TRIM28 silences endogenous retroviruses in neural progenitor cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Adamandia Kapopoulou
PROVIDER: E-GEOD-45930 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Publications
TRIM28 represses transcription of endogenous retroviruses in neural progenitor cells.
Fasching Liana L Kapopoulou Adamandia A Sachdeva Rohit R Petri Rebecca R Jönsson Marie E ME Männe Christian C Turelli Priscilla P Jern Patric P Cammas Florence F Trono Didier D Jakobsson Johan J
Cell reports 20141224 1
TRIM28 is a corepressor that mediates transcriptional silencing by establishing local heterochromatin. Here, we show that deletion of TRIM28 in neural progenitor cells (NPCs) results in high-level expression of two groups of endogenous retroviruses (ERVs): IAP1 and MMERVK10C. We find that NPCs use TRIM28-mediated histone modifications to dynamically regulate transcription and silencing of ERVs, which is in contrast to other somatic cell types using DNA methylation. We also show that derepression ...[more]
Similar Datasets
Project description:Here we show that in neural progenitor cells (NPCs) TRIM28 silences transcription of two groups of endogenous retroviruses (ERVs): IAP1 and MMERVK10C. Derepression of ERVs in Trim28-deficient NPCs was associated with a loss of H3K9me3 and resulted in transcriptional upregulation and reverse transcription. These findings demonstrate a unique dynamic transcriptional regulation of ERVs in NPCs.
2015-01-07 | GSE45930 | GEO
Project description:Endogenous retroviruses (ERVs) have rewired host gene networks. To explore the origins of co-option, we employed an active murine ERV, IAPEz, and an embryonic stem cell (ESC) to neural progenitor cell (NPC) differentiation model. Epigenetic silencing via TRIM28 maps to a 190bp sequence encoding the IAP signal peptide, which confers retrotransposition activity. A subset of ‘escapee’ IAPs (~15%) exhibit significant genetic divergence from this sequence. Canonical repressed IAPs succumb to a previously undocumented demarcation by H3K9me3 and H3K27me3 in NPCs. Escapee IAPs, in contrast, evade epigenetic repression in both cell types, resulting in their transcriptional derepression, particularly in NPCs. We validate the enhancer function of a 47bp sequence within the U3 region of the LTR and show that escapee IAPs convey an activating effect on nearby neural genes. In sum, co-opted ERVs stem from genetic escapees that have lost vital sequences required for both TRIM28 restriction and autonomous retrotransposition.
2023-05-10 | GSE207184 | GEO
Project description:Endogenous retroviruses (ERVs) make up a large fraction of mammalian genome and are thought to contribute to human disease, including brain disorders. Aberrant activation of ERVs constitute a potential trigger for neuroinflammation, but mechanistic insight into this phenomenon remains unclear. Using CRISPR/Cas9-based gene disruption of the epigenetic co-repressor protein Trim28, we found a dynamic H3K9me3-dependent regulation of ERVs in proliferating neural progenitor cells (NPCs), but not in adult neurons. In vivo disruption of Trim28 in cortical NPCs during brain development resulted in viable offspring expressing high levels of ERVs in excitatory neurons in the adult brain of mice. Neuronal ERV expression was linked to inflammation, including activated microglia, and aggregates of ERV-derived proteins. This study demonstrates that brain development is a critical period for the silencing of ERVs and provides causal in vivo evidence demonstrating that transcriptional activation of ERV in neurons results in neuroinflammation.
2021-02-24 | GSE154196 | GEO
Project description:Endogenous retroviruses (ERVs), which make up 8% of the human genome, have been proposed to participate in the control of gene regulatory networks. In this study, we find a region- and developmental stage-specific expression pattern of ERVs in the developing human brain, which is linked to a transcriptional network based on ERVs. We demonstrate that almost ten thousand, primarily primate-specific ERVs, act as docking platforms for the epigenetic co-repressor protein TRIM28 in human neural progenitor cells, which results in the establishment of local heterochromatin. Thereby, TRIM28 represses ERVs and consequently regulates the expression of neighboring genes. These results uncover a gene regulatory network based on ERVs that participates in control of gene expression of protein-coding transcripts important for brain development.
2017-01-03 | GSE84259 | GEO
Project description:Background: MORC proteins are involved in epigenetic gene silencing in a wide variety of eukaryotic organisms. Deletion of MORCs result in several developmental abnormalities and their dysregulation has been implicated in developmental disease and multiple cancers. Specifically, mutations of mammalian MORC3 have been associated with immune system defects, Down syndrome and human cancers such as bladder, uterine, stomach, and lung cancers, and diffuse large B cell lymphomas. While previous studies have shown that MORC3 binds to H3K4me3 in vitro and overlaps with H3K4me3 ChIP-seq peaks in mouse embryonic stem cells, the mechanism by which MORC3 regulates gene expression is unknown. Results: In this study, we find that MORC3 functions as an epigenetic silencer of endogenous retroviruses (ERVs) in mouse embryonic stem cells (mESCs). Loss of MORC3 results in upregulation of ERVs, specifically those belonging to the LTR class of retrotransposons. Using ChIP-seq, we measure the genome-wide localization of MORC3 in wild-type cells and find that MORC3 binds to ERVs suggesting its direct role in regulating ERV expression. Previous studies have shown that these ERVs are marked by repressive histone mark H3K9me3 which plays a key role in their silencing. Interestingly, we find that the levels of H3K9me3 do not change substantially upon the loss of MORC3 indicating that MORC3 possibly acts downstream of the TRIM28/SETDB1 complex that deposits H3K9me3 at these loci. Instead, we discover that loss of MORC3 results in increased chromatin accessibility at the ERVs suggesting that MORC3 silences ERVs by compacting DNA in mESCs. Conclusions: Our results reveal MORC3 as a novel regulator of ERV silencing in mouse embryonic stem cells. As early mammalian development is characterized by dynamic changes in ERV expression, the role of MORC3 in silencing ERVs is exciting and could potentially explain the abnormalities observed due to its misregulation during mammalian development.
2021-10-28 | GSE173910 | GEO
Project description:Background: MORC proteins are involved in epigenetic gene silencing in a wide variety of eukaryotic organisms. Deletion of MORCs result in several developmental abnormalities and their dysregulation has been implicated in developmental disease and multiple cancers. Specifically, mutations of mammalian MORC3 have been associated with immune system defects, Down syndrome and human cancers such as bladder, uterine, stomach, and lung cancers, and diffuse large B cell lymphomas. While previous studies have shown that MORC3 binds to H3K4me3 in vitro and overlaps with H3K4me3 ChIP-seq peaks in mouse embryonic stem cells, the mechanism by which MORC3 regulates gene expression is unknown. Results: In this study, we find that MORC3 functions as an epigenetic silencer of endogenous retroviruses (ERVs) in mouse embryonic stem cells (mESCs). Loss of MORC3 results in upregulation of ERVs, specifically those belonging to the LTR class of retrotransposons. Using ChIP-seq, we measure the genome-wide localization of MORC3 in wild-type cells and find that MORC3 binds to ERVs suggesting its direct role in regulating ERV expression. Previous studies have shown that these ERVs are marked by repressive histone mark H3K9me3 which plays a key role in their silencing. Interestingly, we find that the levels of H3K9me3 do not change substantially upon the loss of MORC3 indicating that MORC3 possibly acts downstream of the TRIM28/SETDB1 complex that deposits H3K9me3 at these loci. Instead, we discover that loss of MORC3 results in increased chromatin accessibility at the ERVs suggesting that MORC3 silences ERVs by compacting DNA in mESCs. Conclusions: Our results reveal MORC3 as a novel regulator of ERV silencing in mouse embryonic stem cells. As early mammalian development is characterized by dynamic changes in ERV expression, the role of MORC3 in silencing ERVs is exciting and could potentially explain the abnormalities observed due to its misregulation during mammalian development.
2021-10-28 | GSE173915 | GEO
Project description:TRIM28 (KAP1 - KRAB-associated protein 1) is critical for the silencing of endogenous retroviruses (ERVs) in embryonic stem (ES) cells. Here, we reveal that an essential impact of this process is the protection of cellular gene expression in early embryos from perturbation by cis-acting activators contained within these genetic invaders. In TRIM28-depleted ES cells, repressive chromatin marks at ERVs are replaced by histone modifications typical of active enhancers, stimulating transcription of nearby cellular genes, notably those harboring bivalent promoters. Correspondingly, ERV-derived sequences can repress or enhance expression from an adjacent promoter in transgenic embryos depending on their TRIM28-sensitivity in ES cells. TRIM28-mediated control of ERVs is therefore crucial not just to prevent retrotransposition, but more broadly to safeguard the transcriptional dynamics of early embryos. Analyses of transcriptional profiles and chromatin state in TRIM28 WT and KO cells
2012-12-04 | E-GEOD-41903 | biostudies-arrayexpress
Project description:Background: MORC proteins are involved in epigenetic gene silencing in a wide variety of eukaryotic organisms. Deletion of MORCs result in several developmental abnormalities and their dysregulation has been implicated in developmental disease and multiple cancers. Specifically, mutations of mammalian MORC3 have been associated with immune system defects, Down syndrome and human cancers such as bladder, uterine, stomach, and lung cancers, and diffuse large B cell lymphomas. While previous studies have shown that MORC3 binds to H3K4me3 in vitro and overlaps with H3K4me3 ChIP-seq peaks in mouse embryonic stem cells, the mechanism by which MORC3 regulates gene expression is unknown. Results: In this study, we find that MORC3 functions as an epigenetic silencer of endogenous retroviruses (ERVs) in mouse embryonic stem cells (mESCs). Loss of MORC3 results in upregulation of ERVs, specifically those belonging to the LTR class of retrotransposons. Using ChIP-seq, we measure the genome-wide localization of MORC3 in wild-type cells and find that MORC3 binds to ERVs suggesting its direct role in regulating ERV expression. Previous studies have shown that these ERVs are marked by repressive histone mark H3K9me3 which plays a key role in their silencing. Interestingly, we find that the levels of H3K9me3 do not change substantially upon the loss of MORC3 indicating that MORC3 possibly acts downstream of the TRIM28/SETDB1 complex that deposits H3K9me3 at these loci. Instead, we discover that loss of MORC3 results in increased chromatin accessibility at the ERVs suggesting that MORC3 silences ERVs by compacting DNA in mESCs. Conclusions: Our results reveal MORC3 as a novel regulator of ERV silencing in mouse embryonic stem cells. As early mammalian development is characterized by dynamic changes in ERV expression, the role of MORC3 in silencing ERVs is exciting and could potentially explain the abnormalities observed due to its misregulation during mammalian development.
2021-10-28 | GSE173913 | GEO
Project description:Background: MORC proteins are involved in epigenetic gene silencing in a wide variety of eukaryotic organisms. Deletion of MORCs result in several developmental abnormalities and their dysregulation has been implicated in developmental disease and multiple cancers. Specifically, mutations of mammalian MORC3 have been associated with immune system defects, Down syndrome and human cancers such as bladder, uterine, stomach, and lung cancers, and diffuse large B cell lymphomas. While previous studies have shown that MORC3 binds to H3K4me3 in vitro and overlaps with H3K4me3 ChIP-seq peaks in mouse embryonic stem cells, the mechanism by which MORC3 regulates gene expression is unknown. Results: In this study, we find that MORC3 functions as an epigenetic silencer of endogenous retroviruses (ERVs) in mouse embryonic stem cells (mESCs). Loss of MORC3 results in upregulation of ERVs, specifically those belonging to the LTR class of retrotransposons. Using ChIP-seq, we measure the genome-wide localization of MORC3 in wild-type cells and find that MORC3 binds to ERVs suggesting its direct role in regulating ERV expression. Previous studies have shown that these ERVs are marked by repressive histone mark H3K9me3 which plays a key role in their silencing. Interestingly, we find that the levels of H3K9me3 do not change substantially upon the loss of MORC3 indicating that MORC3 possibly acts downstream of the TRIM28/SETDB1 complex that deposits H3K9me3 at these loci. Instead, we discover that loss of MORC3 results in increased chromatin accessibility at the ERVs suggesting that MORC3 silences ERVs by compacting DNA in mESCs. Conclusions: Our results reveal MORC3 as a novel regulator of ERV silencing in mouse embryonic stem cells. As early mammalian development is characterized by dynamic changes in ERV expression, the role of MORC3 in silencing ERVs is exciting and could potentially explain the abnormalities observed due to its misregulation during mammalian development.
2021-10-28 | GSE173912 | GEO
Project description:Background: MORC proteins are involved in epigenetic gene silencing in a wide variety of eukaryotic organisms. Deletion of MORCs result in several developmental abnormalities and their dysregulation has been implicated in developmental disease and multiple cancers. Specifically, mutations of mammalian MORC3 have been associated with immune system defects, Down syndrome and human cancers such as bladder, uterine, stomach, and lung cancers, and diffuse large B cell lymphomas. While previous studies have shown that MORC3 binds to H3K4me3 in vitro and overlaps with H3K4me3 ChIP-seq peaks in mouse embryonic stem cells, the mechanism by which MORC3 regulates gene expression is unknown. Results: In this study, we find that MORC3 functions as an epigenetic silencer of endogenous retroviruses (ERVs) in mouse embryonic stem cells (mESCs). Loss of MORC3 results in upregulation of ERVs, specifically those belonging to the LTR class of retrotransposons. Using ChIP-seq, we measure the genome-wide localization of MORC3 in wild-type cells and find that MORC3 binds to ERVs suggesting its direct role in regulating ERV expression. Previous studies have shown that these ERVs are marked by repressive histone mark H3K9me3 which plays a key role in their silencing. Interestingly, we find that the levels of H3K9me3 do not change substantially upon the loss of MORC3 indicating that MORC3 possibly acts downstream of the TRIM28/SETDB1 complex that deposits H3K9me3 at these loci. Instead, we discover that loss of MORC3 results in increased chromatin accessibility at the ERVs suggesting that MORC3 silences ERVs by compacting DNA in mESCs. Conclusions: Our results reveal MORC3 as a novel regulator of ERV silencing in mouse embryonic stem cells. As early mammalian development is characterized by dynamic changes in ERV expression, the role of MORC3 in silencing ERVs is exciting and could potentially explain the abnormalities observed due to its misregulation during mammalian development.
2021-10-28 | GSE173911 | GEO