There are 3 possibilities for the decline in mature oligodendrocytes: i) reduced pool of OPCs; ii) deficiency in OPC differentiation; iii) extensive cell death occurring to the OLs. Both the total number and the proliferation index of PDGFRa+ OPCs were comparable between control and mutant mice (Fig. 5a and Supplementary Fig. 6a). During regeneration, the recruitment of OPCs was not affected by Setdb1 deletion (Supplementary Fig. 6b, c). Under both myelination and remyelination circumstance, Enpp6+ (a newly identified marker of iOL30) cells were evidently reduced in the mutant mice (Fig. 5b, c and Supplementary Fig. 6d, e). The expression of Enpp6 was declined in vivo and in vitro due to either SETDB1 inhibition or OLIG2-VP64 overexpression (Fig. 5d). Thus, OLIG2-SETDB1 repressive complex is required for iOLs generation.
