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Silencing of TRIM28 in human iPSC

ABSTRACT: TRIM28, a multi-domain protein, is crucial in the development of mouse embryos and the maintenance of embryonic stem cells (ESC) self-renewal potential. As the epigenetic factor modulating the structure of chromatin, TRIM28 regulates the expression of numerous genes and is associated with progression and poor prognosis in many types of cancer. IPSC served as a model of the cells with stem cell-like phenotype, e.g., cancer stem cells. We evaluated the role of TRIM28 in pluripotency maintenance in iPSC by silencing endogenous TRIM28 expression with siRNA (iPSC-siTRIM28). IPSC treated with siRNA with no target sequence served as a control (siCTRL) of the experiment. Cells lacking TRIM28 lose the expression of pluripotency markers, as well as the ability to self-renew, and they start to differentiate. Pathway enrichment analysis using Gene Ontology datasets showed significant upregulation of pathways related to apoptosis, differentiation, cellular response to DNA damage stimulus and cell cycle regulation in iPSC-siTRIM28, relative to reference iPSC (iPSC-WT and iPSC-siCTRL).

ORGANISM(S): Homo sapiens

PROVIDER: GSE153726 | GEO | 2020/07/03

REPOSITORIES: GEO

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TRIM28 regulates RNA polymerase II promoter proximal pausing and entry into processive elongation

Project description:Analysis of total PolII and Ser2-phosphorylated PolII genomic occupancy in control-transfected (WT) or Trim28-knockdown (Trim28-KD) embryonic stem cells. Embryonic stem cells were transfected with luciferase siRNA (WT) or Trim28 siRNA (Trim28 KD) in duplicate experiments. 48 hrs after transfection, cells were crosslinked with formaldehyde, collected, lysed, and chromatin was fragmented with sonication. Total PolII or Ser2-phosphorylated PolII genomic occupancy in WT or Trim28 KD cells were determined by ChIP-seq.

2014-07-28 | E-GEOD-48253 | biostudies-arrayexpress

TRIM28-Regulated Transposon Repression Is Required for Human Germline Competency and Not Primed or Naive Human Pluripotency

Project description:Transition from primed to naive pluripotency is associated with dynamic changes in transposable element (TE) expression and demethylation of imprinting control regions (ICRs). In mouse, ICR methylation and TE expression are each regulated by TRIM28; however, the role of TRIM28 in humans is less clear. Here, we show that a null mutation in TRIM28 causes significant alterations in TE expression in both the naive and primed states of human pluripotency, and phenotypically this has limited effects on self-renewal, instead causing a loss of germline competency. Furthermore, we discovered that TRIM28 regulates paternal ICR methylation and chromatin accessibility in the primed state, with no effects on maternal ICRs. Taken together, our study shows that abnormal TE expression is tolerated by self-renewing human pluripotent cells, whereas germline competency is not.

2018-01-04 | GSE99215 | GEO

TRIM28 interacts with EZH2 and SWI/SNF to activate genes that promote mammosphere formation

Project description:EZH2 is generally associated with H3K27 methylation and gene silencing. Mass spectrometry of the EZH2-interactome in MCF7 cells revealed EZH2-interactions with SWI/SNF subunits and TRIM28, which formed a complex with EZH2 distinct from PRC2. Transcriptome profiling showed that EZH2 primarily activates transcription in MCF7 cells and with TRIM28 co-regulates a set of genes associated with stem cell maintenance and poor survival of breast cancer patients. TRIM28 depletion repressed EZH2 recruitment and expression of this gene set, in parallel with decreased CD44hi/CD24lo mammosphere formation. These results support PRC2-independent functions of EZH2 and TRIM28 in mammary stem cell enrichment and maintenance.

2017-07-18 | GSE76271 | GEO

Silencing of TRIM28 in human iPSC

Project description:Silencing of TRIM28 in human iPSC

| PRJNA643817 | ENA

TRIM28-dependent SUMOylation protects the adult ovary from the male pathway (ChIP-Seq 2)

Project description:We study the role of the protein Trim28 in the maintenance of sexual identity of the adult ovary. With the help of conditional knock out (cKO) of Trim28 using the Nr5a1:Cre, we observed that deletion of the Trim28 gene in granulosa cells of the adult ovary induces their transdifferentiation into Sertoli cells, the supporting cell lineage of the testicular seminiferous tubules. FOXL2 expression has disappeared and follicles were completely remodeled into tubular structures with cells that expressed the Sertoli cell markers SOX8, SOX9 and DMRT1. Histological analysis confirmed the progressive reorganization of ovarian follicles into tubular structures and the and the transdifferentiation of granulosa cells by cells with a Sertoli cell morphology. TRIM28 acts as a SUMO-E3 ligase by interacting with the SUMO-E2 conjugating enzyme UBC9 (encoded by the Ube2i gene) via the Plant homeodomain (PHD), and can self-SUMOylate. To study in vivo the role of TRIM28-dependent SUMOylation, we generated a point mutation in exon 13 of mouse Trim28 within the PHD domain of the TRIM28 protein (C651F) that abrogates its SUMO-E3 ligase activity. We generated Trim28Phd/cKO mice (termed PHD mutant). Like in cKO ovaries, FOXL2 expression was undetectable, whereas we observed expression of the Sertoli cell markers SOX9, SOX8 and DMRT1 within structures organized in pseudo-tubules in PHD ovaries. Our results indicate that maintenance of the female pathway in the adult ovary depends on the E3-SUMO ligase activity of TRIM28.

2022-05-24 | GSE166384 | 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

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

RNA-seq of the U2OS cell line (Human Bone Osteosarcoma Epithelial Cells) treated with ZMYM2, TRIM28 or ADNP knock down against the control conditions.

Project description:In order to investigate the functions of the zinc finger transcription regulator ZMYM2 and the different types of ZMYM2 binding complex with TRIM28 or ADNP, we generated the RNA-seq data with ZMYM2, TRIM28 or ADNP siRNA in U2OS cells and the control cases with siNT in U2OS cells as well.

2023-06-01 | E-MTAB-12291 | biostudies-arrayexpress

INO80 complex in the core regulatory network governing ESC self-renewal [728_subunits]

Project description:Embryonic stem cell (ESC) self-renewal and pluripotency is controlled by the coordinated action of transcription factors and chromatin regulators. Compared to the pluripotency transcription factors, the function of the chromatin regulators, especially the ATP-dependent chromatin remodelers, remains poorly understood in ESCs. Here, we show that INO80, a SWI/SNF family chromatin remodeling complex, is essential for ESC self-renewal, pluripotency, somatic cell reprogramming, and embryonic development. Ino80, the ATPase of the complex, forms an auto-regulatory loop with the ESC master transcription factors Oct4, Nanog, and Sox2. More importantly, it co-occupies the enhancer regions of most key pluripotency genes with the master transcription factors, and positively regulates their expression by maintaining an open chromatin structure. Our data suggests that INO80 is an integral component of the pluripotency transcription network, and plays a critical role in both the maintenance and establishment of pluripotency Mouse J1 cells were transfected with non-targeting (NT), Ino80, Ino80b, Ino80c or Ino80e siRNAs, and RNA was isolated 96 hours after transfection. agent: non-targeting siRNA: Mock_1, Mock_2 agent: Ino80 siRNA: Ino80a_1, Ino80a_2 agent: Ino80b siRNA: Ino80b_1, Ino80b_2 agent: Ino80c siRNA: Ino80c_1, Ino80c_2 agent: Ino80e siRNA: Ino80e_1, Ino80e_2 cell line: mouse J1 ESC: Mock_1, Mock_2, Ino80a_1, Ino80a_2, Ino80b_1, Ino80b_2, Ino80c_1, Ino80c_2, Ino80e_1, Ino80e_2 time: 96 hours: Mock_1, Mock_2, Ino80a_1, Ino80a_2, Ino80b_1, Ino80b_2, Ino80c_1, Ino80c_2, Ino80e_1, Ino80e_2 biological replicate: Ino80a_1, Ino80a_2 biological replicate: Ino80b_1, Ino80b_2 biological replicate: Ino80c_1, Ino80c_2 biological replicate: Ino80e_1, Ino80e_2 biological replicate: Mock_1, Mock_2

2014-05-16 | E-GEOD-49251 | biostudies-arrayexpress

TRIM28 regulates RNA polymerase II promoter proximal pausing and entry into processive elongation

Project description:Analysis of total PolII and Ser2-phosphorylated PolII genomic occupancy in control-transfected (WT) or Trim28-knockdown (Trim28-KD) embryonic stem cells.

2014-07-28 | GSE48253 | GEO

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