoreceptor cells. This homeodomain protein is necessary for the maintenance of normal cone and rod function.
E2F6			The protein encoded by this gene is a member of the E2F family of transcription factors. The E2F family plays a crucial role in the control of cell cycle and action of tumor suppressor proteins and is also a target of the transforming proteins of small DNA tumor viruses.
EBF1			Transcriptional activator which recognizes variations of the palindromic sequence 5'-ATTCCCNNGGGAATT-3'
ELK1			The protein encoded by this gene is a nuclear target for   the ras-raf-MAPK signaling cascade.
EN1			Homeobox-containing genes are thought to have a role in controlling development.
FOS			The Fos gene family consists of 4 members: FOS, FOSB, FOSL1, and FOSL2. These genes encode leucine zipper proteins that can dimerize with proteins of the JUN family, thereby forming the transcription factor complex AP-1. The FOS proteins have been implicated as regulators of cell proliferation, differentiation, and transformation. Controls osteoclast survival and size. As a dimer with JUN, activates LIF transcription.
FOSL2			The Fos gene family consists of 4 members: FOS, FOSB, FOSL1, and FOSL2. These genes encode leucine zipper proteins that can dimerize with proteins of the JUN family, thereby forming the transcription factor complex AP-1. The FOS proteins have been implicated as regulators of cell proliferation, differentiation, and transformation.   Controls osteoclast survival and size. As a dimer with JUN, activates LIF transcription. Activates CEBPB transcription in PGE2-activated osteoblasts.
FOXA1			Transcription factor that is involved in embryonic development, establishment of tissue-specific gene expression and regulation of gene expression in differentiated tissues.
FOXA2			Involved in embryonic development, establishment of tissue-specific gene expression and regulation of gene expression in differentiated tissues.
FOXC1			This gene belongs to the forkhead family of transcription factors which is characterized by a distinct DNA-binding forkhead domain. An important regulator of cell viability and resistance to oxidative stress.
FOXD1			This gene belongs to the forkhead family of transcription factors which are characterized by a distinct forkhead domain. Studies of the orthologous mouse protein indicate that it functions in kidney development by promoting nephron progenitor differentiation, and it also functions in the development of the retina and optic chiasm.
FOXD3			This gene belongs to the forkhead family of transcription factors which is characterized by a distinct DNA-binding forkhead domain. Acts are a transcriptional activator and repressor.
FOXH1			Transcriptional activator. Recognizes and binds to the DNA sequence 5-TGTGTGTATT-3. Required for induction of the goosecoid (GSC) promoter by TGF-beta or activin signaling.
FOXI1			This gene belongs to the forkhead family of transcription factors which is characterized by a distinct DNA-binding forkhead domain. Transcriptional activator required for the development of normal hearing, sense of balance and kidney function.
FOXL1			FOX transcription factors are characterized by a distinct DNA-binding forkhead domain and play critical roles in the regulation of multiple processes including metabolism, cell proliferation and gene expression during ontogenesis. Transcriptional repressor. It plays an important role in the specification and differentiation of lung epithelium.
FOXO1			Transcription factor that is the main target of insulin signaling and regulates metabolic homeostasis in response to oxidative stress.
FOXO3			This gene belongs to the forkhead family of transcription factors which are characterized by a distinct forkhead domain. This gene likely functions as a trigger for apoptosis through expression of genes necessary for cell death.
FOXP1			This gene belongs to subfamily P of the forkhead box (FOX) transcription factor family. Forkhead box transcription factors play important roles in the regulation of tissue- and cell type-specific gene transcription during both development and adulthood. Transcriptional repressor. Plays an important role in the specification and differentiation of lung epithelium.
FOXQ1			This gene belongs to the forkhead family of transcription factors which is characterized by a distinct DNA-binding forkhead domain. Plays a role in hair follicle differentiation.
FOXP2			Transcriptional repressor that may play a role in the specification and differentiation of lung epithelium. May also play a role in developing neural, gastrointestinal and cardiovascular tissues.
GATA1			The protein plays an important role in erythroid development by regulating the switch of fetal hemoglobin to adult hemoglobin.
GATA2			A member of the GATA family of zinc-finger transcription factors that are named for the consensus nucleotide sequence they bind in the promoter regions of target genes and play an essential role in regulating transcription of genes involved in the development and proliferation of hematopoietic and endocrine cell lineages.
GATA3			Plays an important role in endothelial cell biology.
GATA4			This protein is thought to regulate genes involved in embryogenesis and in myocardial differentiation and function. Promotes cardiac myocyte enlargement.
HIF1a: ARNT			HIF1 is a homodimeric basic helix-loop-helix structure composed of HIF1a, the alpha subunit, and the aryl hydrocarbon receptor nuclear translocator (Arnt), the beta subunit. The protein encoded by HIF1 is a Per-Arnt-Sim (PAS) transcription factor found in mammalian cells growing at low oxygen concentrations. It plays an essential role in cellular and systemic responses to hypoxia.
HLTF		This gene encodes a member of the SWI/SNF family. Members of this family have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes.
HNF1A		Transcriptional activator that regulates the tissue specific expression of multiple genes, especially in pancreatic islet cells and in liver.
HNF4a		The encoded protein controls the expression of several genes, including hepatocyte nuclear factor 1 alpha, a transcription factor which regulates the expression of several hepatic genes
HNF4g		Transcription factor. Has a lower transcription activation potential than HNF4-alpha
HOXA5		Sequence-specific transcription factor which is part of a developmental regulatory system that provides cells with specific positional identities on the anterior-posterior axis.
JUN (var.2)		This gene is the putative transforming gene of avian sarcoma virus 17. It encodes a protein which is highly similar to the viral protein, and which interacts directly with specific target DNA sequences to regulate gene expression.
JUN::FOS		Promotes activity of NR5A1 when phosphorylated by HIPK3 leading to increased steroidogenic gene expression upon cAMP signaling pathway stimulation. Has a critical function in regulating the development of cells destined to form and maintain the skeleton. It is thought to have an important role in signal transduction, cell proliferation and differentiation.
JUNB		Transcription factor involved in regulating gene activity following the primary growth factor response. Binds to the DNA sequence 5-TGACGTCA-3
KLF5		Transcription factor that binds to GC box promoter elements. Activates transcription of genes.
LHX3		This gene encodes a member a large protein family which carry the LIM domain, a unique cysteine-rich zinc-binding domain. The encoded protein is a transcription factor that is required for pituitary development and motor neuron specification.
MAFB		The encoded nuclear protein represses ETS1-mediated transcription of erythroid-specific genes in myeloid cells. This protein plays an essential role in the regulation of hematopoiesis and may play a role in tumorigenesis.
MAFF		The protein encoded by this gene is a basic leucine zipper (bZIP) transcription factor that lacks a transactivation domain. Interacts with the upstream promoter region of the oxytocin receptor gene. May be involved in the cellular stress response
415290786765000MAFK		Since they lack a putative transactivation domain, the small Mafs behave as transcriptional repressors when they dimerize among themselves. they seem to serve as transcriptional activators by dimerizing with other (usually larger) basic-zipper proteins and recruiting them to specific DNA-binding sites. Small Maf proteinS heterodimerize with Fos and may act as competitive repressors of the NF-E2 transcription factor.
MAX		The protein encoded by this gene is a member of the basic helix-loop-helix leucine zipper (bHLHZ) family of transcription factors
MEF2C		Transcription activator which binds specifically to the MEF2 element present in the regulatory regions of development. many muscle-specific genes. Controls cardiac morphogenesis and myogenesis, and is also involved in vascular development.
MZF1_1-4	Binds to target promoter DNA and functions as trancription regulator. May be one regulator of transcriptional events during hemopoietic development. Isoforms of this protein have been shown to exist at protein level.
MZF1_5-13	Binds to target promoter DNA and functions as trancription regulator. May be one regulator of transcriptional events during hemopoietic development. Isoforms of this protein have been shown to exist at protein level.
NFE2L1:MAFG	Nuclear factor erythroid 2-related factor (Nrf2) coordinates the up-regulation of cytoprotective genes via the antioxidant response element (ARE). MafG is a ubiquitously expressed small maf protein that is nvolved in cell differentiation of erythrocytes. It dimerizes with P45 NF-E2 protein and activates expression of a and b-globin.
NFIL3	Expression of interleukin-3 (IL3; MIM 147740) is restricted to activated T cells, natural killer (NK) cells, and mast cell lines.
NKX2-5	This gene encodes a member of the NK family of homeobox-containing proteins. Transcriptional repressor that acts as a negative regulator of chondrocyte maturation.
NKX3-1	This gene encodes a homeobox-containing transcription factor. This transcription factor functions as a negative regulator of epithelial cell growth in prostate tissue.
Nr1h3::Rxra	The protein encoded by this gene belongs to the NR1 subfamily of the nuclear receptor superfamily. The NR1 family members are key regulators of macrophage function, controlling transcriptional programs involved in lipid homeostasis and inflammation. This protein is highly expressed in visceral organs, including liver, kidney and intestine. It forms a heterodimer with retinoid X receptor (RXR), and regulates expression of target genes containing retinoid response elements. Studies in mice lacking this gene suggest that it may play an important role in the regulation of cholesterol homeostasis.
NR3C1	Glucocorticoids regulate carbohydrate, protein and fat metabolism, modulate immune responses through supression of chemokine and cytokine production and have critical roles in constitutive activity of the CNS, digestive, hematopoietic, renal and reproductive systems.
PAX2	Probable transcription factor that may have a role in kidney cell differentiation.
PDX1	Activates insulin, somatostatin, glucokinase, islet amyloid polypeptide and glucose transporter type 2 gene transcription. Particularly involved in glucose-dependent regulation of insulin gene transcription.
POU5F1::SOX2	This gene encodes a transcription factor containing a POU homeodomain that plays a key role in embryonic development and stem cell pluripotency. Aberrant expression of this gene in adult tissues is associated with tumorigenesis. Forms a trimeric complex with SOX2 on DNA and controls the expression of a number of genes involved in embryonic development such as YES1, FGF4, UTF1 and ZFP206.
PRRX2	The DNA-associated protein encoded by this gene is a member of the paired family of homeobox proteins. Expression is localized to proliferating fetal fibroblasts and the developing dermal layer, with downregulated expression in adult skin.
RFX1	This gene is a member of the regulatory factor X gene family, which encodes transcription factors that contain a highly-conserved winged helix DNA binding domain. The protein encoded by this gene is structurally related to regulatory factors X2, X3, X4, and X5. Regulatory factor essential for MHC class II genes expression. Binds to the X boxes of MHC class II genes.
RFX5	Activates transcription from class II MHC promoters. Recognizes X-boxes.
RORA_1	The protein encoded by this gene is a member of the NR1 subfamily of nuclear hormone receptors. Orphan nuclear receptor. Binds DNA as a monomer to hormone response elements (HRE) containing a single core motif half-site preceded by a short A-T-rich sequence.
RUNX2	Transcription factor involved in osteoblastic differentiation and skeletal morphogenesis. Essential for the maturation of osteoblasts and both intramembranous and endochondral ossification.
RXRa	Retinoid X receptors (RXRs) and retinoic acid receptors (RARs), are nuclear receptors that mediate the biological effects of retinoids by their involvement in retinoic acid-mediated gene activation.
SOX2	This intronless gene encodes a member of the SRY-related HMG-box (SOX) family of transcription factors involved in the regulation of embryonic development and in the determination of cell fate. The product of this gene is required for stem-cell maintenance in the central nervous system, and also regulates gene expression in the stomach.
SOX3	Transcription factor required during the formation of the hypothalamo-pituitary axis. May function as a
	switch in neuronal development. Keeps neural cells undifferentiated by counteracting the activity of proneural
SOX5	This gene encodes a member of the SOX (SRY-related HMG-box) family of transcription factors involved in the
	regulation of embryonic development and in the determination of the cell fate.
	The encoded protein may act as a transcriptional regulator after forming a protein complex with other proteins
	and may play a role in chondrogenesis.
SOX6	The encoded protein is a transcriptional activator that is required for normal
	development of the central nervous system, chondrogenesis and maintenance of cardiac and skeletal muscle cells.
SOX9	Plays an important role in the normal skeletal development. May regulate the expression of other genes
	involved in chondrogenesis by acting as a transcription factor for these genes
SOX10	This gene encodes a member of the SOX (SRY-related HMG-box) family of transcription factors involved
	in the regulation of embryonic development and in the determination of the cell fate.
SOX17	Acts as transcription regulator that binds target promoter DNA and bends the DNA.
SP1	Can activate or repress transcription in response to physiological and
	pathological stimuli. Regulates the expression of a large number of
	genes involved in a variety of processes such as cell growth,
	apoptosis, differentiation and immune responses.
SPI1	This gene encodes an ETS-domain transcription factor that activates gene expression during myeloid
	and B-lymphoid cell development
SPIB	The protein encoded by this gene is a transcriptional activator that binds to the
	PU-box (5'-GAGGAA-3') and acts as a lymphoid-specific enhancer.
SRF	This gene encodes a ubiquitous nuclear protein that stimulates both cell proliferation and differentiation.
	This protein binds to the serum response element (SRE) in the promoter region of target genes.
	Required for cardiac differentiation and maturation.
SREBF1	Transcriptional activator required for lipid homeostasis. Regulates transcription of the LDL receptor gene as well as the fatty acid and to a lesser degree the cholesterol synthesis pathway.
SREBF2	This gene encodes a member of the a ubiquitously expressed transcription factor that controls cholesterol homeostasis by regulating transcription of sterol-regulated genes. The encoded protein contains a basic helix-loop-helix-leucine zipper (bHLH-Zip) domain and binds the sterol regulatory element 1 motif.
SRY	Transcriptional regulator that controls a genetic switch in male development. It is necessary and sufficient for initiating male sex determination by directing the development of supporting cell precursors
STAT1	The protein encoded by this gene is a member of the STAT protein family. In response to cytokines and growth factors, STAT family members are phosphorylated by the receptor associated kinases, and then form homo- or heterodimers that translocate to the cell nucleus where they act as transcription activators. This protein can be activated by various ligands including interferon-alpha, interferon-gamma, EGF, PDGF and IL6. This protein mediates the expression of a variety of genes, which is thought to be important for cell viability in response to different cell stimuli and pathogens.
STAT3	Signal transducer and transcription activator that mediates cellular responses to interleukins, KITLG/SCF and other growth factors
STAT4	Carries out a dual function: signal transduction and activation of transcription. Involved in IL12 signaling This protein is essential for mediating responses to IL12 in lymphocytes, and regulating the differentiation of arthritis. T helper cells. Mutations in this gene may be associated with systemic lupus erythematosus and rheumatoid arthritis.
STAT5A:STAT5B	Carries out a dual function: signal transduction and activation of transcription. Regulates the expression of milk proteins during lactation.
STAT6	This protein plays a central role in exerting IL4 mediated biological responses. It is found to induce the expression of BCL2L1/BCL-X(L), which is responsible for the anti-apoptotic activity of IL4. Carries out a dual function: signal t ransduction and activation of transcription. Involved in IL4/interleukin-4- and IL3/interleukin-3-mediated signaling.
T	The protein encoded by this gene is an embryonic nuclear transcription factor that binds to a specific DNA element, the palindromic T-site. It binds through a region in its N-terminus, called the T-box, and effects transcription of genes required for mesoderm formation and differentiation.
TBP	General transcription factor that functions at the core of the DNA-binding multiprotein factor TFIID. Binding of TFIID to the TATA box is the initial transcriptional step of the pre-initiation complex (PIC), playing a role in the activation of eukaryotic genes transcribed by RNA polymerase II.
TFAP2C	Sequence-specific DNA-binding protein that interacts with inducible viral and cellular enhancer elements to regulate transcription of selected genes. AP-2 factors bind to the consensus sequence 5'-GCCNNNGGC-3' and activate genes involved in a large spectrum of important biological functions including proper eye, face, body wall, limb and neural tube development.
THAP1	DNA-binding transcription regulator that regulates endothelial cell proliferation and G1/S cell-cycle progression.
ZBTB33	This gene encodes a transcriptional regulator with bimodal DNA-binding specificity, which binds to methylated CGCG and also to the non-methylated consensus KAISO-binding site TCCTGCNA. The protein contains an N-terminal POZ/BTB domain and 3 C-terminal zinc finger motifs. It recruits the N-CoR repressor complex to promote histone deacetylation and the formation of repressive chromatin structures in target gene promoters. It may contribute to the repression of target genes of the Wnt signaling pathway, and may also activate transcription of a subset of target genes by the recruitment of catenin delta-2 (CTNND2).
ZNF263	Might play an important role in basic cellular processes as a transcriptional repressor.
ZNF354C	May function as a transcription repressor.

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