Abstract
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.
Highlights
Many gene loci important for tissue functions move away from the nuclear envelope (NE) as they become activated during differentiation (Kosak et al, 2002; Williams et al, 2006; Morey et al, 2008; Szczerbal et al, 2009), whereas other genes inhibitory to differentiation move from the interior to the NE as they are shut down (Peric-Hupkes et al, 2010; Robson et al, 2016)
One study recapitulated a human developmental disorder in mice by genome deletions that disrupted the formation of local topological domains and the ability to establish long-scale enhancer–promoter interactions (Lupianez et al, 2015), whereas another found point mutations in previously unlinked Emery-Dreifuss muscular dystrophy patients occurring in muscle-specific NE transmembrane proteins (NETs) that block their function in establishing tissue-specific patterns of radial genome organization (Meinke et al, 2019)
Most of the set of 26 genes that changed both position and expression upon Tm7sf2-KO have clear liver functions, many of which impact on important metabolic pathways that can explain animal pathology, regarding cholesterol biosynthesis and insulin regulation as demonstrated here
Summary
Many gene loci important for tissue functions move away from the nuclear envelope (NE) as they become activated during differentiation (Kosak et al, 2002; Williams et al, 2006; Morey et al, 2008; Szczerbal et al, 2009), whereas other genes inhibitory to differentiation move from the interior to the NE as they are shut down (Peric-Hupkes et al, 2010; Robson et al, 2016). Overexpression of this NET in myoblasts, where these genes are normally expressed and in the nuclear interior, resulted in their recruitment to the NE in the absence of myogenesis; unlike their disrupted repositioning to the periphery in myotubes, this altered positioning did not affect Nid expression. This suggests that the full effects of changes in spatial genome organization require additional factors only present in the tissues where a particular pattern of genome organization is manifested. Several defects in the KO mice including weight gain, insulin sensitivity, and a big drop in levels of active Akt kinase correlate with genes changing in position and so are likely due to genome organization defects
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