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Remembering through the genome: the role of chromatin states in brain functions and diseases.

ABSTRACT: Chromatin is the physical substrate of the genome that carries the DNA sequence and ensures its proper functions and regulation in the cell nucleus. While a lot is known about the dynamics of chromatin during programmed cellular processes such as development, the role of chromatin in experience-dependent functions remains not well defined. Accumulating evidence suggests that in brain cells, environmental stimuli can trigger long-lasting changes in chromatin structure and tri-dimensional (3D) organization that can influence future transcriptional programs. This review describes recent findings suggesting that chromatin plays an important role in cellular memory, particularly in the maintenance of traces of prior activity in the brain. Inspired by findings in immune and epithelial cells, we discuss the underlying mechanisms and the implications for experience-dependent transcriptional regulation in health and disease. We conclude by presenting a holistic view of chromatin as potential molecular substrate for the integration and assimilation of environmental information that may constitute a conceptual basis for future research.

SUBMITTER: Arzate-Mejia RG

PROVIDER: S-EPMC10090084 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Remembering through the genome: the role of chromatin states in brain functions and diseases.

Arzate-Mejia Rodrigo G RG Mansuy Isabelle M IM

Translational psychiatry 20230411 1

Chromatin is the physical substrate of the genome that carries the DNA sequence and ensures its proper functions and regulation in the cell nucleus. While a lot is known about the dynamics of chromatin during programmed cellular processes such as development, the role of chromatin in experience-dependent functions remains not well defined. Accumulating evidence suggests that in brain cells, environmental stimuli can trigger long-lasting changes in chromatin structure and tri-dimensional (3D) org ...[more]

PMID: 37041131

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Project description:Advances in genomic studies have led to significant progress in understanding the epigenetically controlled interplay between chromatin structure and nuclear functions. Epigenetic modifications were shown to play a key role in transcription regulation and genome activity during development and differentiation or in response to the environment. Paradoxically, the molecular mechanisms that regulate the initiation and the maintenance of the spatio-temporal replication program in higher eukaryotes, and in particular their links to epigenetic modifications, still remain elusive. By integrative analysis of the genome-wide distributions of thirteen epigenetic marks in the human cell line K562, at the 100 kb resolution of corresponding mean replication timing (MRT) data, we identify four major groups of chromatin marks with shared features. These states have different MRT, namely from early to late replicating, replication proceeds though a transcriptionally active euchromatin state (C1), a repressive type of chromatin (C2) associated with polycomb complexes, a silent state (C3) not enriched in any available marks, and a gene poor HP1-associated heterochromatin state (C4). When mapping these chromatin states inside the megabase-sized U-domains (U-shaped MRT profile) covering about 50% of the human genome, we reveal that the associated replication fork polarity gradient corresponds to a directional path across the four chromatin states, from C1 at U-domains borders followed by C2, C3 and C4 at centers. Analysis of the other genome half is consistent with early and late replication loci occurring in separate compartments, the former correspond to gene-rich, high-GC domains of intermingled chromatin states C1 and C2, whereas the latter correspond to gene-poor, low-GC domains of alternating chromatin states C3 and C4 or long C4 domains. This new segmentation sheds a new light on the epigenetic regulation of the spatio-temporal replication program in human and provides a framework for further studies in different cell types, in both health and disease.

Project description:BackgroundThe functional annotation of genomes, including chromatin accessibility and modifications, is important for understanding and effectively utilizing the increased amount of genome sequences reported. However, while such annotation has been well explored in a diverse set of tissues and cell types in human and model organisms, relatively little data are available for livestock genomes, hindering our understanding of complex trait variation, domestication, and adaptive evolution. Here, we present the first complete global landscape of regulatory elements in cattle and explore the dynamics of chromatin states in rumen epithelial cells induced by the rumen developmental regulator-butyrate.ResultsWe established the first global map of regulatory elements (15 chromatin states) and defined their coordinated activities in cattle, through genome-wide profiling for six histone modifications, RNA polymerase II, CTCF-binding sites, DNA accessibility, DNA methylation, and transcriptome in rumen epithelial primary cells (REPC), rumen tissues, and Madin-Darby bovine kidney epithelial cells (MDBK). We demonstrated that each chromatin state exhibited specific enrichment for sequence ontology, transcription, methylation, trait-associated variants, gene expression-associated variants, selection signatures, and evolutionarily conserved elements, implying distinct biological functions. After butyrate treatments, we observed that the weak enhancers and flanking active transcriptional start sites (TSS) were the most dynamic chromatin states, occurred concomitantly with significant alterations in gene expression and DNA methylation, which was significantly associated with heifer conception rate and stature economic traits.ConclusionOur results demonstrate the crucial role of functional genome annotation for understanding genome regulation, complex trait variation, and adaptive evolution in livestock. Using butyrate to induce the dynamics of the epigenomic landscape, we were able to establish the correlation among nutritional elements, chromatin states, gene activities, and phenotypic outcomes.

Dataset Information

Remembering through the genome: the role of chromatin states in brain functions and diseases.

Publications

Remembering through the genome: the role of chromatin states in brain functions and diseases.

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