Center for Precision Environmental Health, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
Department of Biological Sciences, University of North Texas, 1155 Union Circle #305220, Denton, TX 76203, USA.
J Exp Biol. 2020 Jul 3;223(Pt 13):jeb220632. doi: 10.1242/jeb.220632.
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.
表观基因组决定了在 DNA 序列不变的情况下，基因表达的可遗传模式。其结果是，从单个生物体基因组中编程出不同的细胞、组织和器官特异性表型。构成表观基因组的表观遗传标记（例如甲基化）被放置在染色质（组蛋白和 DNA）上或从染色质上去除，以指导调节基因表达和染色质结构的效应物的活性。最近，细胞骨架已被确定为细胞表观遗传机制的第二个靶标。已经发现几种重塑染色质的表观遗传“读取器、写入器和擦除器”也重塑细胞骨架，调节微管和肌动蛋白丝的结构和功能。这指向了一种新兴的双功能重塑剂范例，具有“染色质-细胞骨架”活性，可整合细胞质和核功能。例如，SET 结构域包含 2 甲基转移酶 (SETD2) 具有染色质-细胞骨架活性，甲基化组蛋白和微管。染色质上的 SETD2 甲基标记对于有效的 DNA 修复是必需的，其微管甲基标记对于有丝分裂期间正确的染色体分离是必需的。SETD2 活性在组蛋白和微管上的这种出乎意料的汇聚，以维持基因组稳定性，这表明在细胞中，阅读、写入和擦除细胞骨架和染色质上甲基标记的染色质-细胞骨架蛋白可能具有扩展的作用。甲基标记的协调使用，重塑表观基因组和（表观）细胞骨架，为其他高级功能（如肌肉收缩或学习和记忆）的综合调节（我们称之为“epiregulation”）开辟了可能性，甚至可能具有进化意义。
