Ago1 controls myogenic differentiation by regulating eRNA-mediated CBP-guided epigenome reprogramming

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.

Automated summary

This study elucidates the role of Ago1 in skeletal muscle differentiation, showing that it directly controls global H3K27 acetylation and eRNA-CBP interactions to support enhancer-driven gene activation. Specifically required for MyoD and downstream myogenic gene activation, Ago1 depletion leads to failure of CBP acetyltransferase activation and blocking of the myogenic program, establishing its role in epigenome regulation and developmental programs.