Unknown,Transcriptomics,Genomics,Proteomics

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HDAC1/2 and CD4+ T cells

ABSTRACT: Dynamic changes in histone acetylation patterns are mediated by the activity of histone acetyltransfereases (HATs) and histone deacetylases (HDACs) and are key events in the epigenetic regulation of gene expression. The application of HDAC inhibitors revealed a variety of T cell functions controlled by reversible lysine acetylation and HDAC1, HDAC2, HDAC3, HDAC7 and HDAC9 have been implicated in regulating T cell development and function. Nevertheless, unique functions of individual HDAC members in T cells and specific T cell functions that are regulated by HDACs are still only poorly understood. We previously showed that T cell-specific loss of HDAC1 (using the Cd4Cre deleter strain) leads to enhanced allergic airway inflammation and increased Th2 cytokine production. Interestingly, late T cell development was not impaired in these mice. However, HDAC2 was up-regulated in the absence of HDAC1, thus we hypothesized compensatory pathways/function between these two closely related class I HDAC family members in T cells. To investigate redundant and non-redundant functions of HDAC1 and HDAC2, we generated mice with a conditional T cell-specific (using Cd4Cre) combined loss of HDAC1 and HDAC2. As part of our study, we determined and compared the transcriptome of peripheral wild-type and HDAC1/2-null CD4+ T cells. Since loss of HDAC1/HDAC2 during late T cell development led to the appearance of MHC class II-selected CD4+ helper T cells that expressed CD8 lineage genes such as Cd8a and Cd8b1, we also analyzed the transcriptome of HDAC1/2-null CD4+CD8+ T cells.

ORGANISM(S): Mus musculus

SUBMITTER: Wilfried Ellmeier

PROVIDER: E-MTAB-2184 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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).

Project description:Histone deacetylase 1 and 2 (HDAC1/2) are the core catalytic components of co-repressor complexes which modulate gene expression. In most cell types, deletion of both Hdac1 and Hdac2 is required to generate a discernible phenotype, suggesting their activity is largely redundant. We have therefore generated an embryonic stem cell (ES) line in which Hdac1 and Hdac2 can be inactivated simultaneously using a Tamoxifen inducible CreER fusion. Loss of HDAC1/2 results in a 60% reduction in total HDAC activity and a loss of cell viability. Cell death is cell cycle dependent, since differentiated, non-proliferating cells, retain their viability. Furthermore, we observe increased mitotic defects, lagging chromosomes and micronuclei, suggesting HDAC1/2 maintain chromosomal stability. Consistent with a critical role in the regulation of gene expression, microarray analysis of Hdac1/2 deleted cells reveals 1,708 differentially expressed genes. Significantly for the maintenance of stem cell self-renewal, we detected a reduction in the expression of the pluripotent transcription factors, Oct4, Nanog and Rex1. HDAC1/2 activity is regulated through binding of inositol tetraphosphate molecule [Ins(1,4,5,6)P4] (IP4) sandwiched between the HDAC and its cognate co-repressor. This raises the important question of whether the IP4 actually regulates the activity of the complex in cells. By rescuing the viability of DKO cells, we demonstrate for the first time that mutations which abolish IP4 binding reduce the activity of HDAC1/2 in vivo. Our data indicate that HDAC1/2 have a generic, but essential role in cellular proliferation and regulate stem cell self-renewal by maintaining expression of key pluripotent transcription factors. Comparative gene expression profiles of wild type (Day 0) were compared to Hdac1lox/lox, Hdac2lox/lox; CreER ES cells on days 1, 2 and 3 following for OHT treatment using the Illumina mouseWG-6 v2 expression BeadChip platform. wild type (Day 0) were compared to Hdac1lox/lox, Hdac2lox/lox; CreER ES cells on days 1, 2 and 3 following for OHT treatment. Four time points were analyzed in triplicate.

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HDAC1/2 and CD4+ T cells

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