Changes In Transcription Factor Binding Sites Research Articles

Evolution of the sperm methylome of primates is associated with retrotransposon insertions and genome instability.

Changes in gene expression resulting from epigenetic and/or genetic changes play an important role in the evolutionary divergence of phenotypes. To explore how epigenetic and genetic changes are linked during primate evolution, we have compared the genome-wide DNA methylation profiles (methylomes) of humans and chimpanzees, which have a 1.2% DNA sequence divergence, of sperm, the frontal cortices, B cells, and neutrophils. We revealed that species-specific differentially methylated regions (S-DMRs), ranging from several hundred base pairs (bp) to several kilo base pairs (kb), were frequently associated with sequence changes in transcription factor-binding sites and insertions of Alu and SVA retrotransposons. We then generated a reference macaque sperm methylome map and revealed, in sperm, that both human and chimpanzee S-DMRs arose more frequently owing to methylation loss rather than gain. Moreover, we observed that the sperm methylomes contained many more hypomethylated domains (HMDs), ranging from 20 to 500 kb, than did the somatic methylomes. Interestingly, the sperm HMDs changed rapidly during primate evolution; hundreds of sperm HMDs were specific to humans, whereas most somatic HMDs were highly conserved between humans and chimpanzees. Notably, these human-specific sperm HMDs frequently occurred in regions exhibiting copy number variations. Our findings indicate that primate evolution, particularly in the germline, is significantly impacted by reciprocal changes in the genome and epigenome.

Identifying Changes in Punitive Transcriptional Factor Binding Sites Created by PPAR<i>α/δ/γ</i> SNPs Associated with Disease

Single nucleotide polymorphisms (SNPs) located in the PPARα/δ/γ genes that have been previously found to be significantly associated with human disease or a condition were also found to alter the genes punitive transcriptional factor binding sites (TFBS). Two alleles (C/G) of the PPARα SNP (rs1800206) were found to generate 7 common and 8 unique punitive TFBS. One of the unique TFBS created by the minor G (0.02) allele is for the T-Box 4 (TBX4) transcription factor which is associated with heritable pulmonary arterial hypertension. Two alleles (A/G) of the PPARδ SNP (rs2016520) were found to generate 20 unique punitive TFBS while the two alleles (C/G) of the PPARδ SNP (rs9794) were found to generate 11 common and 11unique punitive TFBS. The alleles of the PPARγ SNPs (rs10865710, rs12629751, rs709158, rs1805192 and rs3856806) were found to generate 15, 12, 16, 2 and 21 common and 9, 4, 12, 4 and 7 unique punitive TFBS, respectively. These changes in TFBS are discussed with relation to alterations in gene expression that may result in disease or change in human condition.

Computational STAT4 rSNP Analysis, Transcriptional Factor Binding Sites And Disease

Purpose : The DIO2 gene transcribes the deiodinase type 2 enzyme that changes the thyroid prohormone, thyroxine (T4), to the biologically active triiodothyronine (T3) hormone. T3 plays a vital part in the regulation of energy balance and glucose metabolism. DIO2 single - nucleotide polymorphisms (SNPs) were computationally examined with respect to changes in punitive transc riptional factor binding sites (TFBS) and these changes were discussed in relation to human disease. Methods : The JASPAR CORE and ConSite databases were instrumental in identifying the TFBS. The Vector NTI Advance 11.5 computer program was employed in loc ating all the TFBS in the DIO2 gene from 2.4 kb upstream of the transcriptional start site to 508 bp past the 3’UTR. The JASPAR CORE database was also involved in computing each nucleotide occurrence (%) within the TFBS. Results : Regulatory SNPs (rSNPs) i n the promoter region novel SNP ( - 2035bp), 5’UTR (rs12885300), intron one (rs225010, 225011 and rs225012), exon two [rs225014 (Thr92Ala)] and 3’ UTR (rs6574549, rs225015 and rs225017) of the DIO2 gene are in linkage disequilibrium. These rSNP alleles were found to alter the DNA landscape for potential transcriptional factors (TFs) to attach resulting in changes in TFBS. Conclusion : The alleles of each rSNP were found to generate unique TFBS resulting in potential Short Research Article

Identification and characterization of human xylosyltransferase II promoter single nucleotide variants

The human isoenzymes xylosyltransferase-I and -II (XT-I, XT-II) catalyze the rate-limiting step in proteoglycan biosynthesis. Therefore, serum XT activity, mainly representing XT-II activity, displays a powerful biomarker to quantify the actual proteoglycan synthesis rate. Serum XT activity is increased up to 44% in disorders which are characterized by an altered proteoglycan metabolism, whereby underlying regulatory mechanisms remain unclear. The aim of this study was to investigate new regulatory pathways by identifying and characterizing naturally occurring XYLT2 promoter sequence variants as well as their potential influence on promoter activity and serum XT activity.XYLT2 promoter single nucleotide variants (SNVs) were identified and genotyped in the genomic DNA of 100 healthy blood donors by promoter amplification and sequencing or restriction fragment length polymorphism analysis. The SNVs were characterized by an in silico analysis considering genetic linkage and transcription factor binding sites (TBSs). The influence of SNVs on promoter activity and serum XT activity was determined by dual luciferase reporter assay and HPLC-ESI mass spectrometry.Allele frequencies of seven XYLT2 promoter sequence variants identified were investigated. In silico analyses revealed a strong genetic linkage of SNVs c.-80delG and c.-188G > A, c.-80delG and c.-1443G > A, as well as c.-188G > A and c.-1443G > A. However, despite the generation of several SNV-associated changes in TBSs in silico, XYLT2 promoter SNVs did not significantly affect promoter activity. Serum XT activities of SNV carriers deviated up to 8% from the wild-type, whereby the differences were also not statistically significant.This is the first study which identifies, genotypes and characterizes XYLT2 promoter SNVs. Our results reveal a weak genetic heterogeneity and a strong conservation of the human XYLT2 promoter region. Since the SNVs detected could be excluded as causatives for strong interindividual variabilities in serum XT activity, our data provide increasing evidence that XT-II activity is obviously regulated by hitherto unknown complex genetic pathways, such as cis- or trans-acting enhancers, silencers or miRNAs.

VEGFA SNPs (rs34357231 & rs35569394), Transcriptional Factor Binding Sites and Human Disease

Purpose: The human vascular endothelial growth factor ( VEGF)-A gene transcribes a signaling protein involved in the regulation of angiogenesis, vasculogenesis and endothelial cell growth. Two insertion/deletion (I/D) simple nucleotide polymorphisms (SNPs, rs34357231 & rs35569394) in the promoter region of the gene have been significantly associated with several human diseases. These SNPs were computationally examined with respect to changes in punitive transcriptional factor binding sites (TFBS) and these changes were discussed in relation to the diseases. Methods: The JASPAR CORE and ConSite databases were instrumental in identifying the TFBS. The Vector NTI Advance 11.5 computer program was employed in locating all the TFBS in the VEGFA gene from 2.7 kb upstream of the transcriptional start site to 1.6 kb past the 3’UTR. The JASPAR CORE database was also involved in computing each nucleotide occurrence (%) within the TFBS. Results: Regulatory SNPs (rSNPs) in the promoter region of the VEGFA gene alter the DNA landscape for potential transcriptional factors (TFs) to attach resulting in changes in TFBS. The VEGFA -deletion (D) allele of these SNPs has been found to be a risk factor for diabetic