Affect Transcription Factor Binding Research Articles

Defining a Haplotype Encompassing the LCORL-NCAPG Locus Associated with Increased Lean Growth in Beef Cattle.

Numerous studies have shown genetic variation at the LCORL-NCAPG locus is strongly associated with growth traits in beef cattle. However, a causative molecular variant has yet to be identified. To define all possible candidate variants, 34 Charolais-sired calves were whole-genome sequenced, including 17 homozygous for a long-range haplotype associated with increased growth (QQ) and 17 homozygous for potential ancestral haplotypes for this region (qq). The Q haplotype was refined to an 814 kb region between chr6:37,199,897-38,014,080 and contained 218 variants not found in qq individuals. These variants include an insertion in an intron of NCAPG, a previously documented mutation in NCAPG (rs109570900), two coding sequence mutations in LCORL (rs109696064 and rs384548488), and 15 variants located within ATAC peaks that were predicted to affect transcription factor binding. Notably, rs384548488 is a frameshift variant likely resulting in loss of function for long isoforms of LCORL. To test the association of the coding sequence variants of LCORL with phenotype, 405 cattle from five populations were genotyped. The two variants were in complete linkage disequilibrium. Statistical analysis of the three populations that contained QQ animals revealed significant (p < 0.05) associations with genotype and birth weight, live weight, carcass weight, hip height, and average daily gain. These findings affirm the link between this locus and growth in beef cattle and describe DNA variants that define the haplotype. However, further studies will be required to define the true causative mutation.

A statistical approach for identifying single nucleotide variants that affect transcription factor binding

Non-coding variants located within regulatory elements may alter gene expression by modifying transcription factor (TF) binding sites, thereby leading to functional consequences. Different TF models are being used to assess the effect of DNA sequence variants, such as single nucleotide variants (SNVs). Often existing methods are slow and do not assess statistical significance of results. We investigated the distribution of absolute maximal differential TF binding scores for general computational models that affect TF binding. We find that a modified Laplace distribution can adequately approximate the empirical distributions. A benchmark on invitro and invivo datasets showed that our approach improves upon an existing method in terms of performance and speed. Applications on eQTLs and on a genome-wide association study illustrate the usefulness of our statistics by highlighting cell type-specific regulators and target genes. An implementation of our approach is freely available on GitHub and as bioconda package.

Computational exploration of SLC14A1 genetic variants through structure modeling, protein-ligand docking, and molecular dynamics simulation

The urea transporter UT-B1, encoded by the SLC14A1 gene, has been hypothesized to be a significant protein whose deficiency and dysfunction contribute to the pathogenesis of bladder cancer and many other diseases. Several studies reported the association of genetic alterations in the SLC14A1 (UT-B1) gene with bladder carcinogenesis, suggesting a need for thorough characterization of the UT-B1 protein's coding and non-coding variants. This study used various computational techniques to investigate the commonly occurring germ-line missense and non-coding SNPs (ncSNPs) of the SLC14A1 gene (UT-B1) for their structural, functional, and molecular implications for disease susceptibility and dysfunctionality. SLC14A1 missense variants, primarily identified from the ENSEMBL genome browser, were screened through twelve functionality prediction tools leading to two variants D280Y (predicted detrimental by maximum tools) and D280N (high global MAF) for rs1058396. Subsequently, the ConSurf and NetSurf tools revealed the D280 residue to be in a variable site and exposed on the protein surface. According to I-Mutant2.0 and MUpro, both variants are predicted to cause a significant effect on protein stability. Analysis of molecular docking anticipated these two variants to decrease the binding affinity of UT-B1 protein for the examined ligands to a significant extent. Molecular dynamics also disclosed the possible destabilization of the UT-B1 protein due to single nucleotide polymorphism compared to wild-type protein which may result in impaired protein function. Furthermore, several non-coding SNPs were estimated to affect transcription factor binding and regulation of SLC14A1 gene expression. Additionally, two ncSNPs were found to affect miRNA-based post-transcriptional regulation by creating new seed regions for miRNA binding. This comprehensive in-silico study of SLC14A1 gene variants may serve as a springboard for future large-scale investigations examining SLC14A1 polymorphisms.

A regulatory element associated to NAFLD in the promoter of DIO1 controls LDL-C, HDL-C and triglycerides in hepatic cells

BackgroundGenome-wide association studies (GWAS) have identified genetic variants linked to fat metabolism and related traits, but rarely pinpoint causative variants. This limitation arises from GWAS not considering functional implications of noncoding variants that can affect transcription factor binding and potentially regulate gene expression. The aim of this study is to investigate a candidate noncoding functional variant within a genetic locus flagged by a GWAS SNP associated with non-alcoholic fatty liver disease (NAFLD), a condition characterized by liver fat accumulation in non-alcohol consumers.MethodsCRISPR-Cas9 gene editing in HepG2 cells was used to modify the regulatory element containing the candidate functional variant linked to NAFLD. Global gene expression in mutant cells was assessed through RT-qPCR and targeted transcriptomics. A phenotypic assay measured lipid droplet accumulation in the CRISPR-Cas9 mutants.ResultsThe candidate functional variant, rs2294510, closely linked to the NAFLD-associated GWAS SNP rs11206226, resided in a regulatory element within the DIO1 gene's promoter region. Altering this element resulted in changes in transcription factor binding sites and differential expression of candidate target genes like DIO1, TMEM59, DHCR24, and LDLRAD1, potentially influencing the NAFLD phenotype. Mutant HepG2 cells exhibited increased lipid accumulation, a hallmark of NAFLD, along with reduced LDL-C, HDL-C and elevated triglycerides.ConclusionsThis comprehensive approach, that combines genome editing, transcriptomics, and phenotypic assays identified the DIO1 promoter region as a potential enhancer. Its activity could regulate multiple genes involved in the NAFLD phenotype or contribute to defining a polygenic risk score for enhanced risk assessment in NAFLD patients.

Genetic variation is a key determinant of chromatin accessibility and drives differences in the regulatory landscape of C57BL/6J and 129S1/SvImJ mice.

Most common genetic variants associated with disease are located in non-coding regions of the genome. One mechanism by which they function is through altering transcription factor (TF) binding. In this study, we explore how genetic variation is connected to differences in the regulatory landscape of livers from C57BL/6J and 129S1/SvImJ mice fed either chow or a high-fat diet. To identify sites where regulatory variation affects TF binding and nearby gene expression, we employed an integrative analysis of H3K27ac ChIP-seq (active enhancers), ATAC-seq (chromatin accessibility) and RNA-seq (gene expression). We show that, across all these assays, the genetically driven (i.e. strain-specific) differences in the regulatory landscape are more pronounced than those modified by diet. Most notably, our analysis revealed that differentially accessible regions (DARs, N=29635, FDR<0.01 and fold change>50%) are almost always strain-specific and enriched with genetic variation. Moreover, proximal DARs are highly correlated with differentially expressed genes. We also show that TF binding is affected by genetic variation, which we validate experimentally using ChIP-seq for TCF7L2 and CTCF. This study provides detailed insights into how non-coding genetic variation alters the gene regulatory landscape, and demonstrates how this can be used to study the regulatory variation influencing TF binding.

Human-genome single nucleotide polymorphisms affecting transcription factor binding and their role in pathogenesis.

Single nucleotide polymorphisms (SNPs) are the most common type of variation in the human genome. The vast majority of SNPs identified in the human genome do not have any effect on the phenotype; however, some can lead to changes in the function of a gene or the level of its expression. Most SNPs associated with certain traits or pathologies are mapped to regulatory regions of the genome and affect gene expression by changing transcription factor binding sites. In recent decades, substantial effort has been invested in searching for such regulatory SNPs (rSNPs) and understanding the mechanisms by which they lead to phenotypic differences, primarily to individual differences in susceptibility to diseases and in sensitivity to drugs. The development of the NGS (next-generation sequencing) technology has contributed not only to the identification of a huge number of SNPs and to the search for their association (genome-wide association studies, GWASs) with certain diseases or phenotypic manifestations, but also to the development of more productive approaches to their functional annotation. It should be noted that the presence of an association does not allow one to identify a functional, truly disease-associated DNA sequence variant among multiple marker SNPs that are detected due to linkage disequilibrium. Moreover, determination of associations of genetic variants with a disease does not provide information about the functionality of these variants, which is necessary to elucidate the molecular mechanisms of the development of pathology and to design effective methods for its treatment and prevention. In this regard, the functional analysis of SNPs annotated in the GWAS catalog, both at the genome-wide level and at the level of individual SNPs, became especially relevant in recent years. A genome-wide search for potential rSNPs is possible without any prior knowledge of their association with a trait. Thus, mapping expression quantitative trait loci (eQTLs) makes it possible to identify an SNP for which - among transcriptomes of homozygotes and heterozygotes for its various alleles - there are differences in the expression level of certain genes, which can be located at various distances from the SNP. To predict rSNPs, approaches based on searches for allele-specific events in RNA-seq, ChIP-seq, DNase-seq, ATAC-seq, MPRA, and other data are also used. Nonetheless, for a more complete functional annotation of such rSNPs, it is necessary to establish their association with a trait, in particular, with a predisposition to a certain pathology or sensitivity to drugs. Thus, approaches to finding SNPs important for the development of a trait can be categorized into two groups: (1) starting from data on an association of SNPs with a certain trait, (2) starting from the determination of allele-specific changes at the molecular level (in a transcriptome or regulome). Only comprehensive use of strategically different approaches can considerably enrich our knowledge about the role of genetic determinants in the molecular mechanisms of trait formation, including predisposition to multifactorial diseases.

Short tandem repeats bind transcription factors to tune eukaryotic gene expression.

Short tandem repeats (STRs) are enriched in eukaryotic cis-regulatory elements and alter gene expression, yet how they regulate transcription remains unknown. We found that STRs modulate transcription factor (TF)-DNA affinities and apparent on-rates by about 70-fold by directly binding TF DNA-binding domains, with energetic impacts exceeding many consensus motif mutations. STRs maximize the number of weakly preferred microstates near target sites, thereby increasing TF density, with impacts well predicted by statistical mechanics. Confirming that STRs also affect TF binding in cells, neural networks trained only on in vivo occupancies predicted effects identical to those observed in vitro. Approximately 90% of TFs preferentially bound STRs that need not resemble known motifs, providing a cis-regulatory mechanism to target TFs to genomic sites.

The Aryl Hydrocarbon Receptor, Epigenetics and the Aging Process.

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor, classically associated with the regulation of xenobiotic metabolism in response to environmental toxins. In recent years, transgenic rodent models have implicated AhR in aging and longevity. Moreover, several AhR ligands, such as resveratrol and quercetin, are compounds proven to extend the lifespan of model organisms. In this paper, we first review AhR biology with a focus on aging and highlight several AhR ligands with potential anti-aging properties. We outline how AhR-driven expression of xenobiotic metabolism genes into old age may be a key mechanism through which moderate induction of AhR elicits positive benefits on longevity and healthspan. Furthermore, via integration of publicly available datasets, we show that liver-specific AhR target genes are enriched among genes subject to epigenetic aging. Changes to epigenetic states can profoundly affect transcription factor binding and are a hallmark of the aging process. We suggest that the interplay between AhR and epigenetic aging should be the subject of future research and outline several key gaps in the current literature. Finally, we recommend that a broad range of non-toxic AhR ligands should be investigated for their potential to promote healthspan and longevity.

Gene-wide significant association analyses of DNMT1 genetic variants with Parkinson's disease.

Background: DNA methylation plays an important role in Parkinson's disease (PD) pathogenesis. DNA methyltransferase 1 (DNMT1) is critical for maintaining DNA methylation in mammals. The link between DNMT1 polymorphisms and PD remains elusive. Methods: The DNMT1 gene contained a total of 28 single nucleotide polymorphisms (SNPs). Four representing tag-SNPs (rs16999593, rs2162560, rs11880553, and rs9305012) were identified and genotyped in a Han Chinese population comprising 712 PD patients and 696 controls. Association analyses were performed at gene-wide significance (p < 1.8 × 10-3). Results: Rs9305012, but not the other 3 tag-SNPs, was gene-wide significantly associated with PD risk (p = 0.8 × 10-3). The rs9305012/C was a protective allele against PD (p = 1.5 × 10-3, OR 0.786, 95% CI 0.677-0.912). No significant association was observed in individual genders or PD subtypes. Haplotypes of the 4 tag-SNPs showed a significant overall distribution difference between PD patients and controls (p < 1 × 10-4). The 3-allele ACC module in the order of rs2162560, rs11880553, and rs9305012 was the highest-risk haplotype associated with PD (p < 1 × 10-4, OR 2.439, 95% CI 1.563-3.704). Rs9305012 displayed certain probability to affect transcription factor binding and target gene expression based on functional annotation analyses. Conclusion: The DNMT1 variant rs9305012 together with its haplotypes may gene-wide significantly modulate PD susceptibility. Our results support a role of DNMT1 in PD pathogenesis and provide novel insights into the genetic connection in between.

Association of genetic variants of CircCHST15 with oral squamous cell carcinoma in the Chinese Han population.

Oral squamous cell carcinoma (OSCC) is the most common cancer in the oral cavity. The relationship between the genetic susceptibility of circCHST15 and OSCC remains unclear. Genetic variants of circCHST15 were screened using a genotyping analysis from 1044 patients with OSCC and 3199 healthy participants. The circCHST15 expression was detected in 32 pairs of OSCC tissues. The circular RNA quantitative trait locus analysis and the reporter gene assay were performed for verification. The circCHST15 expression was upregulated in OSCC (Wilcoxon p < 1e-3). The genotyping analysis screened out 61 loci in circCHST15 associated with the risk of OSCC. After adjustment and annotation, rs28707473 (A > C, odds ratio=1.21, 95% CI: 1.076-1.361, p=1.453e-3) was selected. This genetic variation could elevate the circCHST15 expression level possibly by altering the structure of circular RNAs and affecting transcription factor binding. The results of this study suggested that genetic variants of circCHST15 may contribute to OSCC susceptibility.

The association of ARRB1 polymorphisms with response to antidepressant treatment in depressed patients.

Introduction: β-arrestin 1, a protein encoded by ARRB1 involved in receptor signaling, is a potential biomarker for the response to antidepressant drug (ATD) treatment in depression. We examined ARRB1 genetic variants for their association with response following ATD treatment in METADAP, a cohort of 6-month ATD-treated depressed patients. Methods: Patients (n = 388) were assessed at baseline (M0) and after 1 (M1), 3 (M3), and 6months (M6) of treatment for Hamilton Depression Rating Scale (HDRS) changes, response, and remission. Whole-gene ARRB1 variants identified from high-throughput sequencing were separated by a minor allele frequency (MAF)≥5%. Frequent variants (i.e., MAF≥5%) annotated by RegulomeDB as likely affecting transcription factor binding were analyzed using mixed-effects models. Rare variants (i.e., MAF<5%) were analyzed using a variant set analysis. Results: The variant set analysis of rare variants was significant in explaining HDRS score changes (T = 878.9; p = 0.0033) and remission (T = -1974.1; p = 0.034). Rare variant counts were significant in explaining response (p = 0.016), remission (p = 0.022), and HDRS scores at M1 (p = 0.0021) and M3 (p=<0.001). rs553664 and rs536852 were significantly associated with the HDRS score (rs553664: p = 0.0055 | rs536852: p = 0.046) and remission (rs553664: p = 0.026 | rs536852: p = 0.012) through their interactions with time. At M6, significantly higher HDRS scores were observed in rs553664 AA homozygotes (13.98 ± 1.06) compared to AG heterozygotes (10.59 ± 0.86; p = 0.014) and in rs536852GG homozygotes (14.88 ± 1.10) compared to AG heterozygotes (11.26 ± 0.95; p = 0.0061). Significantly lower remitter rates were observed in rs536852GG homozygotes (8%, n = 56) compared to AG heterozygotes (42%, n = 105) at M6 (p = 0.0018). Conclusion: Our results suggest ARRB1 variants may influence the response to ATD treatment in depressed patients. Further analysis of functional ARRB1 variants and rare variant burden in other populations would help corroborate our exploratory analysis. β-arrestin 1 and genetic variants of ARRB1 may be useful clinical biomarkers for clinical improvement following ATD treatment in depressed individuals. Clinical Trial Registration: clinicaltrials.gov; identifier NCT00526383.

Autoimmune Disease Associated CLEC16A Variants Convey Risk of Parkinson's Disease in Han Chinese.

CLEC16A is a membrane-associated endosomal protein implicated in regulating autophagy and antigen presentation. Its genetic variants are broadly associated with multiple autoimmune diseases. Parkinson’s disease (PD), which undergoes autophagy disruption and neuroinflammation, has been clinically observed, for an extensive amount of time, to be associated with autoimmune diseases. In this study, we aimed to understand whether the autoimmune disease associated CLEC16A variants pleiotropically modulate PD risk. Five of such CLEC16A variants, including rs6498169, rs12708716, rs12917716, rs7200786, and rs2903692, were selected and analyzed in a Han Chinese cohort comprising 515 sporadic PD patients and 504 controls. Results showed that rs6498169 and rs7200786 were significantly associated with PD susceptibility (p = 0.005 and 0.004, respectively; recessive model, p = 0.002 and 0.001, respectively). Rs6498169 was also associated with the PD subtype of postural instability/gait difficulty (p = 0.002). Haplotype analysis showed that the AAG module in order of rs6498169, rs12708716, and rs2903692 was associated with the highest risk for PD (p = 0.0047, OR = 1.42, 95% CI = 1.11–1.82). Functional annotation analyses suggested that rs6498169 had high probability to affect transcription factor binding and target gene expression. In summary, the current study demonstrates that the autoimmune disease associated CLEC16A variants convey risk of PD in Han Chinese. Our findings suggest a pleiotropic role of CLEC16A and strengthen the link between PD and autoimmune diseases.

Genetic polymorphism of ADAM17 and decreased bilirubin levels are associated with allergic march in the Korean population

BackgroundThe “allergic march” refers to changes in the frequency and intensity of allergic diseases with age. Classically, the allergic march begins with atopic dermatitis in infancy and leads to asthma and rhinitis as it continues. There are many factors that induce the allergic march; however, TNF-α may play an important role in inducing inflammation. Therefore, the therapeutic potential of TNF alpha-targeting agents is being considered for allergic march treatment.MethodsWe performed a correlation study to determine whether genetic polymorphisms of ADAM17 and clinical serum values between allergic and normal groups affect disease development by using the cohort data of the Korean genome epidemiologic research project. Gene association study was performed using PLINK version 1.07 (http://pngu.mgh.harvard.edu/–purcell/plink) and other statistical analysis was performed using PASW Statistics (version 18.0, SPSS Inc. Chicago, IL, USA).ResultsADAM17 (also called TNF-α converting enzyme or TACE) showed a statistically significant association with the allergic march. The 13 and 8 SNPs in ADAM17 were significantly associated with asthma and allergies, respectively. Among them, on average, SNP of rs6432011 showed the greatest statistical correlation with asthma (P = 0.00041, OR = 1.95, 95% CI 1.35–2.82) and allergies (P = 0.02918, OR = 1.35, 95% CI 1.03–1.78). The effect of SNPs in ADAM17 on transcription factor binding was confirmed using RegulomeDB. The six SNPs are located in the genomic expression quantitative trait loci (eQTL) region and can affect transcription factor binding and gene expression. In clinical serum analysis, bilirubin levels were significantly decreased in the allergic group. The multivariate logistic regression analysis revealed that the low-bilirubin groups indicated a 3.22-fold increase in the prevalence of asthma compared with the high-bilirubin group.ConclusionsThe ADAM17 gene and low bilirubin levels are associated with the allergic march in the Korean population, which can provide new guidelines for managing this disease progression phenomena.

Flanking Disorder of the Folded αα-Hub Domain from Radical Induced Cell Death1 Affects Transcription Factor Binding by Ensemble Redistribution

Protein intrinsic disorder is essential for organization of transcription regulatory interactomes. In these interactomes, the majority of transcription factors as well as their interaction partners have co-existing order and disorder. Yet, little attention has been paid to their interplay. Here, we investigate how order is affected by flanking disorder in the folded αα-hub domain RST from Radical-Induced Cell Death1 (RCD1), central in a large interactome of transcription factors. We show that the intrinsically disordered C-terminal tail of RCD1-RST shifts its conformational ensemble towards a pseudo-bound state through weak interactions with the ligand-binding pocket. An unfolded excited state is also accessible on the ms timescale independent of surrounding disordered regions, but its population is lowered by 50% in their presence. Flanking disorder additionally lowers transcription factor binding-affinity without affecting the dissociation rate constant, in accordance with similar bound-states assessed by NMR. The extensive dynamics of the RCD1-RST domain, modulated by flanking disorder, is suggestive of its adaptation to many different transcription factor ligands. The study illustrates how disordered flanking regions can tune fold and function through ensemble redistribution and is of relevance to modular proteins in general, many of which play key roles in regulation of genes.

Association of Myopia and Genetic Variants of TGFB2-AS1 and TGFBR1 in the TGF-β Signaling Pathway: A Longitudinal Study in Chinese School-Aged Children.

BackgroundMyopia is a complex multifactorial condition which involves several overlapping signaling pathways mediated by distinct genes. This prospective cohort study evaluated the associations of two genetic variants in the TGF-β signaling pathway with the onset and progression of myopia and ocular biometric parameters in Chinese school-aged children.MethodsA total of 556 second grade children were examined and followed up for 3.5 years. Non-cycloplegic refraction and ocular biometric parameters were measured annually. Multivariate regression analysis was used to assess the effect of the TGFBR1 rs10760673 and TGFB2-AS1 rs7550232 variants on the occurrence and progression of myopia. A 10,000 permutations test was used to correct for multiple testing. Functional annotation of single nucleotide polymorphisms (SNPs) was performed using RegulomeDB, HaploReg, and rVarBase.ResultsA total of 448 children were included in the analysis. After adjustments for gender, age, near work time and outdoor time with 10,000 permutations, the results indicated that the C allele and the AC or CC genotypes of rs7550232 adjacent to TGFB2-AS1 were associated with a significantly increased risk of the onset of myopia in two genetic models (additive: P’ = 0.022; dominant: P’ = 0.025). Additionally, the A allele and the AA or AG genotypes of rs10760673 of TGFBR1 were associated with a significant myopic shift (additive: P’ = 0.008; dominant: P’ = 0.028; recessive: P’ = 0.027). Furthermore, rs10760673 was associated with an increase in axial length (AL) (P’ = 0.013, β = 0.03) and a change in the ratio of AL to the corneal radius of curvature (AL/CRC) (P’ = 0.031, β = 0.003). Analysis using RegulomeDB, HaploReg, and rVarBase indicated that rs7550232 is likely to affect transcription factor binding, any motif, DNase footprint, and DNase peak.ConclusionThe present study indicated that rs10760673 and rs7550232 may represent susceptibility loci for the progression and onset of myopia, respectively, in school-aged children. Associations of the variants of the TGFBR1 and TGFB2-AS1 genes with myopia may be mediated by the TGF-β signaling pathway; this hypothesis requires validation in functional studies. This trial was registered as ChiCTR1900020584 at www.Chictr.org.cn.

Polymorphisms of microRNAs are associated with salt sensitivity in a Han Chinese population: the EpiSS study.

The majority of single-nucleotide polymorphism (SNP) association studies of salt sensitivity (SS) have focused on SNPs in protein-coding genes rather than on SNPs in noncoding RNAs. This study attempted to identify the association between whole blood microRNA (miRNA)-related SNPs and the risk of SS in a Han Chinese population. A case-control study of 762 individuals was performed. A modified Sullivan's acute oral saline load and diuresis shrinkage test was used to assess SS. All SNPs were analysed by RT-PCR on a Sequenom Mass ARRAY Platform (Sequenom, San Diego, CA, USA). A genetic risk score (GRS) was used to evaluate the joint genetic effect. In total, 24 miRNA-related SNPs were genotyped, four of which (miR-1307-5p/rs11191676, miR-1307-5p/rs2292807, miR-145/rs41291957 and miR-4638-3p/rs6601178) were associated with both SS and salt sensitivity of blood pressure (SSBP) (p ≤ 0.05). MiR-382-5p/rs4906032 and miR-15b-5/rs10936201 were associated with SSBP. Weighted GRS showed that participants in the second, third and fourth quartiles had 1.760-fold (95% CI: 1.068-2.903), 2.450-fold (95% CI: 1.470-4.083) and 2.774-fold (95% CI: 1.680-4.582) increased risk of SS, respectively. Bioinformatics analysis indicated that these four SNP risk alleles may affect transcription factor binding and influence promoter activity. A total of six miRNA-related SNPs were found to be associated with SS or SSBP, and the presence of multiple risk alleles resulted in increased risk level.

Host-Pathogen Interactions in Human Polyomavirus 7‒Associated Pruritic Skin Eruption

Host-Pathogen Interactions in Human Polyomavirus 7‒Associated Pruritic Skin Eruption

Tuberculosis risk is associated with genetic polymorphisms in the LRP2, CUBN, and VDR genes.

Vitamin D (Vit. D) is used extensively during tuberculosis treatment. Low levels of serum Vit. D increase the risk of active tuberculosis development. Altered expression of the proteins involved in Vit. D metabolism impairs cathelicidin production, thereby increasing the host susceptibility to tuberculosis. We are trying to investigate whether single nucleotide polymorphisms (SNPs) in LRP2, CUBN, and VDR genes could affect tuberculosis development. We included participants of the Korean Association Resource (KARE), part of the Korean Genome and Epidemiology Study (KoGES), and used their recorded data. A total of 8840 people (4182 men and 4658 women) were eligible subjects. The 5-kb regions from the ends of transcripts of GC, LRP2, CUBN, and VDR genes were amplified to select 13, 47, 70, and 15 SNPs, respectively. For association analysis and statistical analysis, PLINK version 1.07 and PASW Statistics version 18.0 were used. Significant correlation was observed in 11, 2, and 1 SNPs in LRP2, CUBN, and VDR genes. The effect of rs6747692 of LRP2 on transcription factor binding was confirmed using RegulomeDB. We confirmed that rs2239182 of VDR is located in the genomic eQTL region and can affect transcription factor binding and gene expression. Genetic polymorphisms in genes encoding proteins involved in Vit. D metabolism influence immune system components. Therefore, such polymorphisms may influence the susceptibility to Mycobacterium tuberculosis invasion and alter the defense mechanisms against Mycobacterium tuberculosis infection. The correlation between genetic variation and tuberculosis development can provide new guidelines for the management of tuberculosis.

Methylation of a CGATA element inhibits binding and regulation by GATA-1

Alterations in DNA methylation occur during development, but the mechanisms by which they influence gene expression remain uncertain. There are few examples where modification of a single CpG dinucleotide directly affects transcription factor binding and regulation of a target gene in vivo. Here, we show that the erythroid transcription factor GATA-1 — that typically binds T/AGATA sites — can also recognise CGATA elements, but only if the CpG dinucleotide is unmethylated. We focus on a single CGATA site in the c-Kit gene which progressively becomes unmethylated during haematopoiesis. We observe that methylation attenuates GATA-1 binding and gene regulation in cell lines. In mice, converting the CGATA element to a TGATA site that cannot be methylated leads to accumulation of megakaryocyte-erythroid progenitors. Thus, the CpG dinucleotide is essential for normal erythropoiesis and this study illustrates how a single methylated CpG can directly affect transcription factor binding and cellular regulation.

Targeting transcription factors in cancer - from undruggable to reality.

Mutated or dysregulated transcription factors represent a unique class of drug targets that mediate aberrant gene expression, including blockade of differentiation and cell death gene expression programmes, hallmark properties of cancers. Transcription factor activity is altered in numerous cancer types via various direct mechanisms including chromosomal translocations, gene amplification or deletion, point mutations and alteration of expression, as well as indirectly through non-coding DNA mutations that affect transcription factor binding. Multiple approaches to target transcription factor activity have been demonstrated, preclinically and, in some cases, clinically, including inhibition of transcription factor-cofactor protein-protein interactions, inhibition of transcription factor-DNA binding and modulation of levels of transcription factor activity by altering levels of ubiquitylation and subsequent proteasome degradation or by inhibition of regulators of transcription factor expression. In addition, several new approaches to targeting transcription factors have recently emerged including modulation of auto-inhibition, proteolysis targeting chimaeras (PROTACs), use of cysteine reactive inhibitors, targeting intrinsically disordered regions of transcription factors and combinations of transcription factor inhibitors with kinase inhibitors to block the development of resistance. These innovations in drug development hold great promise to yield agents with unique properties that are likely to impact future cancer treatment.