Open Journal of Genetics, 2013, 3, 253-261 OJGen
http://dx.doi.org/10.4236/ojgen.2013.34028 Published Online December 2013 (http://www.scirp.org/journal/ojgen/)
ATF3 rSNPs, transcriptional factor binding sites
and human etiology*
Norman E. Buroker
Department of Pediatrics, University of Washington, Seattle, USA
Received 26 September 2013; revised 25 October 2013; accepted 15 November 2013
Copyright © 2013 Norman E. Buroker. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Three rSNPs (rs3125289, rs1877474 and rs11119982)
in one intron of the activating transcription factor 3
(ATF3) gene have been significantly associated with
the human etiology of hypospadias and may be asso-
ciated with human disease. These rSNP alleles alter
the DNA landscape for potential transcriptional fac-
tors (TFs) to attach resulting in changes in transcrip-
tional factor binding sites (TFBS). These TFBS chan-
ges are examined with respect to the human etiology
of hypospadias which has been found to be signifi-
cantly associated with the rSNPs.
Keywords: ATF3; rSNPs; TFBS; Human Etiology
1. INTRODUCTION
The activating transcription factor 3 (ATF 3) gene is a
member of the activating transcription factor/cAMP re-
sponsive element binding (CREB) protein family of
transcription factors, which share the basic region-leu-
cine zipper (bZip) DNA binding motif (TGACGTCA).
This gene is induced by a variety of signals including
many of those encountered by cancer cells, and is in-
volved in the complex process of cellular stress response
[1-3]. AT F 3 has been viewed as a hub of the cellular
adaptive response network which allows cells adapt to
disturbances in homeostasis [4]. This gene has been
shown to be up-regulated during sexual differentiation [5]
which indicates a potential role in hypospadias. Three
unlinked AT F 3 SNPs (rs3125289, rs1877474 and
rs11119982) which span a 16 kb region of intron one
have been independently found to be significantly asso-
ciated with the risk of hypospadias [6]. This suggests that
these SNPs in intron one may be part of a regulatory re-
gion for the AT F3 gene. To follow up on this possibility,
the SNPs were examined for associations to potential
transcription factor binding sites (TFBS).
Single nucleotide changes that affect gene expression
by impacting gene regulatory sequences such as promot-
ers, enhancers, and silencers are known as regulatory
SNPs (rSNPs) [7-10]. A rSNPs within a transcriptional
factor binding site (TFBS) can change a transcriptional
factor’s (TF) ability to bind its TFBS [11-14], in which
case the TF would be unable to effectively regulate its
target gene [15-19]. This concept is examined for the
above AT F3 SNPs of intron one and their allelic associa-
tion with TFBS. In this report, I discuss these SNP asso-
ciations with changes in potential TFBS and their possi-
ble relationship to human etiology.
2. MATERIALS AND METHODS
Identifying TFBS
The JASPAR CORE database [20,21] and ConSite [22]
were used to identify the TFBS in this study. JASPAR is
a collection of transcription factor DNA-binding prefer-
encesused for scanning genomic sequences where Con-
Site is a web-based tool for finding cis-regulatory ele-
ments in genomic sequences. The Vector NTI Advance
11 computer program (Invitrogen, Life Technologies)
was used to locate the TFBS in the AT F3 gene (NCBI
Ref Seq NM_001674) from 51 kb upstream of the tran-
scriptional start site to 766 bp past the 3’UTR which
represents a total of 57.6 Kbp. The JASPAR CORE da-
tabase was also used to compute each nucleotide occur-
rence (%) 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 1 & Supplement).
3. RESULTS
ATF3 rSNPs and TFBS
*Conflict of interest statement: The author declares that there is no
conflict of interests. The AT F3 gene encodes a member of the mammalian
OPEN ACCESS 253

N. E. Buroker / Open Journal of Genetics 3 (2013) 253-261 254
Table 1. The ATF3 SNPs from intron 1 that were examined in this study. Also listed are the transcriptional factors (TF), their poten-
tial binding sites (TFBS) containing these SNPs and DNA strand orientation. TFs in red differ between the rSNP 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 numbers (#) 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
rs3125289 C ARNT aryl hydrocarbon receptor nuclear translocator 7 cAcGaG minus
(C/T) G = 100%
ARNT aryl hydrocarbon receptor nuclear translocator 7 ctCGTG plus
C = 100%
ARNT:AHR aryl hydrocarbon receptor nuclear translocator 7 CtCGTG plus
aryl hydrocarbon receptor C = 96%
ELF5 E74-like factor 5 17 agctTCCtc plus
(ets domain transcription factor) c = 18%
FOXC1 Forkhead box C1 1 ctcgtGTA plus
c = 31%
GABPA GA binding protein transcription factor, alpha 1 gaGGAAgctct minus
g = 19%
MYC v-myc myelocytomatosis viral oncogene homolog1 taCACGaGga minus
G = 90%
MYCN v-myc myelocytomatosis viral related 1 taCACGaGga minus
oncogene, neuroblastoma derived G = 90%
MZF1_1-4 Myeloid zinc finger 1 11 cGaGGA minus
G = 95%
SPIB Spi-B transcription factor (Spi-1/PU.1 related) 12 cgaGGAA minus
g = 59%
TBP TATA box binding protein 1 ctATAtAcacgagga minus
g = 33%
USF1 Upstream transcription factor 1 2 CtCGTGt plus
C = 93%
USF1 Upstream transcription factor 1 3 CACGaGg minus
G = 97%
T ELF5 E74-like factor 5 2 agctTCCtt plus
(ets domain transcription factor) t = 48%
FOXA1 Forkhead box A1 1 TgTgTatatag plus
T = 98%
FOXA2 Forkhead box A2 1 TgTgtatatagg plus
T = 100%
FOXA2 Forkhead box A2 1 TaTatacacaag minus
a = 52%
FOXC1 Forkhead box C1 2 cttgtGTA plus

N. E. Buroker / Open Journal of Genetics 3 (2013) 253-261 255
Continued
t = 31%
FOXL1 Forkhead box L1 5 tgtgtATA plus
t = 48%
FOXL1 Forkhead box L1 5 tatacAcA minus
A = 96%
FOXO3 Forkhead box O3 5 tatAcACA minus
A = 92%
HLTF Helicase-like transcription factor 2 ttcCtTgtgt plus
T = 100%
SOX10 SRY (sex determining region Y)-box 10 27 cctTgT plus
T = 100%
SOX10 SRY (sex determining region Y)-box 10 50 ttgTgT plus
t = 45%
SOX17 SRY (sex determining region Y)-box 17 4 ttccTTGTg plus
T = 100%
SRY Sex determining region Y 1 gtagACAAt minus
A = 100%
TBP TATA box binding protein 1 ctATAtAcacaagga minus
a = 22%
rs1877474 C HLTF Helicase-like transcription factor 7 agcCtTttcg plus
(C/T) c = 24%
SPIB Spi-B transcription factor (Spi-1/PU.1 related) 12 agcGaAA minus
G = 96%
T ETS1 Protein C-ets-1 54 ttTgCt plus
T = 98%
HLTF Helicase-like transcription factor 1 agcCtTtttg plus
t = 14%
FOXA1 Forkhead box A1 1 TtTTTgCtctg plus
T = 91%
SOX10 SRY (sex determining region Y)-box 10 119 cttTtT plus
T = 95%
SPIB Spi-B transcription factor (Spi-1/PU.1 related) 12 acaGcAA minus
A = 98%
rs11119982 C ARNT:AHR aryl hydrocarbon receptor nuclear translocator 10 cGaGTG minus
(C/T) aryl hydrocarbon receptor G = 96%
GATA2 GATA binding protein 2 23 cGATg plus
c = 25%
GATA3 GATA binding protein 3 4 cGATgg plus

N. E. Buroker / Open Journal of Genetics 3 (2013) 253-261 256
Continued
c = 22%
HLTF Helicase-like transcription factor 1 ggcCaTcgag minus
g = 37%
NKX3-2 Natural killer 3 homeobox 2 1 tcgAGTgtc minus
g = 13%
PAX2 Paired box gene 2 3 agaCActc plus
c = 35%
TFAP2A Transcription factor AP-2 alpha 1 GCCatcgag minus
(activating enhancer binding protein 2 alpha) G = 43%
T ARID3A AT rich interactive domain 3A (BRIGHT-like) 30 ATcAAg minus
A = 100%
ARNT aryl hydrocarbon receptor nuclear translocator 33 cAaGTG minus
A = 95%
ARNT aryl hydrocarbon receptor nuclear translocator 33 cActTG plus
A = 100%
GATA2 GATA binding protein 2 136 tGATg plus
t = 17%
GATA3 GATA binding protein 3 342 tGATgg plus
t = 32%
MAX MYC associated factor X 5 agaCACtTGa plus
T = 100%
MYB v-myb myeloblastosis viral oncogene homolog 1 gaCacTTg plus
T = 100%
NKX2-5 Natural killer 2 homeobox 5 13 tcAAgtg minus
A = 100%
NKX3-2 Natural killer 3 homeobox 2 6 tcaAGTgtc minus
a = 8%
PAX2 Paired box gene 2 7 agaCactt plus
t = 26%
PAX2 Paired box gene 2 2 catCaagt minus
a = 84%
TFAP2A Transcription factor AP-2 alpha 4 GCCatcaag minus
(activating enhancer binding protein 2 alpha) a = 29%
USF1 upstream transcription factor 1 7 CAaGTGt minus
A = 100%
USF1 upstream transcription factor 1 13 CACtTGa plus
T = 93%
ZEB1 Zinc finger E-box binding homeobox 1 33 cACTTg plus
T = 98%

N. E. Buroker / Open Journal of Genetics 3 (2013) 253-261 257
activation transcription factor/cAMP responsive element-
binding (CREB) protein family of transcription factors.
This gene is one of seven ATFs that influence cellular
physiologic processes by regulating the expression of
downstream target genes, which are related to growth,
survival, and other cellular activities. The three ATF3
rSNPs [rs3125289 (C/T), rs1877474 (C/T) and rs-
11119982 (C/T)] in intron one has been found to be sig-
nificantly associated with the risk of hypospadias [6].
The rs3125289 and rs1877474 AFT3-T alleles have a
significantly greater occurrence in the case subjects com-
pared to the corresponding control group where the
rs11119982 ATF3-C allele has a significantly greater
advantage [6].
The rs3125289 AT F 3-C allele creates eight unique
TFBS for the ARNT, ARNT:AHR, GABPA, MYC,
MYCN, MZF1_1-4, SPIB and USF1 TFs which are in-
volved in xenobiotic metabolism, cell cycle progression,
apoptosis, cellular transformation, a variety of tumors,
lymphoid-specific enhancer and cellular transcription,
respectively (Table 1). The rs3125289 ATF 3-T allele
also creates eight unique TFBS for the FOXA1 & 2,
FOXL1, FOXO3, HLTF, SOX10 & 17 and SRY TFs
which are involved in embryonic development, apoptosis,
chromatin structure, cell fate and male development,
respectively (Table 1 & Supplement). Three TFBS have
been conserved between the two rs3125289 alleles which
are for the ELF4, FOXC1 and TBP TFs that regulate
epithelium-specific genes, resistance to oxidative stress
and a core factor in DNA binding for TFIID, respectively
(Table 1).
The rs1877474 AFT3-C allele creates no unique TFBS
while the AFT3-T allele creates three unique TFBS
which are for the ETS1, FOXA1 and SOX10 TFs which
interact with TTRAP, UBE2I and Death associated pro-
teins and regulates embryonic development, respectively
(Table 1). Two TFBS have been conserved between the
two alleles which are HLTF and SPIB TFs that are in-
volved in altering chromatin structure and act as a lym-
phoid-specific enhancer, respectively (Table 1).
The rs11119982 AT F 3-C allele creates one unique
TFBS for the HLTF TF which is involved with altering
chromatin structure. The AT F 3-T allele creates five
unique TFBS for the ARID3A, MAX, MYB, USF1 and
ZEB1 TFs. These TFs are involved with the AT-rich in-
teraction domain, transcription regulation, hematopoietic
progenitor cells control, cellular transcription and repres-
sion, respectively (Table 1). Eight TFBS have been con-
served between the two alleles which are ARNT, ARNT:
AHR, GATA2 & 3, HKX2 & 3, PAX2 and TFAP2A TFs
that are involved with xenobiotic metabolism, hemato-
poietic and endocrine cell lineages, endothelial cell boil-
ogy, transcription repression, kidney cell differentiation
and transcription activation, respectively (Table 1).
4. DISCUSSION
GWAS over the last decade have identified nearly 6500
disease or trait-predisposing SNPs where only 7% of
these are located in protein-coding regions of the genome
[23,24] and the remaining 93% are located within non-
coding areas [25,26] such as regulatory or intergenic re-
gions. SNPs which occur in the putative regulatory re-
gion of a gene where a single base change in the DNA
sequence of a potential TFBS may affect the process of
gene expression, which are drawing more attention [7,
9,27]. 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 the
cases, the gene is no longer regulated by the original TF.
Therefore, functional rSNPs in TFBS may result in dif-
ferences in gene expression, phenotypes and susceptibil-
ity to environmental exposure [27]. Examples of rSNPs
associated with disease susceptibility are numerous and
several reviews have been published [27-30].
In this report, the rs3125289 ATF 3-C allele [C (+
strand) or G (−strand)] located in the ARNT and ARNT:
AHR TFBS has a 100% and 96% occurrence, respec-
tively, in humans; however, these BS occurs seven times
in the gene and therefore a change in the TFBS created
by the rSNP would probably not have any impact on the
regulation of the gene (Table 1 & Supplement). The
AT F 3-C allele is also located in the MYC and MYCN
TFBS with a 90% occurrence and this BS occurs only
once in the gene and therefore a nucleotide change cre-
ated by the rSNP on these TFBS would probably have an
impact on the regulation of the gene. The rs3125289
AT F 3-T allele located in the FOXA2 and SRY TFBS has
a 100% occurrence in humans and each BS occurs only
once in the gene; therefore, the rSNP would probably
have an impact on the regulation of the gene. Since the
SRY TF located on the Y chromosome is a transcrip-
tional regulator that controls a genetic switch in male
development, this rSNP might be expected to have an
impact on male etiology as has been shown to be the case
with its risk of hypospadias [6].
The rs1877474 AT F3-T allele [A (−strand) or T (+
strand)] located in the FOXA1 TFBS has an occurrence
of 91% in humans and this BS occurs only once in the
gene and thereby might have an impact on embryonic
development and tissue differentiation (Table 1). The
other two unique TFBS (ETS1 and SOX10) occur multi-
ple times in the gene and would not be expected to have
an impact on gene regulation. The rs1877474 ATF 3-C

N. E. Buroker / Open Journal of Genetics 3 (2013) 253-261 258
allele does not have any unique TFBS and therefore
would not be expected to have any impact on gene regu-
lation.
The rs11119982 ATF3-C allele [C (+strand) or G (−
strand)] located in the HLTF TFBS has an occurrence of
37% in humans (table). While this BS motif occurs only
once in the gene and other HLTF BS motifs are found in
intron one, it is doubtful that a change in the BS created
by the rSNP would have an impaction on gene regulation.
The rs11119982 ATF3-T allele located in the MYB TFBS
has a 100% nucleotide occurrence for that BS motif in
humans and occurs only once in the gene and thereby
may have an impact on gene regulation and in the control
of proliferation and differentiation of hematopoietic pro-
genitor cells. Other rs11119982 AT F 3-T allele unique
TFBS affected by this rSNP occur multiple times in the
gene and would probably have little effect on gene regu-
lation. Since each of these rSNPs can alter TFBS in
AT F 3 intron one, it is easy to understand why the rSNPs
have been found to independently affect the risk of hy-
pospadias [6].
Human diseases or conditions that have been signifi-
cantly associated with these rSNPs of the ATF3 gene are
shown in the table along with rSNP allele-specific TFBS.
What a change in the rSNP alleles can do, is to alter the
DNA landscape around the SNP for potential TFs to at-
tach and regulate a gene. This change in the regulatory
landscape can alter gene regulation which in turn can
result in human disease, a change in condition or illness.
In this report, three intron one rSNPs of the ATF 3 gene
have been described to illustrate that a change in rSNP
alleles can provide different TFBS which in turn are also
significantly associated with human etiology.
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Supplement. TF discription.
TFs TF discription
ARID3A This gene encodes a member of the ARID (AT-rich interaction domain) family of DNA binding proteins.
ARNT Involved in the induction of several enzymes that participate in xenobiotic metabolism.
ARNT:AHR The dimer alters transcription of target genes. Involved in the induction
of several enzymes that participate in xenobiotic metabolism.
ELF5 The protein encoded by this gene is a member of an epithelium-specific subclass of the Etstranscritpion factor family. In
addition to its role in regulating the later stages of terminal differentiation of keratinocytes, it appears to regulate a number
of epithelium-specific genes found in tissues containing glandular epithelium such as salivary gland and prostate.
ETS1 The protein encoded by this gene belongs to the ETS family of transcription factors and has been shown to interact with
TTRAP, UBE2I and Death associated proteins.
FOXA1 Transcription factor that is involved in embryonic development, establishment of tissue-specific gene
expression and regulation of gene expression in differentiated tissues.
FOXA2 Transcription factor that is 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.
FOXL1 This gene encodes a member of the forkhead/winged helix-box (FOX) family of transcription factors.
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.
GABPA This gene encodes one of three GA-binding protein transcription factor subunits which functions as a DNA-binding subunit.
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.
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.
MAX The protein encoded by this gene is a member of the basic helix-loop-helix leucine
zipper (bHLHZ) family of transcription factors. Transcription regulator.
MYB This gene encodes a transcription factor that is a member of the MYB family of transcription factor genes. Transcriptional
activator and plays an important role in the control of proliferation and differentiation of hematopoietic progenitor cells.
MYC The protein encoded by this gene is a multifunctional, nuclear phosphoprotein that plays a role
in cell cycle progression, apoptosis and cellular transformation.
MYCN This gene is a member of the MYC family and encodes a protein with a basic helix-loop-helix (bHLH) domain.
Amplification of this gene is associated with a variety of tumors, most notably neuroblastomas.
MZF1_1-4 Trancription regulator
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.
NKX3-2 This gene encodes a member of the NK family of homeobox-containing proteins. Transcriptional repressor
that acts as a negative regulator of chondrocyte maturation.
PAX2 Probable transcription factor that may have a role in kidney cell differentiation.
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.
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.
SRY Transcriptional regulator that controls a genetic switch in male development.

N. E. Buroker / Open Journal of Genetics 3 (2013) 253-261 261
Continued
TFAP2A The protein encoded by this gene is a transcription factor that binds the consensus sequence 5’-GCCNNNGGC-3’
and activates the transcription of some genes while inhibiting the transcription of others.
TBP General transcription factor that functions at the core of the DNA-binding multiprotein factor TFIID.
USF1 This gene encodes a member of the basic helix-loop-helix leucine zipper family,
and can function as a cellular transcription factor.
ZEB1 This gene encodes a zinc finger transcription factor. Acts as a transcriptional repressor.