Chromatin state transition underlies the temporal changes in gene expression during cardiomyocyte maturation

Congenital heart disease (CHD) is often rooted in aberrant gene expression during heart development. As cells commit to a specific lineage during development, chromatin dynamics and developmental plasticity generally become more limited. However, it remains unclear how differentiated cardiomyocytes (CMs) undergo morphological and functional adaptations to the postnatal environment during the process of CM maturation. We sought to investigate the regulatory mechanisms that control postnatal cardiac gene networks. A time-series transcriptomic analysis of postnatal hearts revealed an integrated, time-ordered transcriptional network that regulates CM maturation. Remarkably, depletion of histone H2B ubiquitin ligase RNF20 after formation of the four-chamber heart disrupted these highly coordinated gene networks. As such, its ablation caused early-onset cardiomyopathy, a phenotype reminiscent of CHD. Furthermore, the dynamic modulation of chromatin accessibility by RNF20 during CM maturation was necessary for the operative binding of cardiac transcription factors that drive transcriptional gene networks. Together, our results reveal how epigenetic-mediated chromatin state transitions modulate time-ordered gene expression for CM maturation.

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Myocardin Marks the Earliest Cardiac Gene Expression and Plays an Important Role in Heart Development

The Anatomical Record ◽

10.1002/ar.20756 ◽

2008 ◽

Vol 291 (10) ◽

pp. 1200-1211 ◽

Cited By ~ 8

Author(s):

Jian-Fu Chen ◽

Shusheng Wang ◽

Qiulian Wu ◽

Dongsun Cao ◽

Thiha Nguyen ◽

...

Keyword(s):

Gene Expression ◽

Heart Development ◽

Cardiac Gene Expression ◽

Cardiac Gene

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An atlas of dynamic chromatin landscapes in mouse fetal development

Nature ◽

10.1038/s41586-020-2093-3 ◽

2020 ◽

Vol 583 (7818) ◽

pp. 744-751 ◽

Cited By ~ 13

Author(s):

David U. Gorkin ◽

Iros Barozzi ◽

Yuan Zhao ◽

Yanxiao Zhang ◽

Hui Huang ◽

...

Keyword(s):

Fetal Development ◽

Target Genes ◽

Developmental Stages ◽

Chromatin Accessibility ◽

Chromatin State ◽

Mammalian Development ◽

Mouse Fetus ◽

Chromatin Dynamics ◽

Mouse Tissues ◽

Genomic Resource

AbstractThe Encyclopedia of DNA Elements (ENCODE) project has established a genomic resource for mammalian development, profiling a diverse panel of mouse tissues at 8 developmental stages from 10.5 days after conception until birth, including transcriptomes, methylomes and chromatin states. Here we systematically examined the state and accessibility of chromatin in the developing mouse fetus. In total we performed 1,128 chromatin immunoprecipitation with sequencing (ChIP–seq) assays for histone modifications and 132 assay for transposase-accessible chromatin using sequencing (ATAC–seq) assays for chromatin accessibility across 72 distinct tissue-stages. We used integrative analysis to develop a unified set of chromatin state annotations, infer the identities of dynamic enhancers and key transcriptional regulators, and characterize the relationship between chromatin state and accessibility during developmental gene regulation. We also leveraged these data to link enhancers to putative target genes and demonstrate tissue-specific enrichments of sequence variants associated with disease in humans. The mouse ENCODE data sets provide a compendium of resources for biomedical researchers and achieve, to our knowledge, the most comprehensive view of chromatin dynamics during mammalian fetal development to date.

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Effective Dynamics of Nucleosome Configurations at the Yeast PHO5 Promoter

10.1101/2020.05.02.072470 ◽

2020 ◽

Author(s):

Michael Roland Wolff ◽

Andrea Schmid ◽

Philipp Korber ◽

Ulrich Gerland

Keyword(s):

Single Molecule ◽

Chromatin Accessibility ◽

State Transitions ◽

Chromatin Dynamics ◽

New Class ◽

Nucleosome Dynamics ◽

Effective Dynamics ◽

Global And Local ◽

Chromatin Opening

AbstractChromatin dynamics are mediated by remodeling enzymes and play crucial roles in gene regulation, as established in a paradigmatic model, the yeast PHO5 promoter. However, effective nucleosome dynamics, i.e. trajectories of promoter nucleosome configurations, remain elusive. Here, we infer such dynamics from the integration of published single-molecule data that capture multi-nucleosome configurations for repressed to fully active PHO5 promoter states with other existing histone turnover and new chromatin accessibility data. We devised and systematically investigated a new class of “regulated on-off-slide” models simulating global and local nucleosome (dis)assembly and sliding. Only seven of 68 145 models agreed well with all data. All seven models involve sliding and the known central role of the N-2 nucleosome, but regulate promoter state transitions by modulating just one assembly rather than disassembly process. This is consistent with but challenges common interpretations of previous observations at the PHO5 promoter and suggests chromatin opening by binding competitions.

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Improved single-cell ATAC-seq reveals chromatin dynamics of in vitro corticogenesis

10.1101/637256 ◽

2019 ◽

Cited By ~ 5

Author(s):

Ryan M. Mulqueen ◽

Brooke A. DeRosa ◽

Casey A. Thornton ◽

Zeynep Sayar ◽

Kristof A. Torkenczy ◽

...

Keyword(s):

Single Cell ◽

Gene Networks ◽

Regulatory Gene ◽

Regulatory Elements ◽

Chromatin Accessibility ◽

Chromatin Dynamics ◽

Cell Library ◽

Fate Decision

AbstractDevelopment is a complex process that requires the precise modulation of regulatory gene networks controlled through dynamic changes in the epigenome. Single-cell-omic technologies provide an avenue for understanding the mechanisms of these processes by capturing the progression of epigenetic cell states during the course of cellular differentiation using in vitro or in vivo models1. However, current single-cell epigenomic methods are limited in the information garnered per individual cell, which in turn limits their ability to measure chromatin dynamics and state shifts. Single-cell combinatorial indexing (sci-) has been applied as a strategy for identifying single-cell-omic originating libraries and removes the necessity of single-cell, single-compartment chemistry2. Here, we report an improved sci-assay for transposase accessible chromatin by sequencing (ATAC-seq), which utilizes the small molecule inhibitor Pitstop 2™ (scip-ATAC-seq)3. We demonstrate that these improvements, which theoretically could be applied to any in situ transposition method for single-cell library preparation, significantly increase the ability of transposase to enter the nucleus and generate highly complex single-cell libraries, without altering biological signal. We applied sci-ATAC-seq and scip-ATAC-seq to characterize the chromatin dynamics of developing forebrain-like organoids, an in vitro model of human corticogenesis4. Using these data, we characterized novel putative regulatory elements, compared the epigenome of the organoid model to human cortex data, generated a high-resolution pseudotemporal map of chromatin accessibility through differentiation, and measured epigenomic changes coinciding with a neurogenic fate decision point. Finally, we combined transcription factor motif accessibility with gene activity (GA) scores to directly observe the dynamics of complex regulatory programs that regulate neurogenesis through developmental pseudotime. Overall, scip-ATAC-seq increases information content per cell and bolsters the potential for future single-cell studies into complex developmental processes.

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Analysis of the SWI/SNF chromatin-remodeling complex during early heart development and BAF250a repression cardiac gene transcription during P19 cell differentiation

Nucleic Acids Research ◽

10.1093/nar/gkt1232 ◽

2013 ◽

Vol 42 (5) ◽

pp. 2958-2975 ◽

Cited By ~ 22

Author(s):

Ajeet Pratap Singh ◽

Trevor K. Archer

Keyword(s):

Gene Expression ◽

Cell Differentiation ◽

Chromatin Remodeling ◽

Heart Development ◽

Molecular Mechanisms ◽

Gene Expression Regulation ◽

Affinity Purification ◽

Specific Gene ◽

Nucleosome Remodeling ◽

Cardiac Gene

Abstract The regulatory networks of differentiation programs and the molecular mechanisms of lineage-specific gene regulation in mammalian embryos remain only partially defined. We document differential expression and temporal switching of BRG1-associated factor (BAF) subunits, core pluripotency factors and cardiac-specific genes during post-implantation development and subsequent early organogenesis. Using affinity purification of BRG1 ATPase coupled to mass spectrometry, we characterized the cardiac-enriched remodeling complexes present in E8.5 mouse embryos. The relative abundance and combinatorial assembly of the BAF subunits provides functional specificity to Switch/Sucrose NonFermentable (SWI/SNF) complexes resulting in a unique gene expression profile in the developing heart. Remarkably, the specific depletion of the BAF250a subunit demonstrated differential effects on cardiac-specific gene expression and resulted in arrhythmic contracting cardiomyocytes in vitro. Indeed, the BAF250a physically interacts and functionally cooperates with Nucleosome Remodeling and Histone Deacetylase (NURD) complex subunits to repressively regulate chromatin structure of the cardiac genes by switching open and poised chromatin marks associated with active and repressed gene expression. Finally, BAF250a expression modulates BRG1 occupancy at the loci of cardiac genes regulatory regions in P19 cell differentiation. These findings reveal specialized and novel cardiac-enriched SWI/SNF chromatin-remodeling complexes, which are required for heart formation and critical for cardiac gene expression regulation at the early stages of heart development.

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Chromatin Dynamics and Gene Expression Response to Heat Exposure in Field-Conditioned versus Laboratory-Cultured Nematostella vectensis

International Journal of Molecular Sciences ◽

10.3390/ijms22147454 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7454

Author(s):

Eviatar Weizman ◽

Mieka Rinsky ◽

Noa Simon-Blecher ◽

Sarit Lampert-Karako ◽

Orly Yaron ◽

...

Keyword(s):

Gene Expression ◽

Acid Metabolism ◽

Heat Exposure ◽

Chromatin Accessibility ◽

Nematostella Vectensis ◽

Rna Seq ◽

Short Term ◽

Gene Expression Response ◽

Chromatin Dynamics ◽

Expression Response

Organisms’ survival is associated with the ability to respond to natural or anthropogenic environmental stressors. Frequently, these responses involve changes in gene regulation and expression, consequently altering physiology, development, or behavior. Here, we present modifications in response to heat exposure that mimics extreme summertime field conditions of lab-cultured and field-conditioned Nematostella vectensis. Using ATAC-seq and RNA-seq data, we found that field-conditioned animals had a more concentrated reaction to short-term thermal stress, expressed as enrichment of the DNA repair mechanism pathway. By contrast, lab animals had a more diffuse reaction that involved a larger number of differentially expressed genes and enriched pathways, including amino acid metabolism. Our results demonstrate that pre-conditioning affects the ability to respond efficiently to heat exposure in terms of both chromatin accessibility and gene expression and reinforces the importance of experimentally addressing ecological questions in the field.

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

10.1101/2021.11.05.467475 ◽

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.

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Genome-wide Chromatin Accessibility is Restricted by ANP32E

10.1101/2020.09.08.288241 ◽

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.

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Defining chromatin state transitions predicts a network that modulates cell wall remodeling in phosphate-starved rice shoots

10.1101/706507 ◽

2019 ◽

Author(s):

Maryam Foroozani ◽

Sara Zahraeifard ◽

Dong-Ha Oh ◽

Guannan Wang ◽

Maheshi Dassanayake ◽

...

Keyword(s):

Cell Wall ◽

Transcription Start Site ◽

Chromatin Structure ◽

Differentially Expressed ◽

Chromatin State ◽

State Transitions ◽

Start Site ◽

Transcription Start ◽

Chromatin Dynamics ◽

Combining Data

AbstractPhosphorus (P) is an essential plant macronutrient vital to fundamental metabolic processes. Plant-available P is low in most soils, making it a frequent limiter of growth. Declining P reserves for fertilizer production exasperates this agricultural challenge. Plants modulate complex responses to fluctuating P levels via global transcriptional regulatory networks. Although chromatin structure plays a substantial role in controlling gene expression, the chromatin dynamics involved in regulating P homeostasis have not been determined. Here we define distinct chromatin states across the rice genome by integrating multiple aspects of chromatin structure, including the H2A.Z histone variant, H3K4me3 modification, and nucleosome positioning. In response to P starvation, 40% of all protein-coding genes exhibit a transition from one chromatin state to another at their transcription start site. Several of these transitions are enriched in subsets of genes differentially expressed by P deficiency. The most prominent subset supports the presence of a coordinated signaling network that targets cell wall structure and is regulated in part via a decrease of H3K4me3 at the transcription start site. The P-starvation induced chromatin dynamics and correlated genes identified here will aid in enhancing P-use efficiency in crop plants, benefitting global agriculture.One sentence summaryCombining data for three components of chromatin structure from control and phosphate-starved rice shoots reveals specific chromatin state transitions that correlate with subsets of functionally distinct differentially-expressed genes.

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The zinc finger proteins Pannier and GATA4 function as cardiogenic factors in Drosophila

Development ◽

10.1242/dev.126.24.5679 ◽

1999 ◽

Vol 126 (24) ◽

pp. 5679-5688 ◽

Cited By ~ 4

Author(s):

K. Gajewski ◽

N. Fossett ◽

J.D. Molkentin ◽

R.A. Schulz

Keyword(s):

Gene Expression ◽

Cell Fate ◽

Zinc Finger ◽

Heart Development ◽

Ectopic Expression ◽

Cell Formation ◽

Homeodomain Protein ◽

Gata Factor ◽

Cardiac Gene Expression ◽

Cardiac Gene

The regulation of cardiac gene expression by GATA zinc finger transcription factors is well documented in vertebrates. However, genetic studies in mice have failed to demonstrate a function for these proteins in cardiomyocyte specification. In Drosophila, the existence of a cardiogenic GATA factor has been implicated through the analysis of a cardial cell enhancer of the muscle differentiation gene D-mef2. We show that the GATA gene pannier is expressed in the dorsal mesoderm and required for cardial cell formation while repressing a pericardial cell fate. Ectopic expression of Pannier results in cardial cell overproduction, while co-expression of Pannier and the homeodomain protein Tinman synergistically activate cardiac gene expression and induce cardial cells. The related GATA4 protein of mice likewise functions as a cardiogenic factor in Drosophila, demonstrating an evolutionarily conserved function between Pannier and GATA4 in heart development.

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