Lamin A, Chromatin and FPLD2: Not Just a Peripheral Ménage-à-Trois

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.

The Cutting Edge: The Role of mTOR Signaling in Laminopathies

“…In FPLD2, it was observed that lamin A connection with chromatin at the nuclear periphery and in the nuclear interior could be affected and associated with tridimensional rearrangements of chromatin [ 128 ]. 3D genome models of fibroblasts from FPLD2 patients have shown a repositioning in the nuclear center of the T/Brachyury gene, a key regulator of mesodermal differentiation, an event favoring gene transcription [ 129 ].…”

The Genomic Health of Human Pluripotent Stem Cells: Genomic Instability and the Consequences on Nuclear Organization

“…With the significant changes at the nuclear lamina between the pluripotent state and the somatic/lineage situation it seems unlikely that there are not changes with respect to LADs associating with the nuclear lamina, even though they have not been revealed. Indeed, LADs can also be internally located near A-type lamins (Briand et al, 2018) and so genome organization would be expected to change substantially after the A-type lamins arrive (Figure 3).…”