ATRX guards against aberrant differentiation in mesenchymal progenitor cells Journal Article
| Authors: | Fang, Y.; Barrows, D.; Dabas, Y.; Carroll, T. S.; Singer, S.; Tap, W. D.; Nacev, B. A. |
| Article Title: | ATRX guards against aberrant differentiation in mesenchymal progenitor cells |
| Abstract: | Alterations in the tumor suppressor ATRX are recurrently observed in mesenchymal neoplasms. ATRX has multiple epigenetic functions including heterochromatin formation and maintenance and regulation of transcription through modulation of chromatin accessibility. Here, we show in murine mesenchymal progenitor cells (MPCs) that Atrx deficiency aberrantly activated mesenchymal differentiation programs. This includes adipogenic pathways where ATRX loss induced expression of adipogenic transcription factors and enhanced adipogenic differentiation in response to differentiation stimuli. These changes are linked to loss of heterochromatin near mesenchymal lineage genes together with increased chromatin accessibility and gains of active chromatin marks. We additionally observed depletion of H3K9me3 at transposable elements, which are derepressed including near mesenchymal genes where they could serve as regulatory elements. Finally, we demonstrated that loss of ATRX in a mesenchymal malignancy, undifferentiated pleomorphic sarcoma, results in similar epigenetic disruption and de-repression of transposable elements. Together, our results reveal a role for ATRX in maintaining epigenetic states and transcriptional repression in mesenchymal progenitors and tumor cells and in preventing aberrant differentiation in the progenitor context. © 2024 Oxford University Press. All rights reserved. |
| Keywords: | signal transduction; controlled study; protein expression; gene mutation; human cell; genetics; mouse; animal; cytology; metabolism; animals; mice; gene expression; dexamethasone; cell differentiation; immunofluorescence; genetic transfection; histone; chromatin immunoprecipitation; epigenesis, genetic; western blotting; immunoblotting; insulin; mesenchymal stem cell; gene control; real time polymerase chain reaction; glyceraldehyde 3 phosphate dehydrogenase; dna extraction; peroxisome proliferator activated receptor gamma; genetic epigenesis; histones; rna extraction; heterochromatin; mesenchymal stem cells; nucleosome; beta actin; colony formation; adipogenesis; dna transposable elements; chondrocyte; high throughput sequencing; alcian blue; troglitazone; humans; human; article; transcriptional regulator atrx; dna transposon; crispr associated endonuclease cas9; x-linked nuclear protein; fatty acid binding protein 4; atrx protein, mouse |
| Journal Title: | Nucleic Acids Research |
| Volume: | 52 |
| Issue: | 9 |
| ISSN: | 0305-1048 |
| Publisher: | Oxford University Press |
| Date Published: | 2024-05-22 |
| Start Page: | 4950 |
| End Page: | 4968 |
| Language: | English |
| DOI: | 10.1093/nar/gkae160 |
| PUBMED: | 38477352 |
| PROVIDER: | scopus |
| PMCID: | PMC11109985 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF -- Source: Scopus |
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