Identification of target genes regulated by NANOG-HDAC1 axis
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE88965 | GEO | 2018/10/18
REPOSITORIES: GEO
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Project description:Histone deacetylase 1 (HDAC1) is an enzyme that promotes deacetylation of acetylated lysine residues in histones and other proteins. Histone acetylation is often associated with gene activation and expression. Los of HDAC1 leads to severe problems in development and proliferation. Moreover, it seems to be the major histone deacetylase in mouse embryonic stem cells. We used microarrays to identify putative HDAC1 target genes. Experiment Overall Design: Wild type and HDAC1 mouse embryonic stem cell, originating from same litter, were used for RNA extraction and hybridization on Affymetrix microarrays.
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Project description: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.
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Project description:Hdac1/2 are important epigenetic factors, yet their functional roles in specific tissues inluding lung is not determined. We used the conditional knockout model of Hdac1/2 to determine their roles in lung development. To explore the genes that are regulated by Hdac1/2 during lung development, we performed microarray analysis of Shhcre control and Hdac1/2DKO lungs at E11.5 embryos.
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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.
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