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MacroH2A1 regulates the balance between self-renewal and differentiation commitment in embryonic and adult stem cells

ABSTRACT: One of the most striking epigenetic alterations that occurs at the level of the nucleosome is the complete exchange of the canonical H2A histones for the macroH2A variant. Here, we provide insight in the function of this unique histone variant in embryonic and adult stem cells. Knockdown of macroH2A1 in mouse embryonic stem (mES) cells limited their capacity to differentiate but not their self-renewal. The loss of macroH2A1 interfered with the proper activation of differentiation genes, most of which are direct target genes of macroH2A. Additionally, macroH2A1-deficient mES cells displayed incomplete inactivation of pluripotency genes and formed defective embryoid bodies. In vivo, macroH2A1-deficient teratomas contained a massive expansion of malignant, undifferentiated carcinoma tissue. In the heterogeneous culture of primary human keratinocytes, macroH2A1 levels negatively correlated with the self-renewal capacity of the pluripotent compartment. Together these results establish macroH2A1 as a critical chromatin component that regulates the delicate balance between self-renewal and differentiation of embryonic and adult stem cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE35087 | GEO | 2012/02/20

SECONDARY ACCESSION(S): PRJNA150921

REPOSITORIES: GEO

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MacroH2A1 regulates the balance between self-renewal and differentiation commitment in embryonic and adult stem cells

Project description:One of the most striking epigenetic alterations that occurs at the level of the nucleosome is the complete exchange of the canonical H2A histones for the macroH2A variant. Here, we provide insight in the function of this unique histone variant in embryonic and adult stem cells. Knockdown of macroH2A1 in mouse embryonic stem (mES) cells limited their capacity to differentiate but not their self-renewal. The loss of macroH2A1 interfered with the proper activation of differentiation genes, most of which are direct target genes of macroH2A. Additionally, macroH2A1-deficient mES cells displayed incomplete inactivation of pluripotency genes and formed defective embryoid bodies. In vivo, macroH2A1-deficient teratomas contained a massive expansion of malignant, undifferentiated carcinoma tissue. In the heterogeneous culture of primary human keratinocytes, macroH2A1 levels negatively correlated with the self-renewal capacity of the pluripotent compartment. Together these results establish macroH2A1 as a critical chromatin component that regulates the delicate balance between self-renewal and differentiation of embryonic and adult stem cells. Examination of the histone variant macroH2A1 in mouse Embryonic stem cells

2012-02-20 | E-GEOD-35087 | biostudies-arrayexpress

MacroH2A1 ChIP-chip

Project description:MacroH2A1 ChIP-chip was performed on custom Nimblegen genomic tiling arrays, to understand the genomic binding patterns of this histone variant and its relationship to gene expression Keywords: ChIP-chip Two macroH2A biological replicates are included. An H3 ChIP-chip sample is included as a control

2010-10-08 | E-GEOD-9607 | biostudies-arrayexpress

macroH2A1 ChIP-seq in G1/S phase and metaphase

Project description:The histone variant macroH2A forms large chromatin domains and serves as a transcriptional repression marker. It has been found that the overall quantity of macroH2A deposition on chromatin undergoes dynamic changes during the cell cycle. However, the genomic features relevant to these dynamic changes in macroH2A1 deposition during the cell cycle remain poorly understood. We combined ChIP‑seq and cell synchronization in mouse NIH-3T3 cells to examine the dynamic changes of macroH2A1 deposition on the genome between G1/S phase and metaphase. Interestingly, we observed that macroH2A1 deposition dynamically changes within the large macroH2A1 domain at G1/S phase and metaphase, which was associated with transcriptional activity. These dynamic changes occurring at gene bodies can specifically mark cell-cycle-specific genes. Taken together, we propose that macroH2A1 is a dynamic histone variant associated with cell-cycle-specific genes and plays a crucial role in cell-cycle-specific transcriptional repression.

2023-10-02 | GSE234016 | GEO

Expression data from macroH2A1/2 double knockout fetal mouse liver

Project description:MacroH2As core histone variants have a unique structure that includes C-terminal nonhistone domain. MacroH2As are highly conserved in vertebrates, and are thought to regulate gene expression. However the nature of genes regulated by macroH2As and the biological significance of macroH2As for the organism remain unclear. Here we examine macroH2A function in vivo by knocking out both macroH2A1 and macroH2A2 in the mouse. We used microarrays to examine how the absence of macroH2A.1 and macroH2A.2 histone variants affect gene expression late fetal mouse liver. Wild-type and macroH2A1/2 double knockout pre-implantation embryos were collected, mixed and implanted into wild-type recipient females. Livers were collected from the resultant fetuses at 18.5 days post coitum and snap frozen with liquid nitrogen. Total RNA was extracted from the livers using Trizol.

2014-10-15 | E-GEOD-57086 | biostudies-arrayexpress

Genome-wide maps of macroH2A and H2B distribution in murine embryonic fibroblasts in dependence of Lsh.

Project description:We report here the distribution of the histone variant macroH2A in murine embryonic fibroblasts derived fom Lsh-/- embryos or Lsh+/+ embryos day 14 gestation using ChIP-seq analysis. We find that macroH2A1 and macroH2A2 deposition are reduced in the absence of Lsh in contrast to H2B deposition. The study identifies Lsh as important regulator of genome wide macroH2A deposition.

2020-08-13 | GSE142082 | GEO

Expression data from macroH2A1/2 double knockout fetal mouse liver

2014-10-15 | GSE57086 | GEO

MacroH2A1 ChIP-chip from IMR90 cells

Project description:MacroH2A1 is a histone variant that is enriched on the inactive X chromosome (Xi) in mammals and is postulated to play an important, but unknown, role in the repression of gene expression. Here we show that although macroH2A1 marks repressed autosomal chromatin, it positively regulates transcription when located in the transcribed regions of many target genes. We used chromatin immunoprecipitation coupled with tiling microarrays (ChIP-chip) to determine the genomic localization of macroH2A1 in IMR90 human primary lung fibroblasts and MCF-7 breast cancer cells. The patterns of macroH2A1 deposition are largely similar across the autosomes of both cell lines. Our studies revealed a genomic localization pattern unique among histone variants, namely the occupation by macroH2A1 of large chromatin domains (>500 kb in some cases) that contain repressive chromatin marks (e.g., histone H3 lysine 27 trimethylation). The boundaries of macroH2A1-containing domains tend to occur in promoter proximal regions. Not all promoters, however, serve as macroH2A1 boundaries; many macroH2A1-containing chromatin domains invade the transcribed regions of genes whose products play key roles in development and cell-cell signaling. Surprisingly, the expression of many of these genes is positively regulated by macroH2A1. MacroH2A1 also plays a role in augmenting signal-regulated transcription, specifically for genes responsive to serum starvation. Collectively, our results document an unexpected role for macroH2A1 in the escape from heterochromatin-associated silencing and the enhancement of autosomal gene transcription. Two macroH2A1 ChIP-chip biological replicates from IMR90 human embryonic lung fibroblasts are included.

2010-06-20 | E-GEOD-18633 | biostudies-arrayexpress

Expression data from fasted macroH2A1/2 double knockout adult mouse liver

2014-10-15 | GSE57088 | GEO

macroH2A histone variants act as a barrier upon reprogramming towards pluripotency

Project description:Here we report that the histone variant macroH2A acts as a barrier to induced pluripotency. Using fibroblasts isolated from macroH2A double knockout mice, we observed enhanced reprogramming efficiency compared to fibroblasts from wild type animals. We further show that macroH2A isoforms act synergistically in this process. Genomic analysis in wild type fibroblasts reveals that macroH2A1 and H3K27me3 domains co-localize and occupy pluripotency genes. While the absence of macroH2A does not affect H3K27me3 in fibroblasts, macroH2A1 is highly enriched at a set of Utx target genes that are reactivated early during iPS reprogramming. Mononucleosomes from Dermal Fibroblasts (from wt and macroH2A1 and macroH2A2 double knockout mice) were isolated and ChIP'd with mH2A1, H3K27me3 and H3K27ac antibodies. DNA from Input and ChIP samples was purified and sequenced on Illumina's Hiseq.

2013-03-01 | E-GEOD-40813 | biostudies-arrayexpress

Histone variant macroH2A1 rewires carbohydrate and lipid metabolism of hepatocellular carcinoma cells towards cancer stem cells

Project description:We recently described the phenotype of HepG2 and Huh-7 hepatocellular carcinoma cells deleted for histone variant macroH2A1, which acquire cancer stem cell phenotype (Lo Re O et al., Hepatology 2017, PMID: 28913935). We found that short hairpin RNA-mediated macroH2A1 knockdown induces acquisition of CSC-like features, including the growth of significantly larger and less differentiated tumors when injected into nude mice. MacroH2A1-depleted HCC cells also exhibited reduced proliferation, resistance to chemotherapeutic agents, and stem-like metabolic changes consistent with enhanced hypoxic responses and increased glycolysis. As macroH2A1 is a potent transcriptional modifier we asked how KD of this histone variant might affect patterns of gene expression, and whether we could identify potential mechanistic links to the observed in vitro and in vivo HCC phenotypes. We obtained and validated an RNA-Seq dataset (Borghesan M et al., Cancer Res 2016, PMID: 26772755; Lo Re O et al., Hepatology 2017, PMID: 28913935), to conduct an unbiased comparison of the transcriptional profiles of HepG2 macroH2A1 KD cells and controls. Using a cut-off of 2 fold change, assessment of differentially expressed genes for macroH2A1 KD versus CTL showed no transcriptional overlap between the different HepG2 cell lines. Considering all differentially-expressed genes, there was significant enrichment (–log(p-value) > 1.3) in several functions and pathways that regulate pluripotency of human embryonic stem cells.

2018-07-21 | GSE117459 | GEO

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