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Skeletal muscle stem cells (also called satellite cells, SCs) are important for maintaining muscle tissue homeostasis and damage-induced regeneration. However, it remains poorly understood how SCs enter cell cycle to become activated upon injury. Here we report that AP-1 family member ATF3 (Activating Transcription Factor 3) prevents SC premature activation. Atf3 is rapidly and transiently induced in SCs upon activation. Short-term deletion of Atf3 in SCs accelerates acute injury-induced regeneration, however, its long-term deletion exhausts the SC pool and thus impairs muscle regeneration. The Atf3 loss also provokes SC activation during voluntary exercise and enhances the activation during endurance exercise. Mechanistically, ATF3 directly activates the transcription of Histone 2B genes, whose reduction accelerates nucleosome displacement and gene transcription required for SC activation. Finally, the ATF3-dependent H2B expression also prevents genome instability and replicative senescence in SCs. Therefore, this study has revealed a previously unknown mechanism for preserving the SC population by actively suppressing precocious activation, in which ATF3 is a key regulator.
Suyang Zhang*, Feng Yang, Yile Huang, Liangqiang He, Yuying Li, Yi Ching Esther Wan, Yingzhe Ding, Kui Ming Chan, Ting Xie, Hao Sun & Huating Wang*
Nature Communications 10.1038/s41467-023-40465-w
Little is known about three-dimensional (3D) genome organization in skeletal muscle stem cells [also called satellite cells (SCs)]. Here, we comprehensively map the 3D genome topology reorganization during mouse SC lineage progression. Specifically, rewiring at the compartment level is most pronounced when SCs become activated. Marked loss in topologically associating domain (TAD) border insulation and chromatin looping also occurs during early activation process. Meanwhile, TADs can form TAD clusters and super-enhancer–containing TAD clusters orchestrate stage-specific gene expression. Furthermore, we uncover that transcription factor PAX7 is pivotal in enhancer-promoter (E-P) loop formation. We also identify cis-regulatory elements that are crucial for local chromatin organization at Pax7 locus and Pax7 expression. Lastly, we unveil that geriatric SC displays a prominent gain in long-range contacts and loss of TAD border insulation. Together, our results uncover that 3D chromatin extensively reorganizes at multiple architectural levels and underpins the transcriptome remodeling during SC lineage development and SC aging.
YU ZHAO*, YINGZHE DING*, LIANGQIANG HE*, QIN ZHOU, XIAONA CHEN, YUYING LI, MARIA VITTORIA ALFONSI, ZHENGUO WU, HAO SUN, HUATING WANG*
Science Advances 10.1126/sciadv.abo1360