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Laminopathies Might Be Epigenetic Disorders, Researchers Suggest

NEW YORK (GenomeWeb) – An international team of researchers has suggested that laminopathies, which cause rare muscle dystrophies, may actually be epigenetic disorders.

Lamin A makes up part of the nuclear lamina, which supports the inner nuclear membrane, and mutations in the lamin A/C gene can lead to muscle dystrophies like Emery-Dreifuss muscular dystrophy (EDMD). It's also thought to help in the epigenomic regulation of chromatin at the nuclear periphery through lamina-associated domains (LADs).

As researchers led by George Washington University School of Medicine's Eric Hoffman reported today in Science Translational Medicine, those mutations disrupt the formation of heterochomatin domains that, in turn, affect the pluripotency, cell cycle, and myogenesis pathways. In EDMD patients, the researchers noted a loss of heterochromatin formation at the Sox2 locus, the overexpression of which they linked to inhibited myogenic differentiation.

"We believe that the epigenetic effects of nuclear envelope disorders provide a unifying molecular model that explains the marked range of clinical phenotypes seen with different lamin A/C missense mutations as well as the clinical phenocopies seen with other nuclear envelope proteins," Hoffman, now at SUNY Binghamton, and his colleagues wrote in their paper.

He and his colleagues extended the DamID approach to uncover euchromatic-heterochromatic transitions at the nuclear envelope during myogenesis. This involved fusing the lamin A protein harboring either the p.R453W mutation linked to EDMD or the p.R482W mutation linked to familial partial lipodystrophy (FPLD) to the bacterial DNA adenine methyltransferase (Dam). They then transduced these constructs or controls into human myogenic cells undergoing differentiation.

By coupling that with sequencing, they found that LMNA mutations affect LADs — both mutations were associated with a significant increase in the number of LADs, including mutation-specific LADs. In particular, they noted that wild-type lamin A had direct interactions with some 11,000 regions of the genome, while the mutated versions had interactions with between 19,000 loci and 21,000 loci.

This, the researchers noted, suggests that the disease-associated mutations lead to allele-specific changes to how chromatin associates with the nuclear envelope.

Further, through examining the lamin A-gene interactions, the research noted that disease-causing lamin A/C mutations led to an increased number of transcription start site-specific nuclear envelope-chromatin interactions.

The researchers confirmed these findings using ChIP-seq in mouse cells as well as using DNA methylation studies in fibroblasts obtained from a patient with an LMNA mutation.

These heterochromatic changes affected a number of cellular programs, the researchers reported. In particular, Hoffman and his colleagues found that these heterochromatin disruptions affect cell cycle programs and the exit from pluripotency.

In wild-type cells, CDK1 and RB1 — both key regulators of the cell cycle — had LAD sites, a finding the researchers said was consistent with exiting the cell cycle. These LAD sites, however, were absent in the EDMD p.R453W LMNA mutant, suggesting that abnormal heterochromatization affects cell cycle exit.

These heterochromatic changes also affected the Sox2-associated pluripotency pathways, the researchers noted. Through both DamID-seq and ChIP-seq, they found that Sox2 loci exhibited progressive gain of heterochromatin during myogenesis. However, lamin A mutations as well as the loss-of-function emerin mutations — another gene in which mutations cause EDMD — led to constant expression of the Sox2 pathway.

In patients with a gain- or change-of-function LMNA mutation or loss-of-function emerin gene mutation, Hoffman and his colleagues observed a loss of heterochromatin at the Sox2 pluripotency locus. This loss, they added, is linked with persistent mRNA expression of Sox2, and its overexpression in immortalized human myoblast cell lines inhibits myogenic differentiation.

"Together, our data suggest that, in the presence of LMNA and EMD mutations and, by extension, all nuclear envelope disorders, there is inappropriate association of heterochromatin with nuclear lamina upon differentiation," the researchers wrote. "This mishap results in three parallel events that may have a cumulative effect: slowing of exit from cell cycle (heterochromatinization of Cdk1 locus), slowing of exit from pluripotency programs (heterochromatinization of Sox2 locus), and poorly coordinated induction of terminal differentiation programs."