ETO/MTG8 Is an Inhibitor of C/EBPβ Activity and a Regulator of Early Adipogenesis

Abstract

The putative transcriptional corepressor ETO/MTG8 has been extensively studied due to its involvement in a chromosomal translocation causing the t(8;21) form of acute myeloid leukemia. Despite this, the role of ETO in normal physiology has remained obscure. Here we show that ETO is highly expressed in preadipocytes and acts as an inhibitor of C/EBPβ during early adipogenesis, contributing to its characteristically delayed activation. ETO prevents both the transcriptional activation of the C/EBPα promoter by C/EBPβ and its concurrent accumulation in centromeric sites during early adipogenesis. ETO expression rapidly reduces after the initiation of adipogenesis, and this is essential to the normal induction of adipogenic gene expression. These findings define, for the first time, a molecular role for ETO in normal physiology as an inhibitor of C/EBPβ and a novel regulator of early adipogenesis.

This study was supported by the Wellcome Trust (J.J.R., R.K.S., K.B.B., D.H., M.M., and S.O.R.), the Deutsche Forschungsgemeinschaft (M.L. and S.S.), the UK MRC (C.C., C.J.L., and C.M.), and the Raymond and Beverly Sackler Foundation (R.K.S.). J.K.S. is a BBSRC David Phillips Fellow.

We are particularly grateful to the members of the O'Rahilly and Siddle labs for many helpful discussions. Q.-Q. Tang and M. D. Lane generously provided C/EBPα promoter and C/EBPβ expression constructs. The C/EBPwt-LUC construct was kindly provided by S. Smola-Hess.