Abstract
Both in vivo and in vitro studies indicate a correlation between reduced acetylation of histone core proteins and oligodendrocyte development. The nature of these histone modifications and the mechanisms mediating them remain undefined. To address these issues, we utilized OLโ1 cells, a rat nontransformed oligodendrocyte cell line, and primary oligodendrocyte cultures. We found that the acetylated histone H3 at lysine 9 and lysine 14 (H3K9/K14ac) is reduced in both the myelin basic protein (MBP) and proteolipid protein (PLP) genes of maturing oligodendroglial OLโ1 cells, and furthermore, this temporally correlates with increases in MBP, PLP, and histone deacetylase (HDAC) 11 expression. Disruption of developmentallyโregulated histone H3 deacetylation within the MBP and PLP genes by the HDAC inhibitor trichostatin A blunts MBP and PLP expression. With its increased expression, interaction of HDAC 11 with acetylated histone H3 and recruitment of HDAC 11 to the MBP and PLP genes markedly increases in maturing OLโ1 cells. Moreover, suppressing HDAC 11 expression with small interfering RNA significantly (1) increases H3K9/K14ac globally and within the MBP and PLP genes, (2) decreases MBP and PLP mRNA expression, and (3) blunts the morphological changes associated with oligodendrocyte development. Our data strongly support a specific role for HDAC 11 in histone deacetylation and in turn the regulation of oligodendrocyteโspecific protein gene expression and oligodendrocyte development. ยฉ 2008 WileyโLiss, Inc.