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TRIM28 is an epigenetic barrier to induced pluripotent stem cell reprogramming

ABSTRACT: Since the discovery of induced pluripotent stem cells there has been intense interest in understanding the mechanisms that allow a somatic cell to be reprogrammed back to a pluripotent state. Several groups have studied the alterations in gene expression that occur as somatic cells modify their genome to that of an embryonic stem cell. Underpinning many of the gene expression changes are modifications to the epigenetic profile of the associated chromatin. We have used a large-scale shRNA screen to identify epigenetic modifiers that act as barriers to reprogramming. We have uncovered an important role for TRIM28 in cells resisting transition between somatic and pluripotent states. TRIM28 achieves this by maintaining the H3K9me3 repressed state and keeping endogenous retroviruses silenced. We propose that knockdown of TRIM28 during reprogramming results in more plastic H3K9me3 domains, dysregulation of genes nearby H3K9me3 marks, and up regulation of endogenous retroviruses, thus facilitating the transition through reprogramming.

ORGANISM(S): Mus musculus

PROVIDER: GSE80550 | GEO | 2016/06/28

SECONDARY ACCESSION(S): PRJNA319261

REPOSITORIES: GEO

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TRIM28 is an epigenetic barrier to induced pluripotent stem cell reprogramming

Project description:Since the discovery of induced pluripotent stem cells there has been intense interest in understanding the mechanisms that allow a somatic cell to be reprogrammed back to a pluripotent state. Several groups have studied the alterations in gene expression that occur as somatic cells modify their genome to that of an embryonic stem cell. Underpinning many of the gene expression changes are modifications to the epigenetic profile of the associated chromatin. We have used a large-scale shRNA screen to identify epigenetic modifiers that act as barriers to reprogramming. We have uncovered an important role for TRIM28 in cells resisting transition between somatic and pluripotent states. TRIM28 achieves this by maintaining the H3K9me3 repressed state and keeping endogenous retroviruses silenced. We propose that knockdown of TRIM28 during reprogramming results in more plastic H3K9me3 domains, dysregulation of genes nearby H3K9me3 marks, and up regulation of endogenous retroviruses, thus facilitating the transition through reprogramming. Gene expression profiling using high through put sequencing at day 7 of Oct4, Sox2, Klf4 and cMyc (OSKM) expression in mouse embryonic fibroblasts with or without Trim28 / Setdb1 knockdown

2016-06-28 | E-GEOD-80550 | biostudies-arrayexpress

TRIM28 silences endogenous retroviruses in neural progenitor cells

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. Analysis of upregulation of ERVs in Trim28-deficient NPCs

2015-01-07 | E-GEOD-45930 | biostudies-arrayexpress

TRIM28 silences endogenous retroviruses in neural progenitor cells

2015-01-07 | GSE45930 | GEO

Interplay of TRIM28 and DNA methylation in controlling human endogenous retroelements

Project description:Reverse transcription-derived sequences account for at least half of the human genome. Although these retroelements are formidable motors of evolution, they can occasionally cause disease, and accordingly are inactivated during early embryogenesis through epigenetic mechanisms. In the mouse, at least for endogenous retroviruses, important mediators of this process are the tetrapod-specific KRAB-containing zinc finger proteins (KRAB-ZFPs) and their cofactor TRIM28. The present study demonstrates that KRAB/TRIM28-mediated regulation is responsible for controlling a very broad range of human-specific endogenous retroelements (EREs) in human embryonic stem (ES) cells and that it exerts, as a consequence, a marked effect on the transcriptional dynamics of these cells. It further reveals reciprocal dependence between TRIM28 recruitment at specific families of EREs and DNA methylation. It finally points to the importance of persistent TRIM28-mediated control of ERE transcriptional impact beyond their presumed inactivation by DNA methylation. Analyses of epigentic effectors and marks in KAP1 WT and KD human embryonic stem cells

2014-05-29 | E-GEOD-57989 | biostudies-arrayexpress

WTX interacts with the transcriptional regulator TRIM28 to mediate cellular differentiation

Project description:WTX encodes a tumor suppressor implicated in Wilms tumor and in mesenchymal differentiation, with distinct functions in the cytoplasm, at the plasma membrane and in the nucleus. Here we report that the transcriptional corepressor TRIM28 is the major binding partner for nuclear WTX. The WTX-TRIM28 interaction supports chromatin binding by TRIM28, enhancing transcriptional silencing of some TRIM28 target sequences. In mouse ES cells, where TRIM28-mediated silencing of repetitive sequences is best characterized, Wtx knockdown similarly derepresses endogenous retroviruses and LINE elements. We performed digital gene expression (DGE) profiling using Helicos RNA sequencing. Helicos sequencing does not involve an amplification step, hence it has less bias, especially in sequencing of repetitive elements. We sequenced RNA extracted from mouse ESCs harboring GFP, Wtx or Trim28 hairpins. The resulting sequence reads were aligned with the RefSeq database as well as Repbase, which is a database for the repetitive sequences.

2015-04-16 | E-GEOD-60418 | biostudies-arrayexpress

TRIM28 and novel interacting KRAB-ZNFs preserve self-renewal of human pluripotent stem cells through H3K9me3 and DNA methylation mediated repression of pro-differentiation genes

Project description:Reprogramming to induced pluripotent stem cells (iPSCs) and differentiation of pluripotent stem cells (PSCs) are primarily regulated by epigenetic machinery. Tripartite motif protein 28 (TRIM28), a universal mediator of Krüppel-associated box domain zinc fingers (KRAB-ZNFs), is known to regulate both processes, however exact mechanism and identity of participating KRAB-ZNF genes remains unknown. Here, using a novel reporter system, we first showed that TRIM28/KRAB-ZNFs alter DNA methylation patterns in addition to H3K9me3 to cause gene repression during reprogramming. Next, using several expression datasets, we identified novel KRAB-ZNFs (ZNF114, ZNF483 and ZNF589) in the human genome that regulate pluripotency. Mechanistically, we demonstrated that these KRAB-ZNFs directly alter gene expression of important developmental genes by modulation of H3K9me3 and DNA methylation on their promoters. In summary, TRIM28 employs novel KRAB-ZNFs to evoke epigenetic silencing of its target differentiation genes by H3K9me3 and DNA methylation.

2017-11-30 | GSE97403 | GEO

WTX interacts with the transcriptional regulator TRIM28 to mediate cellular differentiation

2015-04-16 | GSE60418 | GEO

TRIM28 repression of retrotransposon-based enhancers is necessary to preserve transcriptional dynamics in embryonic stem cells

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

Co-option of endogenous retroviruses through genetic escape from TRIM28 repression

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

Interplay of TRIM28 and DNA methylation in controlling human endogenous retroelements

2014-05-29 | GSE57989 | GEO

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