Histone Methylation in the Nervous System: Functions and Dysfunctions

Abstract

Chromatin remodeling is a key epigenetic process controlling the regulation of gene transcription. Local changes of chromatin architecture can be achieved by post-translational modifications of histones such as methylation, acetylation, phosphorylation, ubiquitination, sumoylation, and ADP-ribosylation. These changes are dynamic and allow for rapid repression or de-repression of specific target genes. Chromatin remodeling enzymes are largely involved in the control of cellular differentiation, and loss or gain of function is often correlated with pathological events. For these reasons, research on chromatin remodeling enzymes is currently very active and rapidly expanding, these enzymes representing very promising targets for the design of novel therapeutics in different areas of medicine including oncology and neurology. In this review, we focus on histone methylation in the nervous system. We provide an overview on mammalian histone methyltransferases and demethylases and their mechanisms of action, and we discuss their roles in the development of the nervous system and their involvement in neurodevelopmental, neurodegenerative, and behavioral disorders.

Unlocking epigenetic codes in neurogenesis

“…In addition, it appears that the RGs are highly heterogeneous, serving as fate-restricted progenitors with the ability to differentiate into various neural subtypes in both embryonic and adult neurogenesis (Kriegstein and Alvarez-Buylla 2009;Ming and Song 2011). Both identity and differentiation potential are determined by the orchestration between extracellular signals-such as Notch, bone morphogenetic proteins (BMPs), Wnt/b-catenin, and Sonic hedgehog (SHH) (Maier et al 2011;Imayoshi et al 2013)-and intrinsic regulators (such as transcription factors) (Long et al 2009) as well as epigenetic modifiers (Hsieh and Eisch 2010;Jobe et al 2012;Pattaroni and Jacob 2013). Many of these transcription factors, like Pax6 (Balmer et al 2012) and Dlx2 (Lim et al 2009), are heavily controlled by distinct epigenetic modulations, such as promoter DNA/histone modifications or post-transcriptional regulation by ncRNAs.…”

“…In fact, epigenetic regulations in ESC and iPSC maintenance and differentiation have been well studied (Hemberger et al 2009;Liang and Zhang 2013). In comparison, epigenetic regulation in mammalian neurogenesis has only emerged as a major focus in recent years (Hsieh and Eisch 2010;Ma et al 2010;Mateus-Pinheiro et al 2011;Sun et al 2011b;Jobe et al 2012;Pattaroni and Jacob 2013). Why do many epigenetic regulators possess dual roles in inhibiting and promoting neurogenesis?…”

“…These histone codes provide binding docks for gene activators or repressors, which manipulate the chromatin structure and determine the accessibility of their underlying DNA sequence. Differently modified histones could have cross-talk with DNA modification factors to give rise to a complicated system for accurately regulating gene expression (Pattaroni and Jacob 2013). Both histone methylation and acetylation are known to play roles in regulating neurogenesis (Hsieh and Eisch 2010; Cold Pereira et al 2010;Sun et al 2011b;Jobe et al 2012).…”

Chromatin-remodeling enzymes in control of Schwann cell development, maintenance and plasticity

“…Activating methylation marks are located on H3K4, H3K36, H3K79, H3R17 and H3R26, and repressive methylation marks on H3K9, H3K27, H4K20 and H3R8, whereas methylation of H3R2 and H4R3 leads either to transcriptional activation or repression, depending on the exact location of the methyl group. There are several families of HMTs and K HDMs, but the existence of R HDMs is not clear [22].…”

“…Activating methylation marks are located on H3K4, H3K36, H3K79, H3R17 and H3R26, and repressive methylation marks on H3K9, H3K27, H4K20 and H3R8, whereas methylation of H3R2 and H4R3 leads either to transcriptional activation or repression, depending on the exact location of the methyl group. There are several families of HMTs and K HDMs, but the existence of R HDMs is not clear [22].Functions of chromatin-remodeling enzymes in SC development and maintenance of PNS integrity SC development from specification of the lineage to terminal differentiation into myelinating cells and maintenance of myelination require transcriptional activation of genes that induce lineage differentiation and acquisition and maintenance of cell stage identity. HDAC1 and HDAC2 (HDAC1/2) and the BAF complex hold major functions in these processes.…”