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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. 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

ORGANISM(S): Mus musculus

SUBMITTER: Denise Miles

PROVIDER: E-GEOD-80550 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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.

2016-06-28 | GSE80550 | GEO

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

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

Comparison of methylation profile of human somatic and pluripotent stem cells

2018-01-10 | GSE95096 | GEO

Hijacking of transcriptional condensates by endogenous retroviruses

Project description:Heterochromatin plays essential roles in repressing retrotransposons, e.g. endogenous retroviruses (ERVs) during mammalian development, but the contribution of retrotransposition to lethality observed in embryonic cells deficient for heterochromatin-mediated ERV repression is poorly understood. Here we report that selective degradation of the TRIM28 heterochromatin adapter protein leads to reduced association of transcriptional condensates with loci encoding super-enhancer -driven pluripotency genes in embryonic stem cells, a collapse of the pluripotency transcriptional circuit, and a pre-lethal restriction of pluripotent lineages in mouse embryos. De-repressed ERVs recruit transcriptional condensates in the absence of TRIM28, and ERV RNA facilitates condensation of RNA Polymerase II in vitro. We propose that retrotransposons contribute to the genomic distribution of nuclear condensates, and that RNA species may facilitate “hijacking” of transcriptional condensates in various developmental and disease contexts.

2022-07-08 | PXD021895 | Pride

Mus musculus

Project description:TRIM28 silences endogenous retroviruses in neural progenitor cells

| PRJNA196678 | ENA

WTX interacts with the transcriptional regulator TRIM28 to mediate cellular differentiation

2015-04-16 | GSE60418 | 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

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