Deciphering chromatin accessibility changes during muscle stem cell quiescence exit and lineage progression

Abstract

Epigenetics regulation plays a critical role in determining cell identity by controlling the accessibility of lineage-specific regulatory regions. In muscle stem cells, epigenetic mechanisms of how chromatin accessibility is modulated during muscle stem cell quiescence exit and lineage progression are not fully understood. Here, we identied a long noncoding RNA, LncMyoD, which functions as a chromatin modulator for myogenic lineage determination and progression. The depletion of LncMyoD in muscle stem cells led to the downregulation of myogenic genes and defects in myogenic differentiation. LncMyoD exclusively binds with MyoD and not other myogenic regulatory factors and promotes transactivation of target genes. The mechanistic study revealed that loss of LncMyoD prevents the establishment of a permissive chromatin environment at myogenic E-box{containing regions, therefore restricts the binding of MyoD. Furthermore, the depletion of LncMyoD strongly impairs the reprogramming of fibroblasts into the myogenic lineage. We further investigated the trajectory of chromatin accessibility changes during muscle stem cell quiescence exit. The results showed that the chromatin structure of muscle stem cells changes dramatically within the first 30 min after injury-induced activation and muscle stem cells establish the most accessible chromatin at 4 hours post-injury. We also identified potential Pax7 enhancers which may be involved in maintaining the quiescent state of muscle stem cells. Taken together, our study showed the dramatic changes of chromatin accessibility during muscle stem cells quiescence exit and lineage progression and found a MyoD-associated lncRNA, LncMyoD, that promotes myogenic gene expression through modulating MyoD accessibility to chromatin to regulate myogenic lineage determination and progression.

Date of Award	2021
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology
Supervisor	Tom CHEUNG (Supervisor)