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HDAC1 and HDAC2 regulates TGF-b during Endothelial-to-Hematopoietic Transition [RNA-Seq]

ABSTRACT: The first hematopoietic stem cells originate from hemogenic endothelium (HE), that trans-differentiate into the lumen to form hematopoietic clusters. The molecular mechanisms driving this transition are only poorly understood. Here, we present a complete and comprehensive study that shows the requirement for Transforming Growth Factor beta (Tgfbeta) signalling as the master regulator of triggering EHT from HE, including Runx1-/- HE. We employed RNA-Seq data on Hdac deficient HE, together with ChIP-Seq for HDAC1 and HDAC2 and on wild type HE that indicated its importance in EHT. We tested our findings extensively on HE derived from different sites/origin. In all instances we observed an increase in the frequency of EHT by decreasing Tgfbeta levels. Poly(A) RNA-sequencing on control and Hdac1 or Hdac2 deficient HE cells

ORGANISM(S): Mus musculus

PROVIDER: GSE101682 | GEO | 2018/04/10

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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HDAC1 and HDAC2 regulates TGF-b during Endothelial-to-Hematopoietic Transition [RNA-Seq]

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