scholarly journals Identification and characterization of BEND2 as a novel and key regulator of meiosis during mouse spermatogenesis

2021 ◽  
Author(s):  
Longfei Ma ◽  
Dan Xie ◽  
Xiwen Lin ◽  
Hengyu Nie ◽  
Jian Chen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Time Window ◽  
Gene Knockout ◽  
Strand Break ◽  
Chromatin Accessibility ◽  
Chromatin State ◽  
Short Time Window ◽  
Associated Proteins ◽  
Meiotic Initiation

The chromatin state undergoes global and dynamic changes during spermatogenesis, and is critical to chromosomal synapsis, meiotic recombination, and transcriptional regulation. However, the key regulators involved and the underlying molecular mechanisms remain poorly understood. Herein we report that mouse BEND2, one of the BEN-domain- containing proteins conserved in vertebrates, was specifically expressed in spermatogenic cells within a short time-window spanning meiotic initiation, and that it plays an essential role in the progression of prophase in meiosis I. Bend2 gene knockout in male mice arrested meiosis at the transition from zygonema to pachynema, disrupted synapsis and DNA double-strand break repair, and induced non-homologous chromosomal pairing. BEND2 interacted with a number of chromatin-associated proteins including ZMYM2, LSD1, CHD4, and ADNP,which are components of certain transcription-repressor complexes. BEND2-binding sites were identified in diverse chromatin states and enriched in simple sequence repeats. BEND2 contributed to shutting down the mitotic gene-expression program and to the activation of meiotic and post-meiotic gene expression, and it regulated chromatin accessibility as well as the modification of H3K4me3. Therefore, our study identified BEND2 as a novel and key regulator of meiosis, gene expression, and chromatin state during mouse spermatogenesis.

scholarly journals Mapping chromatin accessibility and active regulatory elements reveals pathological mechanisms in human gliomas

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Karolina Stępniak ◽  
Magdalena A. Machnicka ◽  
Jakub Mieczkowski ◽  
Anna Macioszek ◽  
Bartosz Wojtaś ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chromatin Structure ◽  
Molecular Mechanisms ◽  
Genome Mapping ◽  
Malignant Gliomas ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Multiple Tumor ◽  
Genes Encoding ◽  
Methylation Patterns

AbstractChromatin structure and accessibility, and combinatorial binding of transcription factors to regulatory elements in genomic DNA control transcription. Genetic variations in genes encoding histones, epigenetics-related enzymes or modifiers affect chromatin structure/dynamics and result in alterations in gene expression contributing to cancer development or progression. Gliomas are brain tumors frequently associated with epigenetics-related gene deregulation. We perform whole-genome mapping of chromatin accessibility, histone modifications, DNA methylation patterns and transcriptome analysis simultaneously in multiple tumor samples to unravel epigenetic dysfunctions driving gliomagenesis. Based on the results of the integrative analysis of the acquired profiles, we create an atlas of active enhancers and promoters in benign and malignant gliomas. We explore these elements and intersect with Hi-C data to uncover molecular mechanisms instructing gene expression in gliomas.

scholarly journals Repurposing of KLF5 activates a cell cycle signature during the progression from a precursor state to Oesophageal Adenocarcinoma

2020 ◽  
Author(s):  
Connor Rogerson ◽  
Samuel Ogden ◽  
Edward Britton ◽  
Yeng Ang ◽  
Andrew D. Sharrocks ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Prognostic Significance ◽  
Gene Expression Signature ◽  
Chromatin Accessibility ◽  
Oesophageal Adenocarcinoma ◽  
Cell Cycle Gene ◽  
A Cell

AbstractOesophageal adenocarcinoma (OAC) is one of the most common causes of cancer deaths and yet compared to other common cancers, we know relatively little about the underlying molecular mechanisms. Barrett’s oesophagus (BO) is the only known precancerous precursor to OAC, but our understanding about the specific events leading to OAC development is limited. Here, we have integrated gene expression and chromatin accessibility profiles of human biopsies of BO and OAC and identified a strong cell cycle gene expression signature in OAC compared to BO. Through analysing associated chromatin accessibility changes, we have implicated the transcription factor KLF5 in the transition from BO to OAC. Importantly, we show that KLF5 expression is unchanged during this transition, but instead, KLF5 is redistributed across chromatin in OAC cells to directly regulate cell cycle genes specifically in OAC. Our findings have potential prognostic significance as the survival of patients with high expression of KLF5 target genes is significantly lower. We have provided new insights into the gene expression networks in OAC and the mechanisms behind progression to OAC, chiefly the repurposing of KLF5 for novel regulatory activity in OAC.

scholarly journals Integration of human pancreatic islet genomic data refines regulatory mechanisms at Type 2 Diabetes susceptibility loci

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Matthias Thurner ◽  
Martijn van de Bunt ◽  
Jason M Torres ◽  
Anubha Mahajan ◽  
Vibe Nylander ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Pancreatic Islet ◽  
Molecular Mechanisms ◽  
Association Studies ◽  
Human Islets ◽  
Chromatin Accessibility ◽  
Chromatin State ◽  
Open Chromatin ◽  
Genome Wide Association Studies

Human genetic studies have emphasised the dominant contribution of pancreatic islet dysfunction to development of Type 2 Diabetes (T2D). However, limited annotation of the islet epigenome has constrained efforts to define the molecular mechanisms mediating the, largely regulatory, signals revealed by Genome-Wide Association Studies (GWAS). We characterised patterns of chromatin accessibility (ATAC-seq, n = 17) and DNA methylation (whole-genome bisulphite sequencing, n = 10) in human islets, generating high-resolution chromatin state maps through integration with established ChIP-seq marks. We found enrichment of GWAS signals for T2D and fasting glucose was concentrated in subsets of islet enhancers characterised by open chromatin and hypomethylation, with the former annotation predominant. At several loci (including CDC123, ADCY5, KLHDC5) the combination of fine-mapping genetic data and chromatin state enrichment maps, supplemented by allelic imbalance in chromatin accessibility pinpointed likely causal variants. The combination of increasingly-precise genetic and islet epigenomic information accelerates definition of causal mechanisms implicated in T2D pathogenesis.

scholarly journals Integration of human pancreatic islet genomic data refines regulatory mechanisms at Type 2 Diabetes susceptibility loci

2017 ◽  
Author(s):  
Matthias Thurner ◽  
Martijn van de Bunt ◽  
Jason M Torres ◽  
Anubha Mahajan ◽  
Vibe Nylander ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Pancreatic Islet ◽  
Molecular Mechanisms ◽  
Association Studies ◽  
Human Islets ◽  
Chromatin Accessibility ◽  
Chromatin State ◽  
Open Chromatin ◽  
Genome Wide Association Studies

AbstractHuman genetic studies have emphasised the dominant contribution of pancreatic islet dysfunction to development of Type 2 Diabetes (T2D). However, limited annotation of the islet epigenome has constrained efforts to define the molecular mechanisms mediating the, largely regulatory, signals revealed by Genome-Wide Association Studies (GWAS). We characterised patterns of chromatin accessibility (ATAC-seq, n=17) and DNA methylation (whole-genome bisulphite sequencing, n=10) in human islets, generating high-resolution chromatin state maps through integration with established ChIP-seq marks. We found enrichment of GWAS signals for T2D and fasting glucose was concentrated in subsets of islet enhancers characterised by open chromatin and hypomethylation, with the former annotation predominant. At several loci (including CDC123, ADCY5, KLHDC5) the combination of fine-mapping genetic data and chromatin state enrichment maps, supplemented by allelic imbalance in chromatin accessibility pinpointed likely causal variants. The combination of increasingly-precise genetic and islet epigenomic information accelerates definition of causal mechanisms implicated in T2D pathogenesis.

scholarly journals AP-1 Contributes to Chromatin Accessibility to Promote Sarcomere Disassembly and Cardiomyocyte Protrusion During Zebrafish Heart Regeneration

2020 ◽  
Vol 126 (12) ◽  
pp. 1760-1778 ◽  
Author(s):  
Arica Beisaw ◽  
Carsten Kuenne ◽  
Stefan Guenther ◽  
Julia Dallmann ◽  
Chi-Chung Wu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
High Throughput Sequencing ◽  
Cardiac Regeneration ◽  
Chromatin Accessibility ◽  
Dominant Negative ◽  
Activator Protein 1 ◽  
Cardiomyocyte Proliferation ◽  
Injured Area

Rationale: The adult human heart is an organ with low regenerative potential. Heart failure following acute myocardial infarction is a leading cause of death due to the inability of cardiomyocytes to proliferate and replenish lost cardiac muscle. While the zebrafish has emerged as a powerful model to study endogenous cardiac regeneration, the molecular mechanisms by which cardiomyocytes respond to damage by disassembling sarcomeres, proliferating, and repopulating the injured area remain unclear. Furthermore, we are far from understanding the regulation of the chromatin landscape and epigenetic barriers that must be overcome for cardiac regeneration to occur. Objective: To identify transcription factor regulators of the chromatin landscape, which promote cardiomyocyte regeneration in zebrafish, and investigate their function. Methods and Results: Using the Assay for Transposase-Accessible Chromatin coupled to high-throughput sequencing (ATAC-Seq), we first find that the regenerating cardiomyocyte chromatin accessibility landscape undergoes extensive changes following cryoinjury, and that activator protein-1 (AP-1) binding sites are the most highly enriched motifs in regions that gain accessibility during cardiac regeneration. Furthermore, using bioinformatic and gene expression analyses, we find that the AP-1 response in regenerating adult zebrafish cardiomyocytes is largely different from the response in adult mammalian cardiomyocytes. Using a cardiomyocyte-specific dominant negative approach, we show that blocking AP-1 function leads to defects in cardiomyocyte proliferation as well as decreased chromatin accessibility at the fbxl22 and ilk loci, which regulate sarcomere disassembly and cardiomyocyte protrusion into the injured area, respectively. We further show that overexpression of the AP-1 family members Junb and Fosl1 can promote changes in mammalian cardiomyocyte behavior in vitro. Conclusions: AP-1 transcription factors play an essential role in the cardiomyocyte response to injury by regulating chromatin accessibility changes, thereby allowing the activation of gene expression programs that promote cardiomyocyte dedifferentiation, proliferation, and protrusion into the injured area.

scholarly journals Genome-wide Chromatin Accessibility is Restricted by ANP32E

2020 ◽  
Author(s):  
Kristin E. Murphy ◽  
Fanju W. Meng ◽  
Claire E. Makowski ◽  
Patrick J. Murphy
Keyword(s):  
Gene Expression ◽  
Nucleosome Positioning ◽  
Chromatin Accessibility ◽  
Chromatin State ◽  
Start Site ◽  
Transcription Start ◽  
Genome Wide ◽  
Expression Potential ◽  
Gene Expression Levels ◽  
Hierarchical Manner

ABSTRACTGenome-wide chromatin state underlies gene expression potential and cellular function. Epigenetic features and nucleosome positioning contribute to the accessibility of DNA, but widespread regulators of chromatin state are largely unknown. Our study investigates how control of genomic H2A.Z localization by ANP32E contributes to chromatin state in mouse fibroblasts. We define H2A.Z as a universal chromatin accessibility factor, and demonstrate that through antagonism of H2A.Z, ANP32E restricts genome-wide DNA access. In the absence of ANP32E, H2A.Z accumulates at promoters in a hierarchical manner. H2A.Z initially localizes downstream of the transcription start site, and if H2A.Z is already present downstream, additional H2A.Z accumulates upstream. This hierarchical H2A.Z accumulation coincides with improved nucleosome positioning, heightened transcription factor binding, and increased expression of neighboring genes. Thus, ANP32E dramatically influences genome-wide chromatin accessibility through refinement of H2A.Z patterns, providing a means to reprogram chromatin state and to hone gene expression levels.

scholarly journals Social status alters chromatin accessibility and the gene regulatory response to glucocorticoid stimulation in rhesus macaques

2018 ◽  
Author(s):  
Noah Snyder-Mackler ◽  
Joaquín Sanz ◽  
Jordan N. Kohn ◽  
Tawni N. Voyles ◽  
Roger Pique-Regi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Regulation ◽  
Social Status ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Rhesus Macaques ◽  
Dominance Rank ◽  
Chromatin Accessibility ◽  
High Status ◽  
Cell Gene

ABSTRACTLow social status is an important predictor of disease susceptibility and mortality risk in humans and other social mammals. These effects are thought to stem in part from dysregulation of the glucocorticoid (GC)-mediated stress response. However, the molecular mechanisms that connect low social status and GC dysregulation to downstream health outcomes remain elusive. Here, we used an in vitro glucocorticoid challenge to investigate the consequences of experimentally manipulated social status (i.e., dominance rank) for immune cell gene regulation in female rhesus macaques, using paired control and GC-treated peripheral blood mononuclear cell samples. We show that social status not only influences immune cell gene expression, but also chromatin accessibility at hundreds of regions in the genome. Social status effects on gene expression were less pronounced following GC treatment than under control conditions. In contrast, social status effects on chromatin accessibility were stable across conditions, resulting in an attenuated relationship between social status, chromatin accessibility, and gene expression post-GC exposure. Regions that were more accessible in high status animals and regions that become more accessible following GC treatment were enriched for a highly concordant set of transcription factor binding motifs, including motifs for the glucocorticoid receptor co-factor AP-1. Together, our findings support the hypothesis that social status alters the dynamics of GC-mediated gene regulation, and identify chromatin accessibility as a mechanism involved in social stress-driven GC resistance. More broadly, they emphasize the context-dependent nature of social status effects on gene regulation and implicate epigenetic remodeling of chromatin accessibility as a contributing factor.

scholarly journals Poly(ADP-ribosyl)ation temporally confines SUMO-dependent ataxin-3 recruitment to control DNA double-strand break repair

2021 ◽  
pp. jcs.247809
Author(s):  
Annika Pfeiffer ◽  
Laura K. Herzog ◽  
Martijn S. Luijsterburg ◽  
Rashmi G. Shah ◽  
Magdalena B. Rother ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Time Window ◽  
Strand Break ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Dna Double Strand Break ◽  
Dna Repair Proteins ◽  
Short Time Window ◽  
Short Time

DNA damage-induced SUMOylation serves as a signal for two antagonizing proteins that both stimulate repair of DNA double strand breaks (DSBs). Here, we demonstrate that the SUMO-dependent recruitment of the deubiquitylating enzyme ataxin-3 to DSBs, unlike recruitment of the ubiquitin ligase RNF4, additionally depends on PARP1-mediated poly(ADP-ribosyl)ation (PARylation). The co-dependence of ataxin-3 recruitment on PARylation and SUMOylation temporally confines its presence at DSBs to a short time window directly following detection of the DNA damage. We propose that this mechanism ensures that ataxin-3 prevents the premature removal of DNA repair proteins only during the early phase of the DSB response and does not interfere with the subsequent timely displacement of DNA repair proteins by RNF4. Thus, our data show that PARylation differentially regulates SUMO-dependent recruitment of ataxin-3 and RNF4 to DSBs, explaining how both proteins can play a stimulatory role at DSBs despite their opposing activities.

scholarly journals A catalog of cis-regulatory mutations in 12 major cancer types

2019 ◽  
Author(s):  
Zhongshan Cheng ◽  
Michael Vermeulen ◽  
Micheal Rollins-Green ◽  
Brian DeVeale ◽  
Tomas Babak
Keyword(s):  
Gene Expression ◽  
Binding Sites ◽  
Molecular Mechanisms ◽  
Somatic Mutations ◽  
Gene Expression Regulation ◽  
Patient Survival ◽  
Chromatin Accessibility ◽  
Regulatory Mutations ◽  
Cancer Types ◽  
Affect Gene Expression

AbstractDespite the recent availability of complete genome sequences of tumors from thousands of patients, isolating disease-causing (driver) non-coding mutations from the plethora of somatic variants is notoriously challenging, and only a handful of validated examples exist. By integrating whole-genome sequencing, gene expression, chromatin accessibility, and genetic data from TCGA, we identified 301 non-coding somatic mutations that affect gene expression in cis. These mutations cluster into 36 hotspot regions with diverse molecular mechanisms of gene expression regulation. We further show that these mutations have hallmark features of noncoding drivers; namely, that they confer a positive selection on growth, functionally disrupt transcription factor binding sites, and contribute to disease progression reflected in decreased overall patient survival.

scholarly journals Genome-wide chromatin accessibility is restricted by ANP32E

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Kristin E. Murphy ◽  
Fanju W. Meng ◽  
Claire E. Makowski ◽  
Patrick J. Murphy
Keyword(s):  
Gene Expression ◽  
Nucleosome Positioning ◽  
Chromatin Accessibility ◽  
Chromatin State ◽  
Start Site ◽  
Transcription Start ◽  
Genome Wide ◽  
Expression Potential ◽  
Gene Expression Levels ◽  
Hierarchical Manner

Abstract Genome-wide chromatin state underlies gene expression potential and cellular function. Epigenetic features and nucleosome positioning contribute to the accessibility of DNA, but widespread regulators of chromatin state are largely unknown. Our study investigates how coordination of ANP32E and H2A.Z contributes to genome-wide chromatin state in mouse fibroblasts. We define H2A.Z as a universal chromatin accessibility factor, and demonstrate that ANP32E antagonizes H2A.Z accumulation to restrict chromatin accessibility genome-wide. In the absence of ANP32E, H2A.Z accumulates at promoters in a hierarchical manner. H2A.Z initially localizes downstream of the transcription start site, and if H2A.Z is already present downstream, additional H2A.Z accumulates upstream. This hierarchical H2A.Z accumulation coincides with improved nucleosome positioning, heightened transcription factor binding, and increased expression of neighboring genes. Thus, ANP32E dramatically influences genome-wide chromatin accessibility through subtle refinement of H2A.Z patterns, providing a means to reprogram chromatin state and to hone gene expression levels.

Sign in / Sign up

Export Citation Format

Share Document