RNA-seq analysis about Dot1l knocked out samples
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE201847 | GEO | 2023/07/18
REPOSITORIES: GEO
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Project description:Endogenous retroviruses (ERVs) are suppressed to maintain host genome stability and it’s regulatory mechanism remains unclear. To determine the restrain mechanism of MERVL, we knocked out Pim3 and analyzed the effect on the expression of transposable elements and coding genes. Our results show that Pim3 as a repressor of MERVL and 2-cell genes in ESCs. This study extends our understandings of the machanism by novel factors regulates MERVL.
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Project description:Endogenous retroviruses (ERVs) were usually silenced by various histone modifications on histone H3 variants and respective histone chaperones in embryonic stem cells (ESCs). However, it is still unknown whether chaperones of other histones could repress ERVs. Here, we show that H2A/H2B histone chaperone FACT plays a critical role in silencing ERVs and ERV-derived cryptic promoters in ESCs. Loss of FACT component Ssrp1 activated MERVL whereas the re-introduction of Ssrp1 rescued the phenotype. Additionally, Ssrp1 interacted with MERVL and suppressed cryptic transcription of MERVL-fused genes. Remarkably, Ssrp1 interacted with and recruited H2B deubiquitinase Usp7 to Ssrp1 target genes. Suppression of Usp7 caused similar phenotypes as loss of Ssrp1. Furthermore, Usp7 acted by deubiquitinating H2Bub and thereby repressed the expression of MERVL-fused genes. Taken together, our study uncovers a unique mechanism by which FACT complex silences ERVs and ERV-derived cryptic promoters in ESCs.
2020-08-24 | PXD017351 | Pride
Project description:Dot1l is a histone methyltransferase without a SET domain and is responsible for H3K79 methylation, which marks active transcription. In contradiction, Dot1l also participates in silencing gene expression. The target regions and mechanism of Dot1l in repressing transcription remain enigmatic. Here, we examined the possibility for Dot1l as an repressor of MERVL, which is a marker of 2-cell-like cells. Mechanistically, Dot1l interacted with and colocalized with Npm1 on MERVL, and depletion of Npm1 similarly augmented MERVL expression.
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Project description:To identify whether Dot1l or Npm1 were enriched in MERVL directly, we performed Dot1l and Npm1 ChIP-seq in wildtype ESCs. We conclude that Dot1l and Npm1 binding were enriched on MERVL-int region, suggesting a direct regulatory role of Dot1l and Npm1 on MERVL expression.
2023-07-18 | GSE201848 | GEO
Project description:Through a loss-of-function approach, we identified that inhibition of the histone methyltransferase, Dot1L, accelerated somatic cell reprogramming, significantly increased the yield of induced pluripotent stem (iPS) cell colonies, and substituted for Klf4 and c-Myc in the reprogramming cocktail. To understand the mechanism by which Dot1L inhibition results in these phenotypes, we carried out gene expression profiling using Affymetrix microarrays. GSM723207-GSM723224: Embryonic stem cell-derived fibroblasts (dH1fs) were retrovirally transduced in culture with vectors expressing either a control shRNA or an shRNA targeting Dot1L. These cells were then superinfected with either Oct4, Sox2, Klf4 and c-Myc (OSKM) retroviruses or Oct4, Sox2 and c-Myc (OSM) retroviruses. Total RNA was harvested 6 days later. There were three biologic replicates for each condition. GSM880675-GSM880682: dH1fs were treated with 10uM Dot1L inhibitor (EPZ004777) and then superinfected with Oct4, Sox2, Klf4 and c-Myc (OSKM) retroviruses. Total RNA was harvested 6 days later. There were two biologic replicates for each condition.
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Project description:Histone chaperones are responsible for the deposition and removal of histones in chromatin and critical to prevent the abnormal activation of retrotransposable elements, which can be harmful to genome stability. One of the important histone chaperones is HIRA complex, which consists of Hira, Ubn1/Ubn2, and Cabin1 and mediates the installment of H3.3-H4 to nucleosome. We studied the function of members of HIRA complex in suppressing ERVs and found that histone H3.3 are enriched on all three classes of ERVs. Different HIRA members act distinctly in silencing ERVs. Ubn2 represses Class III ERVs including MERVL and Hira mainly silences Class I and Class II ERVs. Hira is enriched on Class I and II ERVs whereas its depletion affects the recruitment of H3.3. In contrast, Ubn2 is enriched on Class III ERVs, while its depletion influences H3.3 deposition and H3K9 methylation. This study extends our understandings of the mechanism by novel factors regulates ERVs.
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Project description:Endogenous retroviruses (ERVs) are remnants of ancient parasitic viral integrations and comprise a sizable portion of the genome in most organisms. Deregulated expression of ERVs in human is associated with a plethora of disease conditions, such as cancer and neurodegeneration. Epigenetic mechanisms silence most ERVs by generating a local repressive environment (heterochromatin) to prevent their expression. However, the mechanisms controlling the fate of ERVs residing in euchromatic regions of the genome (e.g. MERVL elements) are not well understood. Here, by integrating multidimensional epigenetic and genomic analyses, we demonstrate that silencing of euchromatic MERVL elements is achieved via transcription-coupled RNA degradation. Disrupting RNA catabolism promotes RNAPII elongation from MERVL promoters, increases MERVL expression and exonization, creating novel chimeric gene isoforms, and directing embryonic stem (ES) cells toward a terminal undifferentiated state. Our results indicate that RNA catabolism is a core regulatory module of gene networks that safeguards cell identity and potency, restricts MERVL functionalization and suppresses gene birth.
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Project description:Endogenous retroviruses (ERVs) are remnants of ancient parasitic viral integrations and comprise a sizable portion of the genome in most organisms. Deregulated expression of ERVs in human is associated with a plethora of disease conditions, such as cancer and neurodegeneration. Epigenetic mechanisms silence most ERVs by generating a local repressive environment (heterochromatin) to prevent their expression. However, the mechanisms controlling the fate of ERVs residing in euchromatic regions of the genome (e.g. MERVL elements) are not well understood. Here, by integrating multidimensional epigenetic and genomic analyses, we demonstrate that silencing of euchromatic MERVL elements is achieved via transcription-coupled RNA degradation. Disrupting RNA catabolism promotes RNAPII elongation from MERVL promoters, increases MERVL expression and exonization, creating novel chimeric gene isoforms, and directing embryonic stem (ES) cells toward a terminal undifferentiated state. Our results indicate that RNA catabolism is a core regulatory module of gene networks that safeguards cell identity and potency, restricts MERVL functionalization and suppresses gene birth.
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Project description:Endogenous retroviruses (ERVs) are remnants of ancient parasitic viral integrations and comprise a sizable portion of the genome in most organisms. Deregulated expression of ERVs in human is associated with a plethora of disease conditions, such as cancer and neurodegeneration. Epigenetic mechanisms silence most ERVs by generating a local repressive environment (heterochromatin) to prevent their expression. However, the mechanisms controlling the fate of ERVs residing in euchromatic regions of the genome (e.g. MERVL elements) are not well understood. Here, by integrating multidimensional epigenetic and genomic analyses, we demonstrate that silencing of euchromatic MERVL elements is achieved via transcription-coupled RNA degradation. Disrupting RNA catabolism promotes RNAPII elongation from MERVL promoters, increases MERVL expression and exonization, creating novel chimeric gene isoforms, and directing embryonic stem (ES) cells toward a terminal undifferentiated state. Our results indicate that RNA catabolism is a core regulatory module of gene networks that safeguards cell identity and potency, restricts MERVL functionalization and suppresses gene birth.
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Project description:Endogenous retroviruses (ERVs) are remnants of ancient parasitic viral integrations and comprise a sizable portion of the genome in most organisms. Deregulated expression of ERVs in human is associated with a plethora of disease conditions, such as cancer and neurodegeneration. Epigenetic mechanisms silence most ERVs by generating a local repressive environment (heterochromatin) to prevent their expression. However, the mechanisms controlling the fate of ERVs residing in euchromatic regions of the genome (e.g. MERVL elements) are not well understood. Here, by integrating multidimensional epigenetic and genomic analyses, we demonstrate that silencing of euchromatic MERVL elements is achieved via transcription-coupled RNA degradation. Disrupting RNA catabolism promotes RNAPII elongation from MERVL promoters, increases MERVL expression and exonization, creating novel chimeric gene isoforms, and directing embryonic stem (ES) cells toward a terminal undifferentiated state. Our results indicate that RNA catabolism is a core regulatory module of gene networks that safeguards cell identity and potency, restricts MERVL functionalization and suppresses gene birth.
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