Tm7sf2 Disruption Alters Radial Gene Positioning in Mouse Liver Leading to Metabolic Defects and Diabetes Characteristics.
Tm7sf2 Disruption Alters Radial Gene Positioning in Mouse Liver Leading to Metabolic Defects and Diabetes Characteristics.
复制标题
DOI：
10.3389/fcell.2020.592573
复制
发表时间：
2020
影响因子：
5.5
通讯作者：
Schirmer EC
中科院分区：
文献类型：
--
作者：
Gatticchi L;de Las Heras JI;Sivakumar A;Zuleger N;Roberti R;Schirmer EC
放射状基因组组织的组织特异性模式有助于基因组调控，并且可以通过核膜蛋白来建立。这一领域的研究经常使用癌细胞系，目前还不清楚这些系统如何概括原代细胞或动物组织的基因组组织;因此，我们试图研究原代肝组织肝细胞中的放射状基因组组织。在这里，我们已经使用了NET 47/Tm 7sf 2-/-肝脏模型，以表明操纵这些核膜蛋白之一足以改变组织特异性基因定位和表达。在原代肝细胞中的Dam-LaminB 1全局分析表明，几乎所有处于这种位置调节下的基因都与肝功能相关/对肝功能重要。有趣的是，Tm 7sf 2是HP 1结合核膜蛋白LBR的一个部分，与Tm 7sf 2一样，LBR也具有甾醇还原的酶功能。Fmo 3基因/基因座径向错位可以与人类野生型，但不是TM 7SF 2突变体缺乏甾醇还原酶功能的救援。受影响的一个中心途径是胆固醇合成途径。在该途径中，Cyp 51和Msmo 1都受到Tm 7sf 2的位置和表达调控。Tm 7sf 2缺失的其他后果包括体重增加、胰岛素敏感性和活性Akt激酶水平降低，表明其调控下存在其他途径，其中几种是通过错位基因突出显示的。这项研究强调了组织特异性放射状基因组组织在组织功能中的重要性，以及研究动物组织和原代细胞中基因组组织的价值。
Tissue-specific patterns of radial genome organization contribute to genome regulation and can be established by nuclear envelope proteins. Studies in this area often use cancer cell lines, and it is unclear how well such systems recapitulate genome organization of primary cells or animal tissues; so, we sought to investigate radial genome organization in primary liver tissue hepatocytes. Here, we have used a NET47/Tm7sf2–/– liver model to show that manipulating one of these nuclear membrane proteins is sufficient to alter tissue-specific gene positioning and expression. Dam-LaminB1 global profiling in primary liver cells shows that nearly all the genes under such positional regulation are related to/important for liver function. Interestingly, Tm7sf2 is a paralog of the HP1-binding nuclear membrane protein LBR that, like Tm7sf2, also has an enzymatic function in sterol reduction. Fmo3 gene/locus radial mislocalization could be rescued with human wild-type, but not TM7SF2 mutants lacking the sterol reductase function. One central pathway affected is the cholesterol synthesis pathway. Within this pathway, both Cyp51 and Msmo1 are under Tm7sf2 positional and expression regulation. Other consequences of the loss of Tm7sf2 included weight gain, insulin sensitivity, and reduced levels of active Akt kinase indicating additional pathways under its regulation, several of which are highlighted by mispositioning genes. This study emphasizes the importance for tissue-specific radial genome organization in tissue function and the value of studying genome organization in animal tissues and primary cells over cell lines.