The nuclear envelope protein Net39 is essential for nuclear integrity, chromatin organization, and muscle growth (RNA-Seq)

Lamins and transmembrane proteins within the nuclear envelope are regulators of nuclear structure and chromatin organization. Nuclear Envelope Transmembrane Protein 39 (Net39) is a muscle-restricted nuclear envelope protein. We show that mice lacking Net39 succumb to severe myopathy and neonatal lethality, with concomitant disruption in nuclear integrity, chromatin accessibility, gene expression and metabolism. These abnormalities resemble those of Emery-Dreifuss muscular dystrophy (EDMD), caused by mutations in A-type Lamins (LMNA) and other genes, like Emerin (EMD). We observe that Net39 is downregulated in EDMD patients, implicating Net39 in the pathogenesis of this disorder. Our findings reveal an intimate role for the nuclear envelope in maintaining muscle chromatin organization, gene expression and function, and highlight the importance of Net39 in these processes and in the molecular etiology of EDMD. Gene expression profile was generated comparing wild type (WT) and Net39 knockout(KO) mice, by deep sequencing, with three biological replicates, using Illumina HiSeq 2500. Two timepoints (9 days of age and 17 days of age) were analyzed.核纤层蛋白（Lamins）与核膜内的跨膜蛋白是核结构及染色质组织的关键调控因子。核膜跨膜蛋白39（Nuclear Envelope Transmembrane Protein 39，Net39）是一种肌肉限制性核膜蛋白。本研究证实，缺失Net39的小鼠会罹患严重肌病并出现新生儿致死表型，同时伴随核完整性、染色质开放状态、基因表达及代谢过程的紊乱。上述异常与A型核纤层蛋白（LMNA）、Emerin（EMD）等基因突变引发的Emery-Dreifuss肌营养不良（Emery-Dreifuss muscular dystrophy，EDMD）表型高度相似。我们观察到EDMD患者体内Net39表达下调，提示Net39参与了该疾病的发病机制。本研究结果揭示了核膜在维持肌肉组织染色质组织、基因表达与功能中的核心作用，并凸显了Net39在上述过程及EDMD分子病因学中的重要性。本数据集通过Illumina HiSeq 2500平台开展深度测序，以3次生物学重复对比野生型（wild type，WT）与Net39基因敲除（knockout，KO）小鼠的基因表达谱，共设置两个检测时间节点：小鼠9日龄与17日龄。