SMCHD1 activates the expression of genes required for the expansion of human myoblasts

被引:0
作者
Wong, Matthew Man-Kin [1 ,2 ]
Hachmer, Sarah [3 ]
Gardner, Ed [1 ,2 ]
Runfola, Valeria [4 ]
Arezza, Eric [1 ]
Megeney, Lynn A. [1 ,2 ]
Emerson Jr, Charles P. [5 ]
Gabellini, Davide [4 ]
Dilworth, F. Jeffrey [1 ,2 ,3 ,6 ]
机构
[1] Ottawa Hosp, Res Inst, Sprott Ctr Stem Cell Res, Regenerat Med Program, Ottawa, ON K1H 8L6, Canada
[2] Univ Ottawa, Dept Cellular & Mol Med, Ottawa, ON K1H 8L6, Canada
[3] Univ Wisconsin, Dept Cell & Regenerat Biol, Madison, WI 53705 USA
[4] IRCCS San Raffaele Sci Inst, Div Genet & Cell Biol, I-20132 Milan, Italy
[5] Univ Massachusetts, Chan Med Sch, Dept Neurol, Wellstone Muscular Dystrophy Program, Worcester, MA 01655 USA
[6] Stanford Univ, Dept Genet, Palo Alto, CA 94304 USA
基金
加拿大健康研究院;
关键词
FACIOSCAPULOHUMERAL MUSCULAR-DYSTROPHY; DISEASE SEVERITY; SEQ DATA; D4Z4; DOMAIN; MODEL; METHYLATION; REPRESSION; MODIFIERS; NUCLEUS;
D O I
10.1093/nar/gkae600
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
SMCHD1 is an epigenetic regulatory protein known to modulate the targeted repression of large chromatin domains. Diminished SMCHD1 function in muscle fibers causes Facioscapulohumeral Muscular Dystrophy (FSHD2) through derepression of the D4Z4 chromatin domain, an event which permits the aberrant expression of the disease-causing gene DUX4. Given that SMCHD1 plays a broader role in establishing the cellular epigenome, we examined whether loss of SMCHD1 function might affect muscle homeostasis through additional mechanisms. Here we show that acute depletion of SMCHD1 results in a DUX4-independent defect in myoblast proliferation. Genomic and transcriptomic experiments determined that SMCHD1 associates with enhancers of genes controlling cell cycle to activate their expression. Amongst these cell cycle regulatory genes, we identified LAP2 as a key target of SMCHD1 required for the expansion of myoblasts, where the ectopic expression of LAP2 rescues the proliferation defect of SMCHD1-depleted cells. Thus, the epigenetic regulator SMCHD1 can play the role of a transcriptional co-activator for maintaining the expression of genes required for muscle progenitor expansion. This DUX4-independent role for SMCHD1 in myoblasts suggests that the pathology of FSHD2 may be a consequence of defective muscle regeneration in addition to the muscle wasting caused by spurious DUX4 expression. Graphical Abstract
引用
收藏
页码:9450 / 9462
页数:13
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