Remodeling the epigenome and (epi)cytoskeleton: a new paradigm for co-regulation by methylation

Abstract

The epigenome determines heritable patterns of gene expression in the absence of changes in DNA sequence. The result is programming of different cellular-, tissue- and organ-specific phenotypes from a single organismic genome. Epigenetic marks that comprise the epigenome (e.g. methylation) are placed upon or removed from chromatin (histones and DNA) to direct the activity of effectors that regulate gene expression and chromatin structure. Recently, the cytoskeleton has been identified as a second target for the cell's epigenetic machinery. Several epigenetic ‘readers, writers and erasers’ that remodel chromatin have been discovered to also remodel the cytoskeleton, regulating structure and function of microtubules and actin filaments. This points to an emerging paradigm for dual-function remodelers with ‘chromatocytoskeletal’ activity that can integrate cytoplasmic and nuclear functions. For example, the SET domain-containing 2 methyltransferase (SETD2) has chromatocytoskeletal activity, methylating both histones and microtubules. The SETD2 methyl mark on chromatin is required for efficient DNA repair, and its microtubule methyl mark is required for proper chromosome segregation during mitosis. This unexpected convergence of SETD2 activity on histones and microtubules to maintain genomic stability suggests the intriguing possibility of an expanded role in the cell for chromatocytoskeletal proteins that read, write and erase methyl marks on the cytoskeleton as well as chromatin. Coordinated use of methyl marks to remodel both the epigenome and the (epi)cytoskeleton opens the possibility for integrated regulation (which we refer to as ‘epiregulation’) of other higher-level functions, such as muscle contraction or learning and memory, and could even have evolutionary implications.

Ezh2 harnesses the intranuclear actin cytoskeleton to remodel chromatin in differentiating Th cells

“…More generally, these findings can provide a proof-of-concept for the way by which the epigenetic machinery harnesses the dynamic mechanical force of the intranuclear actin-skeleton to execute chromatin remodeling. This idea is strengthen by the fact that other epigenetic “readers”, “writers” and “erasers” have been discovered with the ability to remodel actin and microtubule filaments in the cytoplasm (“chromatocytoskeletal” activity) ( Walker and Burggren, 2020 ). It is also possible that the globular actin and actin related proteins function as epigenetic signatures that provide F-actin with nucleation spots and determine heritable patterns of gene expression in proliferating cells.…”

The PI3K/mTOR Pathway Is Targeted by Rare Germline Variants in Patients with Both Melanoma and Renal Cell Carcinoma

“…The common biological pathways highlighted by our results suggest possible shared co-susceptibility to CMM and RCC and possibly other cancers, like that underlaid by the BAP1 gene. Indeed, candidate genes involved in maintaining genome stability, such as RAE1 , SETD2, and CLTCL1 [ 105 , 106 , 107 ], are attractive candidates for broad cancer susceptibility. Germline mutations in genome integrity keepers have long been recognized as a direct cause of increased cancer risk, as extensively demonstrated in breast cancer [ 108 ] as well as cancer-predisposing syndromes [ 109 ].…”

The lysine methyltransferase SETD2 is a dynamically expressed regulator of early neural crest development

“…At this stage, during neural crest specification, we propose that SETD2 and NSD3 work in concert to regulate H3K36 methylation on neural crest genes (Jacques‐Fricke & Gammill, 2014). Alternatively, SETD2 may methylate non‐histone proteins to modulate protein activity during neural crest formation (Chen et al, 2017; Park et al, 2016; Walker & Burggren, 2020). Testing these hypotheses is a priority for future work.…”