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Histone deacetylase 1 maintains lineage integrity through histone acetylome refinement during early embryogenesis

ABSTRACT: Histone acetylation is a pivotal epigenetic modification that controls chromatin structures and regulates gene expression. It plays an essential role in modulating zygotic transcription and cell lineage specification of developing embryos. While the outcomes of many inductive signals have been described to require enzymatic activities of histone acetyltransferases and deacetylases (HDACs), the mechanisms by which HDACs confines the utilization of the zygotic genome are not well-characterized. Here, we show that histone deacetylase 1 (Hdac1) progressively binds to the zygotic genome from early blastula and onward. The recruitment of Hdac1 to the genome at the blastula stage is instructed maternally. Cis-regulatory modules (CRMs) bound by Hdac1 possess distinctive epigenetic signatures. We highlight a dual functional model of Hdac1 where Hdac1 not only sustains a histone hypoacetylation state on inactive chromatin but also participates in dynamic histone acetylation cycles on active chromatin. As a result, Hdac1 maintains differential histone acetylation states of bound CRMs between different germ layers and reinforces the transcriptional program underlying cell lineage identities both in time and space. Taken together, our study reveals a comprehensive role of Hdac1 during early vertebrate embryogenesis.

ORGANISM(S): Xenopus tropicalis

PROVIDER: GSE198378 | GEO | 2023/03/27

REPOSITORIES: GEO

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Project description:Histone deacetylases (Hdac) remove acetyl groups from proteins, influencing global and specific gene expression. Hdacs control inflammation, as shown by Hdac inhibitor-dependent protection from DSS-induced murine colitis. While tissue-specific Hdac knockouts show redundant and specific functions, little is known of their intestinal epithelial cell (IEC) role. We have shown previously that dual Hdac1/Hdac2 IEC-specific loss disrupts cell proliferation and determination, with decreased secretory cell numbers and altered barrier function. We thus investigated how compound Hdac1/Hdac2 or Hdac2 IEC-specific deficiency alters the inflammatory response. Floxed Hdac1 and Hdac2 and villin-Cre mice were interbred. Compound Hdac1/Hdac2 IEC-deficient mice showed chronic basal inflammation, with increased basal Disease Activity Index (DAI) and deregulated Reg gene colonic expression. DSS-treated dual Hdac1/Hdac2 IEC-deficient mice displayed increased DAI, histological score, intestinal permeability and inflammatory gene expression. In contrast to double knockouts, Hdac2 IEC-specific loss did not affect IEC determination and growth, nor result in chronic inflammation. However, Hdac2 disruption protected against DSS colitis, as shown by decreased DAI, intestinal permeability and caspase-3 cleavage. Hdac2 IEC-specific deficient mice displayed increased expression of IEC gene subsets, such as colonic antimicrobial Reg3b and Reg3g mRNAs, and decreased expression of immune cell function-related genes. Our data show that Hdac1 and Hdac2 are essential IEC homeostasis regulators. IEC-specific Hdac1 and Hdac2 may act as epigenetic sensors and transmitters of environmental cues and regulate IEC-mediated mucosal homeostatic and inflammatory responses. Different levels of IEC Hdac activity may lead to positive or negative outcomes on intestinal homeostasis during inflammation Total RNAs from the colon of three control and three Hdac2 IEC-specific knockout mice were isolated with the Rneasy kit (Qiagen, Mississauga, ON, Canada).

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Histone deacetylase 1 maintains lineage integrity through histone acetylome refinement during early embryogenesis

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