ATRX guards against aberrant differentiation in mesenchymal progenitor cells

Alterations in the tumor suppressor ATRX are recurrently observed in several cancer types including sarcomas, which are 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 (Pparγ and Cebpα) 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 at putative enhancer elements and promoters. Finally, we observed depletion of H3K9me3 at transposable elements, which are derepressed including near mesenchymal genes where they could serve as regulatory elements. Our results demonstrate that ATRX functions to buffer against differentiation in mesenchymal progenitor cells, which has implications for understanding ATRX loss of function in sarcomas.