The disintegration of repressive complex by SETDB1 inhibition is equivalent to depriving the role of OLIG2 in transcriptional repression. To investigate the functions of SETDB1 on myelination, Setdb1 was conditionally deleted in OL lineage by crossing mice harboring floxed Setdb1 alleles and mice carrying Olig1-Cre26,27. Setdb1 expression was efficiently eliminated in the oligodendrocyte lineage cells of Olig1-Cre; Setdb1F/F mice (Supplementary Fig. 3a). Transgenic mice crossed with Rosa26-tomato mice for labelling OPC lineage cells28. H3K9me3 level is obviously reduced in the mutant OPC (Supplementary Fig. 3b, c). Setdb1 mutant mice were born at Mendelian frequencies and were indistinguishable from wildtype (WT) and heterozygous littermates (Olig1-Cre; Setdb1F/+) until P10. However, all the mutant mice, but not the WT and heterozygous littermates, developed symptoms associated with myelin-deficiency including tremors, hind limb paralysis, and seizures beginning at P14 (Supplementary Video 1). The mutant mice hardly survived beyond P21 (Fig. 3a). The optic nerve, a myelinated white matter, was translucent from mutant mice (Fig. 3b), indicating a severe deficiency in myelin formation. We did notice a measurable hypomyelination in the heterogenous mice (Supplementary Fig. 3d).
