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Determinants of epigenetic resistance to HDAC inhibitors in dystrophic fibro-adipogenic progenitors

ABSTRACT: Pharmacological treatment of Duchenne Muscular Dystrophy (DMD) with histone deacetylase inhibitors (HDACi) is currently tested in clinical trials; however, pre-clinical studies indicated that the beneficial effects of HDACi are restricted to early stages of disease. We show that FAPs from late-stage mdx mice exhibit aberrant HDAC activity and genome-wide alterations of histone acetylation that are not fully reversed by HDACi. In particular, combinatorial H3K27 and/or H3K9/14 hypo-acetylation at promoters of genes required for cycle activation and progression, as well as glycolysis, are associated with their downregulation in late-stage mdx FAPs. These alterations could not be reversed by HDACi, due to a general resistance to HDACi-induced H3K9/14 hyperacetylation. Conversely, H3K9/14 hyper-acetylation at promoters of Senescence Associated Secretory Phenotype (SASP) genes is associated with their upregulation in late-stage mdx FAPs; however, HDACi could reduce promoter acetylation and blunt SASP gene activation. These data reveal that during DMD progression FAPs develop disease-associated features reminiscent of cellular senescence, through epigenetically distinct and pharmacologically dissociable events. They also indicate that HDACi might retain anti-fibrotic effects at late stages of DMD.

SUBMITTER: Dr. Silvia Consalvi

PROVIDER: S-SCDT-EMBOR-2022-54721-T | biostudies-other |

REPOSITORIES: biostudies-other

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Determinants of epigenetic resistance to HDAC inhibitors in dystrophic fibro-adipogenic progenitors.

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