Foreword

The rapid growth in our understanding of glial cell diversity and functions has been driven by powerful technological advances within the recent years. Historically identified by Virchow in 1856, glial cells were initially classified on the basis of morphological assessment. The introduction of electron microscopy, the refinement of histological techniques and electrophysiological investigations contributed to important functional insights in glial cell biology, while studies on transcriptional networks and related development of genetic reporter mouse lines, led to the identification of cell-specific markers. Finally, genome-wide high resolution studies, conducted on glial cell populations orat single-cell level, have unraveled an unprecedented level of complexity of functional and developmental states. This Special Issue of GLIA highlights this powerful advance in the molecular definition of distinct glial subtypes, by focusing on Epigenetics. The goal is to present the current understanding of the molecular events that define the genomic landscape of glial cells highlighting the exquisite cell-type and cell-stage specificity of the epigenetic "code" and the implications for physiological development and diseases. Glial cells were initially considered a relatively homogeneous “supporting” structure for neurons within the nervous system. Diversity was recognized based on functional specialization and developmental origins. Astrocytes and Oligodendrocytes in the CNS, collectively identified as macroglia, derive from neural stem cells, which display subsequent neurogenic and then gliogenic properties during embryonic development. Microglia, in contrast, are of hematopoietic origin and migrate to the brain during early embryogenesis and therefore are considered brain tissue macrophages. Finally, Schwann Cells, the myelinating cells of the peripheral nerves derive from precursors that are generated from the neural crest. While the importance of transcription factors and signaling pathways leading to glial cell identity is undisputed, it became evident that the responsiveness of a cell to the same signal is not invariable, as glial phenotypes depend strongly on developmental stage and local environment. It is now recognized that DNA in a cell is not simply present as template available for transcription factor binding, but is rather organized in a complex structure called chromatin, whose transcriptional activity is determined by its location within subnuclear domains. Several studies have now shown that modifications to chromatin and DNA determine the cellular phenotype. In addition, with increasing technological and methodological advances, there is a growing awareness of the complexity of various subtypes of neuroglial cell types in the central and peripheral nervous systems. Glial cells display a high degree of heterogeneity. Not only can distinct lineages be distinguished by their terminal differentiation state, but their properties may also adapt to environmental stimuli. Whereas in the past glia phenotypes and function were determined by immunohistochemistry and functional assays, recently, a large number of transcriptomic studies has challenged the traditional concept of the existence of three main glial cell types in the brain. The progressive refinement of single-cell transcriptomic studies, analysis of immune-precipitated chromatin and its conformation, genome-wide studies of DNA methylation, collectively, have led to novel basic knowledge and the identification of specialized glial phenotypes, some emerging only during disease states. The abundance of the newly identified glia cell subtypes implies the existence of distinct modalities of gene expression occurring within the program specific to each lineage-. Clearly, this is the result of adaptive responses of cells to environmental changes, which in turn, result in modifications of gene transcription. The term “epigenetics” is derived from adding the greek prefix “epi” (i.e., “beyond,” “above”), to the noun “genetics,” and was initially introduced by the British developmental biologist Conrad Hal Waddington in 1942, to define the phenotypic adaptation of an organism, resulting from the interaction with the surroundings. Waddington coined the term “epigenetic landscape” to refer to the progressive lineage restriction of cells during differentiation. This metaphor nicely clarifies the concept that, while all cells of a given organism share the same genetic information, each cell type, depending on developmental stage and surrounding environment, displays a unique pattern of gene expression, which is dependent on the organization of the genome in a unique “landscape.” This unique organization of the genome, which affects and determines its transcriptional competence, includes: specific modifications of the DNA (i.e., DNA methylation), post-translational modifications of specific nuclear proteins called histones, long-noncoding and micro-RNAs, as well as ATP-dependent chromatin remodeling complexes, long-range interactions and 3D organization of chromatin within the nucleus of the cells. While it is conceivable that epigenetic modifiers cooperate with transcription factors to rapidly adjust to a given environment, not all Received: 24 April 2020 Accepted: 27 April 2020