Chromatin dynamics: H3K4 methylation and H3 variant replacement during development and in cancer

Abstract

The dynamic nature of chromatin and its myriad modifications play a crucial role in gene regulation (expression and repression) during development, cellular survival, homeostasis, ageing, and apoptosis/death. Histone 3 lysine 4 methylation (H3K4 methylation) catalyzed by H3K4 specific histone methyltransferases is one of the more critical chromatin modifications that is generally associated with gene activation. Additionally, the deposition of H3 variant(s) in conjunction with H3K4 methylation generates an intricately reliable epigenetic regulatory circuit that guides transcriptional activity in normal development and homeostasis. Consequently, alterations in this epigenetic circuit may trigger disease development. The mechanistic relationship between H3 variant deposition and H3K4 methylation during normal development has remained foggy. However, recent investigations in the field of chromatin dynamics in various model organisms, tumors, cancer tissues, and cell lines cultured without and with therapeutic agents, as well as from model reconstituted chromatins reveal that there may be different subsets of chromatin assemblage with specific patterns of histone replacement executing similar functions. In this light, we attempt to explain the intricate control system that maintains chromatin structure and dynamics during normal development as well as during tumor development and cancer progression in this review. Our focus is to highlight the contribution of H3K4 methylation-histone variant crosstalk in regulating chromatin architecture and subsequently its function.

skNAC and Smyd1 in transcriptional control

“…However, the effects of these histone modifications are complex, subject to various cell-type specific control mechanisms and incompletely understood [8], so that further research is necessary to elucidate their effects in differentiating skeletal muscle cells.…”

Understanding the genetic liability to schizophrenia through the neuroepigenome

“…Numerous studies link dysregulation of the epigenome to disease [for examples see (Robertson, 2005) (Mirabella et al, 2015)] such as cancer (Deb et al, 2014), heart disease (Zhang and Liu, 2015) and metabolic disorders (Martinez-Jimenez and Sandoval, 2015). In addition, a number of groups have attempted to assess the role of the epigenome in the etiology of neurological disorders, including autism (Shulha et al, 2012a), addiction (Zhou et al, 2011b), Huntington’s disease (HD) (Bai et al, 2015), multiple sclerosis (MS) (Huynh et al, 2014) and Alzheimer’s disease (De Jager et al, 2014) (Lunnon et al, 2014).…”

Paternal H3K4 methylation is required for minor zygotic gene activation and early mouse embryonic development

“…There are six major histone methyltransferases that catalyze H3K4 methylation-Setd1a, Setd1b, Mll1, Mll2, Mll3, and Mll4-which are divided into three distinct groups according to their sequence similarity and complex formation: Set1a/b, Mll1/2, and Mll3/4 [20][21][22]. Previously, Mll2 was reported to be required for early embryogenesis, based on the observations of decreased H3K4me2/3 in maternal PNs concomitant with~30% reduction of major ZGA and developmental arrest mainly at 2-cell stages, when it was knocked out [23].…”