The Chromatin Environment Around Interneuron Genes in Oligodendrocyte Precursor Cells and Their Potential for Interneuron Reprograming

Abstract

Oligodendrocyte precursor cells (OPCs), also known as NG2 glia, arise from neural progenitor cells in the embryonic ganglionic eminences that also generate inhibitory neurons. They are ubiquitously distributed in the central nervous system, remain proliferative through life, and generate oligodendrocytes in both gray and white matter. OPCs exhibit some lineage plasticity, and attempts have been made to reprogram them into neurons, with varying degrees of success. However, little is known about how epigenetic mechanisms affect the ability of OPCs to undergo fate switch and whether OPCs have a unique chromatin environment around neuronal genes that might contribute to their lineage plasticity. Our bioinformatic analysis of histone posttranslational modifications at interneuron genes in OPCs revealed that OPCs had significantly fewer bivalent and repressive histone marks at interneuron genes compared to astrocytes or fibroblasts. Conversely, OPCs had a greater degree of deposition of active histone modifications at bivalently marked interneuron genes than other cell types, and this was correlated with higher expression levels of these genes in OPCs. Furthermore, a significantly higher proportion of interneuron genes in OPCs than in other cell types lacked the histone posttranslational modifications examined. These genes had a moderately high level of expression, suggesting that the “no mark” interneuron genes could be in a transcriptionally “poised” or “transitional” state. Thus, our findings suggest that OPCs have a unique histone code at their interneuron genes that may obviate the need for erasure of repressive marks during their fate switch to inhibitory neurons.

Life-long oligodendrocyte development and plasticity

“…The age-dependent decline in OPC fate plasticity appears to be correlated with persistent expression of Sox10 after loss of Olig2 in older mice [100], suggesting a switch from an early Olig2-dependent to an Olig2-independent mechanism of maintaining Sox10 expression as OPCs become irreversibly committed to the OL lineage during the first postnatal month. Epigenetic mechanisms such as histone post-translational modifications in different cell types appear to change dramatically with age [102] and significantly affect OL differentiation [103]. Additionally, ATP-dependent chromatin remodeling factors that interact with Olig2 and/or Sox10, such as Brg1 (Brahma-related gene product 1) of the SFI-SNF family and the chromodomain-helicase-DNA-binding proteins Chd7 and Chd8 [104][105][106][107][108], could perhaps be integrating intrinsic and environmental age-dependent signals to seal the window of fate plasticity and irreversibly commit to OLs.…”

Epigenetic regulation of oligodendrocyte differentiation: From development to demyelinating disorders

“…It has been demonstrated to play a role in organizing the 3D genome by repressing lineage inappropriate genes during ESC differentiation (McLaughlin et al, ). Further, chromatin immunoprecipitation followed by deep sequencing (ChIP‐seq) analyses show H3K27me3 to be associated with genes regulating “global alternative lineage choice” in OPCs (Boshans et al, ; Liu et al, ) and “cell migration” in differentiating OLs, although the number of genes associated with H3K27me3 in OPCs was approximately twice as those in differentiating OLs, suggesting that the H3K27me3 mark may play a more critical role in repression at the progenitor state (Liu et al, ). This is in line with earlier genome‐wide occupancy studies, which demonstrated a critical role of EZH2, the KMT which catalyzes the deposition of H3K27me3 on genes regulating alternative fate choices during neural stem cell differentiation toward the OL lineage (Sher et al, ; Sher, Boddeke, Olah, & Copray, ).…”

“…Genes containing bivalent marks are often transcriptionally silenced, but can be rapidly induced or stably inactivated upon resolution of bivalent marks, in what is also referred as a poised state (V. W. Zhou, Goren, & Bernstein, ). Interestingly, OPCs appear to have significantly fewer bivalent marks on a curated set of interneuron genes compared to astrocytes or fibroblasts, suggesting the interneuron genes are less repressed in OPCs (Boshans et al, ). This is in consistent with the higher average transcript levels of bivalently marked interneuron genes in OPCs than other cell types (e.g., astrocyte or fibroblast) (Boshans et al, ), which might be related to a common developmental origin of interneurons and a sub‐population of OPCs.…”

The effects of developmental and current niches on oligodendrocyte precursor dynamics and fate

“…By contrast, transduction of OPCs in the striatum with a different set of transcription factors known to induce dopaminergic neuronal differentiation resulted in the production of functionally active interneurons [51]. It remains to be determined whether the different outcomes of these studies are due to the transduction method or to inherent differences in the sensitivity of OPCs from different germinal zones to neuronal reprogramming factors, possibly due to differences in the chromatin landscape around neuronal genes in OPCs [52].…”