The histone methyltransferases EHMT1 and EHMT2 repress the expression of genes related to excitability and cell death in oligodendrocyte progenitors [RNA-seq]

Oligodendrocyte progenitor cells (OPCs) represent a population of electrically active and dividing cells, which are capable of responding to neuronal activity, by proliferating and differentiating. Here we report that the repressive euchromatic H3K9me2 histone mark, deposited by the histone mehyltransferases EHMT1 and EHMT2 enzymes, increases in proliferating OPCs in mice following optogenetic stimulation of neuronal activity. Using primary cultured OPCs with genetic deletion of Ehmt1 and Ehmt2, and pharmacological inhibition of EHMT enzymatic activity, we reveal the importance of these enzymes in repressing the expression of genes regulating cell death and electrical properties in proliferating OPCs. Consistent with these findings, we detect higher levels of cholinergic muscarinic receptors, fewer numbers of oligodendrocyte lineage cells and lower levels of the myelin basic protein (MBP) in mice with lineage specific ablation of Ehmt1 and Ehmt2. Together these data suggest that the repressive H3K9me2 histone mark, whose levels increase in proliferating OPCs after neuronal stimulation, is an important modulator of cell death and proteins regulating the electrical properties of OPCs. Overall design: To investigate the role of EHMT1/EHMT2 in oligodendrocytes, we performed RNA-sequencing on mouse primary oligodendrocyte progenitors comparing Ehmt1/Ehmt2 knocked down samples to control. Knocked down of Ehmt1 and Ehmt2 was performed in vitro by infecting cells with an Adenovirus expressing Cre recombinase and a RFP protein (knockdown samples), or RFP only (control samples).