Epigenetic regulation of oligodendrocyte myelination in developmental disorders and neurodegenerative diseases

Abstract

Oligodendrocytes are the critical cell types giving rise to the myelin nerve sheath enabling efficient nerve transmission in the central nervous system (CNS). Oligodendrocyte precursor cells differentiate into mature oligodendrocytes and are maintained throughout life. Deficits in the generation, proliferation, or differentiation of these cells or their maintenance have been linked to neurological disorders ranging from developmental disorders to neurodegenerative diseases and limit repair after CNS injury. Understanding the regulation of these processes is critical for achieving proper myelination during development, preventing disease, or recovering from injury. Many of the key factors underlying these processes are epigenetic regulators that enable the fine tuning or reprogramming of gene expression during development and regeneration in response to changes in the local microenvironment. These include chromatin remodelers, histone-modifying enzymes, covalent modifiers of DNA methylation, and RNA modification-mediated mechanisms. In this review, we will discuss the key components in each of these classes which are responsible for generating and maintaining oligodendrocyte myelination as well as potential targeted approaches to stimulate the regenerative program in developmental disorders and neurodegenerative diseases.

Keywords: DNA methylation; RNA modification; chromatin remodelers; developmental disorders; epigenetics; histone-modifying enzymes; multiple sclerosis; myelin repair; myelination; neurodegenerative disease; oligodendrocyte.

Figure 1.. Differentiation of progenitor cells is a highly choreographed process.

( A) A diagram depicts an epigenetic landscape of cellular fate decision-making during oligodendrocyte development from neural progenitor cells. Beginning with neural progenitors, cell differentiation occurs along multiple potential pathways with cells taking on neuronal, astrocyte, or oligodendrocyte lineages. This differentiation from a common progenitor population involves the fine tuning of gene expression and turning on and off of lineage-specific genes and their epigenetic regulators. ( B) Many modulators of gene expression are through epigenetic mechanisms, which alter gene expression on the basis of local environmental factors. These mediators include covalent modifications to DNA or histones, RNA-mediated regulation of gene expression, or the enzymes responsible for mediating the effects of these modifications. BRG1, Brahma-related 1; CHD, chromodomain helicase DNA-binding; cOPC, committed oligodendrocyte progenitor cell; DNMT, DNA methyltransferase; HAT, histone acetyltransferase; HDAC, histone deacetylase; OL, oligodendrocyte; pri-OPC, primitive oligodendrocyte progenitor cell; TET, ten-eleven translocation.

Figure 2.. Global expression levels of key epigenetic regulators during oligodendrocyte differentiation from progenitor cells.

Epigenetic modifiers, including ATP-dependent chromatin remodelers, histone acetyltransferases and deacetylases, histone methyltransferases, and demethylases, are critical components of the differentiation process, according to the data from a bulk RNA sequencing dataset . The change of epigenetic modifiers across oligodendrocyte differentiation is depicted. The global changes of expression levels in the epigenetic modifications themselves are based on the studies ^{, , , , ,} . OPC, oligodendrocyte progenitor cell.