Genomic loci mispositioning in Tmem120a knockout mice yields latent lipodystrophy
Genomic loci mispositioning in Tmem120a knockout mice yields latent lipodystrophy
复制标题
DOI：
10.1101/2021.04.12.439495
复制
发表时间：
2021-04
影响因子：
16.6
通讯作者：
Rafal Czapiewski;Dzmitry G. Batrakou;J. I. de las Heras;R. Carter;A. Sivakumar;M. Sliwinska;Charles R. Dixo
中科院分区：
文献类型：
--
作者：
Rafal Czapiewski;Dzmitry G. Batrakou;J. I. de las Heras;R. Carter;A. Sivakumar;M. Sliwinska;Charles R. Dixo
关于如何建立观察到的三维空间基因组组织的脂肪特异性模式知之甚少。在这里，我们报道了脂肪细胞特异性敲除编码核膜跨膜蛋白Tmem120a的基因会破坏脂肪基因组组织，从而导致脂肪营养不良综合征。Tmem120a缺乏广泛抑制脂质代谢途径基因表达，并通过基因、增强子和mirna编码位点在核外周和核内部的重新定位诱导肌源性基因表达。Tmem120a - / -小鼠，尤其是雌性小鼠，表现出与人类家族性部分脂肪营养不良FPLD2相似的脂肪营养不良综合征，在暴露于致肥性饮食后表现出严重的胰岛素抵抗和代谢缺陷。有趣的是，类似的基因组组织缺陷发生在含有编码LMNA突变的核膜蛋白的FPLD2患者的细胞中。我们的数据表明，TMEM120A基因组组织功能影响许多脂肪功能，其缺失可能导致肥胖谱系障碍，包括一种基于mirna的机制，可以解释人类脂肪营养不良中肌肉肥大的原因。很少有人知道空间基因组组织是如何指导脂肪的；然而，在脂肪形成过程中，关键的前脂肪形成基因从核膜（NE）重新定位到内部。作者发现，脂肪细胞中NE蛋白Tmem120a的缺失会破坏脂肪基因组组织，从而抑制脂质代谢途径，诱导肌源性基因表达。
Little is known about how the observed fat-specific pattern of 3D-spatial genome organisation is established. Here we report that adipocyte-specific knockout of the gene encoding nuclear envelope transmembrane protein Tmem120a disrupts fat genome organisation, thus causing a lipodystrophy syndrome. Tmem120a deficiency broadly suppresses lipid metabolism pathway gene expression and induces myogenic gene expression by repositioning genes, enhancers and miRNA-encoding loci between the nuclear periphery and interior. Tmem120a −/− mice, particularly females, exhibit a lipodystrophy syndrome similar to human familial partial lipodystrophy FPLD2, with profound insulin resistance and metabolic defects that manifest upon exposure to an obesogenic diet. Interestingly, similar genome organisation defects occurred in cells from FPLD2 patients that harbour nuclear envelope protein encoding LMNA mutations. Our data indicate TMEM120A genome organisation functions affect many adipose functions and its loss may yield adiposity spectrum disorders, including a miRNA-based mechanism that could explain muscle hypertrophy in human lipodystrophy. Little is known how spatial genome organization is directed in fat; however, key proadipogenic genes reposition from the nuclear envelope (NE) to the interior during adipogenesis. Here the authors show that deletion of NE protein Tmem120a in adipocytes disrupts fat genome organization, which results in suppression of lipid metabolism pathways and induces myogenic gene expression.