scholarly journals Mutational bias in spermatogonia impacts the anatomy of regulatory sites in the human genome

2021 ◽  
Author(s):  
Vera B. Kaiser ◽  
Lana Talmane ◽  
Yatendra Kumar ◽  
Fiona Semple ◽  
Marie MacLennan ◽  
...  
Keyword(s):  
Chromatin Structure ◽  
Meiotic Recombination ◽  
Binding Sites ◽  
Evolutionary Process ◽  
Mutational Bias ◽  
Open Chromatin ◽  
Structural Variant ◽  
Regulatory Architecture ◽  
Mutational Processes ◽  
Regulatory Sites

Mutation in the germline is the ultimate source of genetic variation, but little is known about the influence of germline chromatin structure on mutational processes. Using ATAC-seq, we profile the open chromatin landscape of human spermatogonia, the most proliferative cell type of the germline, identifying transcription factor binding sites (TFBSs) and PRDM9 binding sites, a subset of which will initiate meiotic recombination. We observe an increase in rare structural variant (SV) breakpoints at PRDM9-bound sites, implicating meiotic recombination in the generation of structural variation. Many germline TFBSs, such as NRF1, are also associated with increased rates of SV breakpoints, apparently independent of recombination. Singleton short insertions (≥5 bp) are highly enriched at TFBSs, particularly at sites bound by testis active TFs, and their rates correlate with those of structural variant breakpoints. Short insertions often duplicate the TFBS motif, leading to clustering of motif sites near regulatory regions in this male-driven evolutionary process. Increased mutation loads at germline TFBSs disproportionately affect neural enhancers with activity in spermatogonia, potentially altering neurodevelopmental regulatory architecture. Local chromatin structure in spermatogonia is thus pervasive in shaping both evolution and disease.

scholarly journals Mutational bias in spermatogonia impacts the anatomy of regulatory sites in the human genome

2021 ◽  
Author(s):  
Vera B Kaiser ◽  
Lana Talmane ◽  
Yatendra Kumar ◽  
Fiona Semple ◽  
Marie MacLennan ◽  
...  
Keyword(s):  
Chromatin Structure ◽  
Meiotic Recombination ◽  
Binding Sites ◽  
Evolutionary Process ◽  
Mutational Bias ◽  
Open Chromatin ◽  
Structural Variant ◽  
Regulatory Architecture ◽  
Mutational Processes ◽  
Regulatory Sites

Mutation in the germline is the ultimate source of genetic variation, but little is known about the influence of germline chromatin structure on mutational processes. Using ATAC-seq, we profile the open chromatin landscape of human spermatogonia, the most proliferative cell-type of the germline, identifying transcription factor binding sites (TFBSs) and PRDM9-binding sites, a subset of which will initiate meiotic recombination. We observe an increase in rare structural variant (SV) breakpoints at PRDM9-bound sites, implicating meiotic recombination in the generation of structural variation. Many germline TFBSs, such as NRF, are also associated with increased rates of SV breakpoints, apparently independent of recombination. Singleton short insertions (>=5 bp) are highly enriched at TFBSs, particularly at sites bound by testis active TFs, and their rates correlate with those of structural variant breakpoints. Short insertions often duplicate the TFBS motif, leading to clustering of motif sites near regulatory regions in this male-driven evolutionary process. Increased mutation loads at germline TFBSs disproportionately affect neural enhancers with activity in spermatogonia, potentially altering neurodevelopmental regulatory architecture. Local chromatin structure in spermatogonia is thus pervasive in shaping both evolution and disease.

scholarly journals Strong replicators associated with open chromatin are sufficient to establish an early replicating domain

2018 ◽  
Author(s):  
Caroline Brossas ◽  
Sabarinadh Chilaka ◽  
Antonin Counillon ◽  
Marc Laurent ◽  
Coralie Goncalves ◽  
...  
Keyword(s):  
Chromatin Structure ◽  
Binding Sites ◽  
Replication Origin ◽  
Molecular Mechanisms ◽  
Open Chromatin ◽  
Strongly Correlated ◽  
Topologically Associating Domains ◽  
Genome Wide ◽  
Close Physical Proximity ◽  
Temporal Program

AbstractVertebrate genomes replicate according to a precise temporal program strongly correlated with their organization into topologically associating domains. However, the molecular mechanisms underlying the establishment of early-replicating domains remain largely unknown. We defined two minimal cis-element modules containing a strong replication origin and chromatin modifier binding sites capable of shifting a targeted mid-late replicating region for earlier replication. When inserted side-by-side, these modules acted in cooperation, with similar effects on two late-replicating regions. Targeted insertions of these two modules at two chromosomal sites separated by 30 kb brought these two modules into close physical proximity and induced the formation of an early-replicating domain. Thus, combinations of strong origins and cis-elements capable of opening the chromatin structure are the basic units of early-replicating domains, and are absent from late-replicated regions. These findings are consistent with those of genome-wide studies mapping strong initiation sites and open chromatin marks in vertebrate genomes.

scholarly journals Genomic Study of Replication Initiation in Human Chromosomes Reveals the Influence of Transcription Regulation and Chromatin Structure on Origin Selection

2010 ◽  
Vol 21 (3) ◽  
pp. 393-404 ◽  
Author(s):  
Neerja Karnani ◽  
Christopher M. Taylor ◽  
Ankit Malhotra ◽  
Anindya Dutta
Keyword(s):  
Rna Polymerase Ii ◽  
Chromatin Structure ◽  
Binding Sites ◽  
Transcription Initiation ◽  
Origin Recognition Complex ◽  
Replication Initiation ◽  
Open Chromatin ◽  
Lambda Exonuclease ◽  
Genomic Study ◽  
Exonuclease Digestion

DNA replication in metazoans initiates from multiple chromosomal loci called origins. Currently, there are two methods to purify origin-centered nascent strands: lambda exonuclease digestion and anti-bromodeoxyuridine immunoprecipitation. Because both methods have unique strengths and limitations, we purified nascent strands by both methods, hybridized them independently to tiling arrays (1% genome) and compared the data to have an accurate view of genome-wide origin distribution. By this criterion, we identified 150 new origins that were reproducible across the methods. Examination of a subset of these origins by chromatin immunoprecipitation against origin recognition complex (ORC) subunits 2 and 3 showed 93% of initiation peaks to localize at/within 1 kb of ORC binding sites. Correlation of origins with functional elements of the genome revealed origin activity to be significantly enriched around transcription start sites (TSSs). Consistent with proximity to TSSs, we found a third of initiation events to occur at or near the RNA polymerase II binding sites. Interestingly, ∼50% of the early origin activity was localized within 5 kb of transcription regulatory factor binding region clusters. The chromatin signatures around the origins were enriched in H3K4-(di- and tri)-methylation and H3 acetylation modifications on histones. Affinity of origins for open chromatin was also reiterated by their proximity to DNAse I-hypersensitive sites. Replication initiation peaks were AT rich, and >50% of the origins mapped to evolutionarily conserved regions of the genome. In summary, these findings indicate that replication initiation is influenced by transcription initiation and regulation as well as chromatin structure.

scholarly journals Functional and genetic determinants of mutation rate variability in regulatory elements of cancer genomes

2020 ◽  
Author(s):  
Christian A. Lee ◽  
Diala Abd-Rabbo ◽  
Jüri Reimand
Keyword(s):  
Binding Sites ◽  
Scale Effects ◽  
Regulatory Elements ◽  
Ctcf Binding ◽  
Mutation Rates ◽  
Driver Gene ◽  
Open Chromatin ◽  
Cancer Driver ◽  
Cancer Genomes ◽  
Mutational Processes

Localised variation of somatic mutation rates affects diverse functional sequence elements in cancer genomes through poorly understood mutational processes. Here, we characterise the mutational landscape of 640,000 gene regulatory and chromatin architectural elements in 2,421 whole cancer genomes using our new statistical model RM2. This method quantifies differential mutation rates and signatures in classes of genomic elements via genetic, trinucleotide and megabase-scale effects. We report a detailed map of localised mutational processes affecting CTCF binding sites, transcription start sites (TSS) and cancer-specific open-chromatin regions. This includes a pan-cancer indel depletion in open-chromatin sites, a TSS-specific mutational process correlated with mRNA abundance in core cellular and cancer-associated processes, a subset of hypermutated, constitutively active CTCF binding sites involved in chromatin architectural interactions, and an enrichment of signature SBS17b in CTCF sites in gastrointestinal cancers. We also detect genetic driver alterations potentially underlying localised mutation rates, including RAD21 amplifications and BRAF mutations associating with mutagenesis of CTCF binding sites, and SDHA amplifications indicative of frequent lung cancer mutations in open-chromatin sites. Our framework and the catalogue of localised mutational processes provide novel perspectives to cancer genome evolution and its implications for oncogenesis, tumor heterogeneity and cancer driver gene discovery.

scholarly journals Functional and genetic determinants of mutation rate variability in regulatory elements of cancer genomes

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Christian A. Lee ◽  
Diala Abd-Rabbo ◽  
Jüri Reimand
Keyword(s):  
Binding Sites ◽  
Mutation Frequency ◽  
Scale Effects ◽  
Regulatory Elements ◽  
Ctcf Binding ◽  
Driver Gene ◽  
Open Chromatin ◽  
Genetic Determinants ◽  
Cancer Genomes ◽  
Mutational Processes

Abstract Background Cancer genomes are shaped by mutational processes with complex spatial variation at multiple scales. Entire classes of regulatory elements are affected by local variations in mutation frequency. However, the underlying mechanisms with functional and genetic determinants remain poorly understood. Results We characterise the mutational landscape of 1.3 million gene-regulatory and chromatin architectural elements in 2419 whole cancer genomes with transcriptional and pathway activity, functional conservation and recurrent driver events. We develop RM2, a statistical model that quantifies mutational enrichment or depletion in classes of genomic elements through genetic, trinucleotide and megabase-scale effects. We report a map of localised mutational processes affecting CTCF binding sites, transcription start sites (TSS) and tissue-specific open-chromatin regions. Increased mutation frequency in TSSs associates with mRNA abundance in most cancer types, while open-chromatin regions are generally enriched in mutations. We identify ~ 10,000 CTCF binding sites with core DNA motifs and constitutive binding in 66 cell types that represent focal points of mutagenesis. We detect site-specific mutational signature enrichments, such as SBS40 in open-chromatin regions in prostate cancer and SBS17b in CTCF binding sites in gastrointestinal cancers. Candidate drivers of localised mutagenesis are also apparent: BRAF mutations associate with mutational enrichments at CTCF binding sites in melanoma, and ARID1A mutations with TSS-specific mutagenesis in pancreatic cancer. Conclusions Our method and catalogue of localised mutational processes provide novel perspectives to cancer genome evolution, mutagenesis, DNA repair and driver gene discovery. The functional and genetic correlates of mutational processes suggest mechanistic hypotheses for future studies.

scholarly journals Promoter G-quadruplexes and transcription factors cooperate to shape the cell type-specific transcriptome

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Sara Lago ◽  
Matteo Nadai ◽  
Filippo M. Cernilogar ◽  
Maryam Kazerani ◽  
Helena Domíniguez Moreno ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Binding Sites ◽  
Specific Gene ◽  
Open Chromatin ◽  
Rna Seq ◽  
Transcript Levels ◽  
Promoter Sequences ◽  
G Quadruplex ◽  
Cell Type Specific ◽  
Folding State

AbstractCell identity is maintained by activation of cell-specific gene programs, regulated by epigenetic marks, transcription factors and chromatin organization. DNA G-quadruplex (G4)-folded regions in cells were reported to be associated with either increased or decreased transcriptional activity. By G4-ChIP-seq/RNA-seq analysis on liposarcoma cells we confirmed that G4s in promoters are invariably associated with high transcription levels in open chromatin. Comparing G4 presence, location and transcript levels in liposarcoma cells to available data on keratinocytes, we showed that the same promoter sequences of the same genes in the two cell lines had different G4-folding state: high transcript levels consistently associated with G4-folding. Transcription factors AP-1 and SP1, whose binding sites were the most significantly represented in G4-folded sequences, coimmunoprecipitated with their G4-folded promoters. Thus, G4s and their associated transcription factors cooperate to determine cell-specific transcriptional programs, making G4s to strongly emerge as new epigenetic regulators of the transcription machinery.

scholarly journals EPEN-30. C11ORF95-RELA FUSION PROTEIN ENGAGES NOVEL GENOMIC LOCI TO DRIVE MURINE EPENDYMOMA GROWTH

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii314-iii314
Author(s):  
Amir Arabzade ◽  
Yanhua Zhao ◽  
Srinidhi Varadharajan ◽  
Hsiao-Chi Chen ◽  
Austin Stuckert ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Binding Sites ◽  
Molecular Targets ◽  
Lead Target ◽  
Open Chromatin ◽  
Rna Seq ◽  
In Utero Electroporation ◽  
Pathway Activation ◽  
Mouse Cells ◽  
Shed Light

Abstract RATIONALE Over 70% of supratentorial (ST) ependymoma are characterized by an oncogenic fusion between C11ORF95 and RELA. C11ORF95-RELA fusion is frequently the sole genetic driver detected in ST ependymoma, thus ranking this genomic event as a lead target for therapeutic investigation. RELA is a transcription factor (TF) central to mediating NF-kB pathway activation in processes such as inflammation, cellular metabolism, and chemotaxis. HYPOTHESIS: We posited that C11ORF95-RELA acts as an oncogenic TF that aberrantly shapes the tumor epigenome to drive aberrant transcription. Approach: To this end we developed an in utero electroporation (IUE) mouse model of ependymoma to express C11ORF95-RELA during embryonic development. Our IUE approach allowed us to develop C11ORF95-RELA driven tumor models and cell lines. We comprehensively characterized the epigenome and transcriptome of C11ORF95-RELA fusion driven mouse cells by H3K27ac ChIP-seq, ATAC-seq, and RNA-seq. RESULTS This data revealed that: 1) C11ORF95-RELA directly engages ‘open’ chromatin and is enriched at regions with known RELA TF binding sites as well as novel genomic loci/motifs, 2) C11ORF95-RELA preferentially binds to both H3K27ac (active) enhancers and promoters, and 3) Bound C11ORF95-RELA promoter loci are associated with increased transcription of genes shared with human ependymoma. CONCLUSION Our findings shed light on the transcriptional mechanisms of C11ORF95-RELA, and reveal downstream targets that may represent cancer dependency genes and molecular targets.

Host–parasite co-evolution

2021 ◽  
pp. 389-416
Author(s):  
Paul Schmid-Hempel
Keyword(s):  
Meiotic Recombination ◽  
Evolutionary Process ◽  
Host Switching ◽  
Response To Selection ◽  
Red Queen ◽  
Arms Races ◽  
Migration Rates ◽  
Frequency Changes ◽  
Host Parasite ◽  
Relative Migration

Macroevolutionary patterns concern phylogenies of hosts and their parasites. From those, co-speciation occurs; but host switching is a common evolutionary process and more likely when hosts are close phylogenetically and geographical ranges overlap. Microevolutionary processes refer to allele frequency changes within population. In arms races, traits of hosts and parasites evolve in one direction in response to selection by the other party. With selective sweeps, advantageous alleles rapidly spread in host or parasite population and can become fixed. With antagonistic negative frequency-dependent fluctuations (Red Queen dynamics) genetic polymorphism in populations can be maintained, even through speciation events. A Red Queen co-evolutionary process can favour sexual over asexual reproduction and maintain meiotic recombination despite its other disadvantages (two-fold cost of sex). Local adaptation of host and parasites exist in various combinations; the relative migration rates of the two parties, embedded in a geographical mosaic, are important for this process.

scholarly journals Spatial density of open chromatin: an effective metric for the functional characterization of topologically associated domains

2020 ◽  
Author(s):  
Shuai Jiang ◽  
Hao Li ◽  
Hao Hong ◽  
Guifang Du ◽  
Xin Huang ◽  
...  
Keyword(s):  
Chromatin Structure ◽  
Functional Characterization ◽  
Regulation Of Gene Expression ◽  
Joint Effect ◽  
Spatial Density ◽  
Open Chromatin ◽  
Temporal Regulation ◽  
Topologically Associated Domains ◽  
Regulatory Landscape

Abstract Topologically associated domains (TADs) are spatial and functional units of metazoan chromatin structure. Interpretation of the interplay between regulatory factors and chromatin structure within TADs is crucial to understand the spatial and temporal regulation of gene expression. However, a computational metric for the sensitive characterization of TAD regulatory landscape is lacking. Here, we present the spatial density of open chromatin (SDOC) metric as a quantitative measurement of intra-TAD chromatin state and structure. SDOC sensitively reflects epigenetic properties and gene transcriptional activity in TADs. During mouse T-cell development, we found that TADs with decreased SDOC are enriched in repressed developmental genes, and the joint effect of SDOC-decreasing and TAD clustering corresponds to the highest level of gene repression. In addition, we revealed a pervasive preference for TADs with similar SDOC to interact with each other, which may reflect the principle of chromatin organization.

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