scholarly journals Quantitative models for accelerated protein dissociation from nucleosomal DNA

2014 ◽  
Vol 42 (15) ◽  
pp. 9753-9760 ◽  
Author(s):  
Cai Chen ◽  
Ralf Bundschuh
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Specific Binding ◽  
Regulation Of Gene Expression ◽  
Transcription Factor Binding ◽  
General Mechanism ◽  
Binding Model ◽  
Factor Binding ◽  
Protein Dissociation

Abstract Binding of transcription factors to their binding sites in promoter regions is the fundamental event in transcriptional gene regulation. When a transcription factor binding site is located within a nucleosome, the DNA has to partially unwrap from the nucleosome to allow transcription factor binding. This reduces the rate of transcription factor binding and is a known mechanism for regulation of gene expression via chromatin structure. Recently a second mechanism has been reported where transcription factor off-rates are dramatically increased when binding to target sites within the nucleosome. There are two possible explanations for such an increase in off-rate short of an active role of the nucleosome in pushing the transcription factor off the DNA: (i) for dimeric transcription factors the nucleosome can change the equilibrium between monomeric and dimeric binding or (ii) the nucleosome can change the equilibrium between specific and non-specific binding to the DNA. We explicitly model both scenarios and find that dimeric binding can explain a large increase in off-rate while the non-specific binding model cannot be reconciled with the large, experimentally observed increase. Our results suggest a general mechanism how nucleosomes increase transcription factor dissociation to promote exchange of transcription factors and regulate gene expression.

scholarly journals Regulatory plasticity within a complex cytokine-sensing mammary enhancer during lactation

2020 ◽  
Author(s):  
Hye Kyung Lee ◽  
Chengyu Liu ◽  
Lothar Hennighausen
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Transcription Factor Binding ◽  
Mouse Genetics ◽  
Biological Information ◽  
Mammary Tissue ◽  
Factor Binding ◽  
Biological Importance

AbstractEnhancers are transcription factor platforms that synergize with promoters to activate gene expression up to several-thousand-fold. While genome-wide structural studies are used to predict enhancers, the in vivo significance is less clear. Specifically, the biological importance of individual transcription factors within enhancer complexes remains to be understood. Here we investigate the structural and biological importance of individual transcription factor binding sites and redundancy among transcription components within a complex enhancer in vivo. The Csn1s2b gene is expressed exclusively in mammary tissue and activated several thousand-fold during pregnancy and lactation. Using ChIP-seq we identified a complex lactation-specific candidate enhancer that binds multiple transcription factors and coincides with activating histone marks. Using experimental mouse genetics, we determined that deletion of canonical binding motifs for the transcription factors NFIB and STAT5, individually and combined, had a limited biological impact. Loss of these sites led to a shift of transcription factor binding to juxtaposed sites, suggesting exceptional plasticity that does not require direct protein-DNA interactions. Additional deletions revealed the critical importance of a non-canonical STAT5 binding site for enhancer activity. Our data also suggest that enhancer RNAs are not required for the activity of this specific enhancer. While ChIP-seq experiments predicted an additional candidate intronic enhancer, its deletion did not adversely affect gene expression, emphasizing the limited biological information provided by structural data. Our study provides comprehensive insight into the anatomy and biology of a composite mammary enhancer that activates its target gene several hundred-fold during lactation.

scholarly journals Landscape of allele-specific transcription factor binding in the human genome

2020 ◽  
Author(s):  
Sergey Abramov ◽  
Alexandr Boytsov ◽  
Dariia Bykova ◽  
Dmitry D. Penzar ◽  
Ivan Yevshin ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Molecular Mechanisms ◽  
Specific Binding ◽  
Transcription Factor Binding ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Specific Transcription Factor ◽  
Factor Binding ◽  
Allele Specific

AbstractSequence variants in gene regulatory regions alter gene expression and contribute to phenotypes of individual cells and the whole organism, including disease susceptibility and progression. Single-nucleotide variants in enhancers or promoters may affect gene transcription by altering transcription factor binding sites. Differential transcription factor binding in heterozygous genomic loci provides a natural source of information on such regulatory variants. We present a novel approach to call the allele-specific transcription factor binding events at single-nucleotide variants in ChIP-Seq data, taking into account the joint contribution of aneuploidy and local copy number variation, that is estimated directly from variant calls. We have conducted a meta-analysis of more than 7 thousand ChIP-Seq experiments and assembled the database of allele-specific binding events listing more than half a million entries at nearly 270 thousand single-nucleotide polymorphisms for several hundred human transcription factors and cell types. These polymorphisms are enriched for associations with phenotypes of medical relevance and often overlap eQTLs, making candidates for causality by linking variants with molecular mechanisms. Specifically, there is a special class of switching sites, where different transcription factors preferably bind alternative alleles, thus revealing allele-specific rewiring of molecular circuitry.

scholarly journals Long-term association of a transcription factor with its chromatin binding site can stabilize gene expression and cell fate commitment

2020 ◽  
Vol 117 (26) ◽  
pp. 15075-15084 ◽  
Author(s):  
J. B. Gurdon ◽  
Khayam Javed ◽  
Munender Vodnala ◽  
Nigel Garrett
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Binding Site ◽  
Residence Time ◽  
Transcription Factor Binding ◽  
Oocyte Nucleus ◽  
Chromatin Binding ◽  
Chromosomal Dna ◽  
Factor Binding

Some lineage-determining transcription factors are overwhelmingly important in directing embryonic cells to a particular differentiation pathway, such asAscl1for nerve. They also have an exceptionally strong ability to force cells to change from an unrelated pathway to one preferred by their action. Transcription factors are believed to have a very short residence time of only a few seconds on their specific DNA or chromatin-binding sites. We have developed a procedure in which DNA containing one copy of the binding site for the neural-inducing factorAscl1is injected directly into aXenopusoocyte nucleus which has been preloaded with a limiting amount of theAscl1transcription factor protein. This is followed by a further injection of DNA as a competitor, either in a plasmid or in chromosomal DNA, containing the same binding site but with a different reporter. Importantly, expression of the reporter provides a measure of the function of the transcription factor in addition to its residence time. The same long residence time and resistance to competition are seen with the estrogen receptor and its DNA response elements. We find that in this nondividing oocyte, the nerve-inducing factorAscl1can remain bound to a specific chromatin site for hours or days and thereby help to stabilize gene expression. This stability of transcription factor binding to chromatin is a necessary part of its action because removal of this factor causes discontinuation of its effect on gene expression. Stable transcription factor binding may be a characteristic of nondividing cells.

scholarly journals A Panel of rSNPs Demonstrating Allelic Asymmetry in Both ChIP-seq and RNA-seq Data and the Search for Their Phenotypic Outcomes through Analysis of DEGs

2021 ◽  
Vol 22 (14) ◽  
pp. 7240
Author(s):  
Elena E. Korbolina ◽  
Leonid O. Bryzgalov ◽  
Diana Z. Ustrokhanova ◽  
Sergey N. Postovalov ◽  
Dmitry V. Poverin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Specific Binding ◽  
Transcription Factor Binding ◽  
Postmortem Brain ◽  
Rna Seq ◽  
Factor Binding ◽  
Protein Protein Interaction ◽  
Human Postmortem Brain ◽  
H3k4me3 Mark

Currently, the detection of the allele asymmetry of gene expression from RNA-seq data or the transcription factor binding from ChIP-seq data is one of the approaches used to identify the functional genetic variants that can affect gene expression (regulatory SNPs or rSNPs). In this study, we searched for rSNPs using the data for human pulmonary arterial endothelial cells (PAECs) available from the Sequence Read Archive (SRA). Allele-asymmetric binding and expression events are analyzed in paired ChIP-seq data for H3K4me3 mark and RNA-seq data obtained for 19 individuals. Two statistical approaches, weighted z-scores and predicted probabilities, were used to improve the efficiency of finding rSNPs. In total, we identified 14,266 rSNPs associated with both allele-specific binding and expression. Among them, 645 rSNPs were associated with GWAS phenotypes; 4746 rSNPs were reported as eQTLs by GTEx, and 11,536 rSNPs were located in 374 candidate transcription factor binding motifs. Additionally, we searched for the rSNPs associated with gene expression using an SRA RNA-seq dataset for 281 clinically annotated human postmortem brain samples and detected eQTLs for 2505 rSNPs. Based on these results, we conducted Gene Ontology (GO), Disease Ontology (DO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses and constructed the protein–protein interaction networks to represent the top-ranked biological processes with a possible contribution to the phenotypic outcome.

scholarly journals Landscape of allele-specific transcription factor binding in the human genome

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Sergey Abramov ◽  
Alexandr Boytsov ◽  
Daria Bykova ◽  
Dmitry D. Penzar ◽  
Ivan Yevshin ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Molecular Mechanisms ◽  
Specific Binding ◽  
Transcription Factor Binding ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Specific Transcription Factor ◽  
Factor Binding ◽  
Allele Specific

AbstractSequence variants in gene regulatory regions alter gene expression and contribute to phenotypes of individual cells and the whole organism, including disease susceptibility and progression. Single-nucleotide variants in enhancers or promoters may affect gene transcription by altering transcription factor binding sites. Differential transcription factor binding in heterozygous genomic loci provides a natural source of information on such regulatory variants. We present a novel approach to call the allele-specific transcription factor binding events at single-nucleotide variants in ChIP-Seq data, taking into account the joint contribution of aneuploidy and local copy number variation, that is estimated directly from variant calls. We have conducted a meta-analysis of more than 7 thousand ChIP-Seq experiments and assembled the database of allele-specific binding events listing more than half a million entries at nearly 270 thousand single-nucleotide polymorphisms for several hundred human transcription factors and cell types. These polymorphisms are enriched for associations with phenotypes of medical relevance and often overlap eQTLs, making candidates for causality by linking variants with molecular mechanisms. Specifically, there is a special class of switching sites, where different transcription factors preferably bind alternative alleles, thus revealing allele-specific rewiring of molecular circuitry.

scholarly journals Integrating binding and expression data to predict transcription factors combined function

BMC Genomics ◽  
2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Mahmoud Ahmed ◽  
Do Sik Min ◽  
Deok Ryong Kim
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Binding Sites ◽  
Regulatory Region ◽  
Transcription Factor Binding ◽  
Expression Data ◽  
Dominant Type ◽  
Factor Binding ◽  
Two Factors

Abstract Background Transcription factor binding to the regulatory region of a gene induces or represses its gene expression. Transcription factors share their binding sites with other factors, co-factors and/or DNA-binding proteins. These proteins form complexes which bind to the DNA as one-units. The binding of two factors to a shared site does not always lead to a functional interaction. Results We propose a method to predict the combined functions of two factors using comparable binding and expression data (target). We based this method on binding and expression target analysis (BETA), which we re-implemented in R and extended for this purpose. target ranks the factor’s targets by importance and predicts the dominant type of interaction between two transcription factors. We applied the method to simulated and real datasets of transcription factor-binding sites and gene expression under perturbation of factors. We found that Yin Yang 1 transcription factor (YY1) and YY2 have antagonistic and independent regulatory targets in HeLa cells, but they may cooperate on a few shared targets. Conclusion We developed an R package and a web application to integrate binding (ChIP-seq) and expression (microarrays or RNA-seq) data to determine the cooperative or competitive combined function of two transcription factors.

scholarly journals Understanding Transcription Factor Regulation by Integrating Gene Expression and DNase I Hypersensitive Sites

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Guohua Wang ◽  
Fang Wang ◽  
Qian Huang ◽  
Yu Li ◽  
Yunlong Liu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Dna Sequences ◽  
Binding Sites ◽  
Transcription Factor Binding Sites ◽  
Transcription Factor Binding ◽  
Interferon Treatment ◽  
Factor Binding ◽  
Hypersensitive Sites

Transcription factors are proteins that bind to DNA sequences to regulate gene transcription. The transcription factor binding sites are short DNA sequences (5–20 bp long) specifically bound by one or more transcription factors. The identification of transcription factor binding sites and prediction of their function continue to be challenging problems in computational biology. In this study, by integrating the DNase I hypersensitive sites with known position weight matrices in the TRANSFAC database, the transcription factor binding sites in gene regulatory region are identified. Based on the global gene expression patterns in cervical cancer HeLaS3 cell and HelaS3-ifnα4h cell (interferon treatment on HeLaS3 cell for 4 hours), we present a model-based computational approach to predict a set of transcription factors that potentially cause such differential gene expression. Significantly, 6 out 10 predicted functional factors, including IRF, IRF-2, IRF-9, IRF-1 and IRF-3, ICSBP, belong to interferon regulatory factor family and upregulate the gene expression levels responding to the interferon treatment. Another factor, ISGF-3, is also a transcriptional activator induced by interferon alpha. Using the different transcription factor binding sites selected criteria, the prediction result of our model is consistent. Our model demonstrated the potential to computationally identify the functional transcription factors in gene regulation.

scholarly journals Distinct Contribution of DNA Methylation and Histone Acetylation to the Genomic Occupancy of Transcription Factors

2019 ◽  
Author(s):  
Martin Cusack ◽  
Hamish W. King ◽  
Paolo Spingardi ◽  
Benedikt M. Kessler ◽  
Robert J. Klose ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Embryonic Stem ◽  
Transcription Factor Binding ◽  
Chromatin Accessibility ◽  
Histone Deacetylation ◽  
Hdac Inhibition ◽  
Factor Binding

AbstractEpigenetic modifications on chromatin play important roles in regulating gene expression. While chromatin states are often governed by multi-layered structure, how individual pathways contribute to gene expression remains poorly understood. For example, DNA methylation is known to regulate transcription factor binding but also to recruit methyl-CpG binding proteins that affect chromatin structure through the activity of histone deacetylase complexes (HDACs). Both of these mechanisms can potentially affect gene expression, but the importance of each, and whether these activities are integrated to achieve appropriate gene regulation, remains largely unknown. To address this important question, we measured gene expression, chromatin accessibility, and transcription factor occupancy in wild-type or DNA methylation-deficient mouse embryonic stem cells following HDAC inhibition. Interestingly, we observe widespread increases in chromatin accessibility at repeat elements when HDACs are inhibited, and this is magnified when cells also lack DNA methylation. A subset of these elements have elevated binding of the YY1 and GABPA transcription factors and increased expression. The pronounced additive effect of HDAC inhibition in DNA methylation deficient cells demonstrate that DNA methylation and histone deacetylation act largely independently to suppress transcription factor binding and gene expression.

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