Histone variant macroH2A1 is a stronger regulator of hippocampal transcription and memory than macroH2A2 in mice
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ABSTRACT:
PROVIDER: PRJNA614641 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11401900_1.fastq.gz | Fastqsanger.gz | |||
| SRR11401900_2.fastq.gz | Fastqsanger.gz | |||
| SRR11401901_1.fastq.gz | Fastqsanger.gz | |||
| SRR11401901_2.fastq.gz | Fastqsanger.gz | |||
| SRR11401902_1.fastq.gz | Fastqsanger.gz |
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Project description:Our work and that of others (Zovkic et al 2014 Nature, Maze et al 2015 Neuron) recently established histone variants as novel regulators of memory, whereby enrichment of H2A.Z, a variant of histone H2A, impairs memory formation. However, H2A has several structurally and functionally distinct members whose function in memory has never been studied. macroH2A (mH2A) is of special interest because it has been implicated as a risk factor for neurodegenerative diseases, particularly Huntington’s (Hu et al 2011 PNAS), but its functional role in the brain is not known. Here, we conducted ChIP sequencing against macroH2A1 (mH2A1) and macroH2A2 (mH2A2) in the mouse hippocampus and showed that both proteins are enriched on transcriptionally silent genes, suggesting that mH2A has a repressive effect on transcription in the brain. However, only mH2A1 binding was dynamically reduced during learning, such that mH2A1 removal was associated with increased gene expression in response to fear conditioning. Additionally, viral vector mediated depletion of mH2A1 protein resulted in extensive dysregulation of gene transcription, whereas mH2A2 depletion had minimal transcriptional consequences. To determine if these differential downstream transcriptomes are functionally relevant, we showed that mH2A1, but not mH2A2 depletion resulted in impaired fear memory. These results suggest that mH2A1 is required for memory and that its dynamic removal during learning promotes training-induced gene expression. In concert with our prior evidence for a suppressive effect of H2A.Z on memory, these data suggest that unique H2A variants have distinct effects on memory formation and as such, implicate altered nucleosome composition as a novel regulator of neuroplasticity.
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Project description:Chip-on-chip experiment with NT2 wildtype cells and cells treated with shRNA for macroH2A1 and macroH2A2 The goal was to determine the genome-wide occupancy of macroH2A1 and macroH2A2 at gene promoters in undifferentiated cells
2009-09-06 | GSE17531 | GEO
Project description:Histone variants H2A.Z and H3.3 are epigenetic regulators of memory, but roles of other variants are not well characterized. macroH2A (mH2A) is a structurally unique histone that contains a globular macrodomain connected to the histone region by an unstructured linker. Here we assessed if mH2A regulates memory and if this role varies for the two mH2A-encoding genes, H2afy (mH2A1) and H2afy2 (mH2A2). We show that fear memory is impaired in mH2A1, but not in mH2A2-deficient mice, whereas both groups were impaired in a non-aversive spatial memory task. However, impairment was larger for mH2A1- deficient mice, indicating a preferential role for mH2A1 over mH2A2 in memory. Accordingly, mH2A1 depletion in the mouse hippocampus resulted in more extensive transcriptional de-repression compared to mH2A2 depletion. mH2A1-depleted mice failed to induce a normal transcriptional response to fear conditioning, suggesting that mH2A1 depletion impairs memory by altering transcription. Using chromatin immunoprecipitation (ChIP) sequencing, we found that both mH2A proteins are enriched on transcriptionally repressed genes, but only mH2A1 occupancy was dynamically modified during learning, displaying reduced occupancy on upregulated genes after training. These data identify mH2A as a regulator of memory and suggest that mH2A1 supports memory by repressing spurious transcription and promoting learning-induced transcriptional activation.
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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
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.
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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 fasted adult mouse liver.
2014-10-15 | GSE57088 | GEO
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 fasted adult mouse liver. Two month old male mice were fasted overnight (~16 hours). Mice were sacrificed between 9:00 and 10:00 AM, livers were collected and snap frozen with liquid nitrogen. Total RNA was extract with Trizol (life technologies) following standard protocol.
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Project description:Our system recapitulates expected characteristics of the well characterized H3.3 histone variant, and show that we gain additional information by using a kinetic approach. Additionaly, our results on the less-studied MacroH2A2 variant revealed differential dynamic profiles of this “repressive” histone variant. Our results represent a novel approach to histone dynamics in mammalian cells, reveal unanticipated dynamic behavior of the MacroH2A2 variant in pluripotent cells, and provide a resource for future studies of tissuespecific histone dynamics in vivo.
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Project description:Our system recapitulates expected characteristics of the well characterized H3.3 histone variant, and show that we gain additional information by using a kinetic approach. Additionaly, our results on the less-studied MacroH2A2 variant revealed differential dynamic profiles of this M-bM-^@M-^\repressiveM-bM-^@M-^] histone variant. Our results represent a novel approach to histone dynamics in mammalian cells, reveal unanticipated dynamic behavior of the MacroH2A2 variant in pluripotent cells, and provide a resource for future studies of tissuespecific histone dynamics in vivo. We use a pulse-chase strategy for carrying out genome-wide measurements of histone dynamics to several histone variants in murine embryonic stem cells and somatic tissues. Genomic binding profiles of histone dynamics in normal ES cells, along with their differentiated counter parts, in MEFs, determined by ChIP-seq.
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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