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Stimulation of preadipocyte differentiation by steroid through targeting of an HDAC1 complex
Author(s) -
WiperBergeron Nadine,
Wu Dongmei,
Pope Louise,
SchildPoulter Caroline,
Haché Robert J.G.
Publication year - 2003
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/cdg218
Subject(s) - corepressor , hdac1 , biology , ccaat enhancer binding proteins , histone deacetylase , glucocorticoid receptor , adipogenesis , histone , endocrinology , microbiology and biotechnology , cellular differentiation , medicine , glucocorticoid , nuclear receptor , transcription factor , biochemistry , nuclear protein , gene , adipose tissue
Glucocorticoids potentiate the early steps of preadipocyte differentiation and promote obesity in Cushing's syndrome and during prolonged steroid therapy. We show that glucocorticoids stimulate 3T3 L1 preadipocyte differentiation through a non‐transcriptional mechanism mediated through the ligand‐binding domain of the glucocorticoid receptor. This enhanced the onset of CCAAT/enhancer binding protein (C/EBPα) expression by potentiating its initial transcriptional activation by C/EBPβ. In the absence of steroid, C/EBPβ associated with a transcriptional corepressor complex containing mSin3A and histone deacetylase 1 (HDAC1), but lacking HDAC2 and RbAp46/48. HDAC1/mSin3A were recruited to the C/EBPα promoter with C/EBPβ and promoted the deacetylation of histone H4. Steroid induced the specific depletion of this corepressor by targeting the HDAC1 within the complex for degradation through the 26S proteasome. Treatment with histone deacetylase inhibitors replaced the effects of steroid treatment on preadipocyte differentiation and C/EBPα expression, while overexpression of HDAC1 abrogated the stimulatory effects of steroid. Recapitulation of the glucocorticoid effect by progestin treatment in the presence of the progesterone receptor ligand‐binding domain suggests a conserved mechanism relevant to many aspects of steroid‐mediated differentiation.