Abstract
ABSTRACTDifferent cell types exhibit distinct patterns of 3D genome organization that correlate with changes in gene expression in tissue and differentiation systems. Several tissue-specific nuclear envelope transmembrane proteins (NETs) have been found to influence the spatial positioning of genes and chromosomes that normally occurs during tissue differentiation. Here we study 3 such NETs: NET29, NET39, and NET47, which are expressed preferentially in fat, muscle and liver, respectively. We found that even when exogenously expressed in a heterologous system they can specify particular genome organization patterns and alter gene expression. Each NET affected largely different subsets of genes. Notably, the liver-specific NET47 upregulated many genes in HT1080 fibroblast cells that are normally upregulated in hepatogenesis, showing that tissue-specific NETs can favor expression patterns associated with the tissue where the NET is normally expressed. Similarly, global profiling of peripheral chromatin after exogenous expression of these NETs using lamin B1 DamID revealed that each NET affected the nuclear positioning of distinct sets of genomic regions with a significant tissue-specific component. Thus NET influences on genome organization can contribute to gene expression changes associated with differentiation even in the absence of other factors and overt cellular differentiation changes.
Highlights
The nuclear envelope (NE) contributes significantly to the 3D spatial organization of the genome.[1,2] There are 2 kinds of NE interactions with the genome: general affinity interactions of NE proteins with heterochromatin[3,4,5] and tissue-specific NE transmembrane proteins (NETs) that alter the 3D positioning of specific genes and chromosomes during differentiation.[6,7] While much work has been done on the former, the latter is relatively newly identified and so there is little understanding of the molecular mechanism for this repositioning and its consequences for gene regulation.There is no clear consensus on the general question of the relationship between gene position and expression
We tested whether the NET-induced chromosome repositioning was accompanied by gene regulation changes in the heterologous HT1080 fibroblasts where these NETs are not normally expressed
NET39 and other muscle-specific NETs recruit critical myogenic genes to the nuclear periphery during muscle differentiation, adding roughly 1/3–2/3 of their normal repression; ectopic expression of these NETs in myoblasts was still able to reposition the genes but without corresponding changes in gene expression.[6]. This suggested that repositioning occurs independently of the mechanism for gene regulation and once at the nuclear periphery some as yet unidentified aspect of the periphery combined with transcriptional regulators induced during differentiation directs the gene expression changes
Summary
The nuclear envelope (NE) contributes significantly to the 3D spatial organization of the genome.[1,2] There are 2 kinds of NE interactions with the genome: general affinity interactions of NE proteins with heterochromatin[3,4,5] and tissue-specific NE transmembrane proteins (NETs) that alter the 3D positioning of specific genes and chromosomes during differentiation.[6,7] While much work has been done on the former, the latter is relatively newly identified and so there is little understanding of the molecular mechanism for this repositioning and its consequences for gene regulation.There is no clear consensus on the general question of the relationship between gene position and expression. Some data argues that repositioning drives changes in expression[6,8,9,10] while other data argues that the activation state of the gene drives its repositioning.[11] As the general tendency is for the periphery to be a silencing environment[3,12,13] and some NETs further recruit silencing enzymes,[14,15] repositioning a gene to the periphery through a directed mechanism would in theory be followed by the acquisition of silencing marks. At the same time activation/unfolding of a gene removes epigenetically silencing marks and might lower the affinity of a locus for the periphery as some NETs exhibit affinity for silenced chromatin.[5,16] designed studies using artificial tethers yielded inconsistent results[8,10,17] while studies using tissue differentiation systems generally could not distinguish whether observed changes in expression of important repositioning genes were due to the gene repositioning or the many other changing facets of differentiation.[18,19,20,21]
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