The role of chromatin-associated RNAi components in the nucleus of mammalian cells and in particular in the context of developmental programs remains to be elucidated. Here, we investigate the function of nuclear Argonaute 1 (Ago1) in gene expression regulation during skeletal muscle differentiation. We show that Ago1 is required for activation of the myogenic program by supporting chromatin modification mediated by developmental enhancer activation. Mechanistically, we demonstrate that Ago1 directly controls global H3K27 acetylation (H3K27ac) by regulating enhancer RNA (eRNA)-CREB-binding protein (CBP) acetyltransferase interaction, a key step in enhancer-driven gene activation. In particular, we show that Ago1 is specifically required for myogenic differentiation 1 (MyoD) and downstream myogenic gene activation, whereas its depletion leads to failure of CBP acetyltransferase activation and blocking of the myogenic program. Our work establishes a role of the mammalian enhancer-associated RNAi component Ago1 in epigenome regulation and activation of developmental programs.
Bibliographical noteKAUST Repository Item: Exported on 2022-01-27
Acknowledgements: We are grateful to Riccardo Aiese Cigliano and his team (Sequentia Biotech) for training B.F. on ChIP-seq analysis and for excellent support; Yao Wu (scientific illustrator at KAUST) for help in drawing the graphical abstract; and the KAUST Bioscience Core Lab for providing sequencing and imaging facilities. The work was supported by King Abdullah University of Science and Technology (KAUST) to V.O.
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology