Abstract
At the nuclear periphery, the genome is anchored to A- and B-type nuclear lamins in the form of heterochromatic lamina-associated domains. A-type lamins also associate with chromatin in the nuclear interior, away from the peripheral nuclear lamina. This nucleoplasmic lamin A environment tends to be euchromatic, suggesting distinct roles of lamin A in the regulation of gene expression in peripheral and more central regions of the nucleus. The hot-spot lamin A R482W mutation causing familial partial lipodystrophy of Dunnigan-type (FPLD2), affects lamin A association with chromatin at the nuclear periphery and in the nuclear interior, and is associated with 3-dimensional (3D) rearrangements of chromatin. Here, we highlight features of nuclear lamin association with the genome at the nuclear periphery and in the nuclear interior. We address recent data showing a rewiring of such interactions in cells from FPLD2 patients, and in adipose progenitor and induced pluripotent stem cell models of FPLD2. We discuss associated epigenetic and genome conformation changes elicited by the lamin A R482W mutation at the gene level. The findings argue that the mutation adversely impacts both global and local genome architecture throughout the nucleus space. The results, together with emerging new computational modeling tools, mark the start of a new era in our understanding of the 3D genomics of laminopathies.
Highlights
A Short Tale of lamina-associated domain (LAD)The periphery of the mammalian nucleus is delineated by the nuclear envelope and by subjacent domains of compact and repressed heterochromatin separated by more open and active regions in the vicinity of nuclear pores
We have recently shown that lamin A LADs mapped in fibroblasts from familial partial lipodystrophy of Dunnigan-type (FPLD2) patients with the R482W mutation and from controls with wild-type lamin A are overall conserved; yet some LADs differ between patients and controls (Paulsen et al, 2017)
The recent findings discussed here illustrate a ménage-à-trois between lamin A, chromatin and FPLD2
Summary
A Short Tale of LADsThe periphery of the mammalian nucleus is delineated by the nuclear envelope and by subjacent domains of compact and repressed heterochromatin separated by more open and active regions in the vicinity of nuclear pores. LADs represent genomic regions that interact with the nuclear lamina when mapped from cell populations using high-throughput genomic techniques (Figure 1A), yet they may dynamically anchor at, and detach from, the nuclear lamina in single cells, providing a variegated assortment of lamin-genome associations (Figure 1B). (iii) Association of chromatin-bound LAP2α with lamin A, in the nuclear interior, would provide an opportunity to distinguish between peripheral and internal lamin A LADs, through a differential analysis of LADs identified in cells containing LAP2α or depleted of LAP2α (Gesson et al, 2016).
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