Lysine methyltransferase 2D regulates muscle fiber size and muscle cell differentiation.
Lysine methyltransferase 2D regulates muscle fiber size and muscle cell differentiation.
复制标题
DOI：
10.1096/fj.202100823r
复制
发表时间：
2021-11
期刊：
影响因子：
--
通讯作者：
Gussoni E
中科院分区：
文献类型：
--
作者：
Wright A;Hall A;Daly T;Fontelonga T;Potter S;Schafer C;Lindsley A;Hung C;Bodamer O;Gussoni E
歌舞伎综合征（KS）是一种罕见的遗传性疾病，主要由组蛋白修饰基因KMT2D和KDM6A突变引起。这些基因在许多器官中具有广泛的时间和空间表达，导致在KS患者中观察到复杂的表型。肌张力过低是与KS相关的临床表现之一，但对KS患者骨骼肌样本的详细检查尚未见报道。我们研究了小鼠和人类肌肉中KMT2D功能丧失的后果。在小鼠中，Kmt2d的杂合缺失导致神经肌肉连接处（NMJ）周长减少，体外肌肉细胞分化减少，体内肌纤维再生受损。来自不同年龄的KS患者的肌肉样本显示肌纤维束之间散布的纤维化组织增加，这在小鼠肌肉中未见。重要的是，当Kmt2d缺陷肌肉干细胞在生理非歌舞伎环境中进行体内移植时，它们的分化潜力恢复到与对照细胞无法区分的水平。因此，由于KMT2D功能丧失引起的表观遗传变化似乎可以通过环境的改变而逆转，从而开辟了潜在的治疗途径。
Kabuki syndrome (KS) is a rare genetic disorder caused primarily by mutations in the histone modifier genes KMT2D and KDM6A. The genes have broad temporal and spatial expression in many organs, resulting in complex phenotypes observed in KS patients. Hypotonia is one of the clinical presentations associated with KS, yet detailed examination of skeletal muscle samples from KS patients has not been reported. We studied the consequences of loss of KMT2D function in both mouse and human muscles. In mice, heterozygous loss of Kmt2d resulted in reduced neuromuscular junction (NMJ) perimeter, decreased muscle cell differentiation in vitro and impaired myofiber regeneration in vivo. Muscle samples from KS patients of different ages showed presence of increased fibrotic tissue interspersed between myofiber fascicles, which was not seen in mouse muscles. Importantly, when Kmt2d‐deficient muscle stem cells were transplanted in vivo in a physiologic non‐Kabuki environment, their differentiation potential is restored to levels undistinguishable from control cells. Thus, the epigenetic changes due to loss of function of KMT2D appear reversible through a change in milieu, opening a potential therapeutic avenue.