Abstracts (poster) - Wissenschaft Online

Michael Haberland, Rusty Montgomery, Eric N. Olson
Histone deacetylases 1 & 2 control adipogenesis
Adipogenesis is a tightly orchestrated process in which mesenchymal precursor cells
differentiate into mature fat cells. This process is under the control of a well established
cascade of transcription factors including the C/EBP family, SREBP and PPARgamma. In
vitro studies have shown that these adipogenic core transcription factors interact with
histone deacetylases, a conserved family of chromatin modifying enzymes that usually
act as transcriptional repressors. Thus, in the classical model of adipocyte differentiation,
HDACs are thought to be inhibitors of the adipogenic program by directly repressing the
transcriptional activity of adipogenic transcription factors.
We used genetic and pharmacological models to test the influence of HDACs on
adipogenesis. Treatment of pre-adipocytes (3T3-L1) and mouse embryonic fibroblasts
(MEFs) with diverse HDAC inhibitors (TSA, SAHA, Scriptaid) lead to a robust block of
adipocyte differentiation in vitro. Time course analyses indicated that distinct phases in
the differentiation program are sensitive to HDAC inhibition. In order to elucidate targets
that are responsible for the observed phenotype, we used MEFs with conditionally
targeted alleles for HDAC1, HDAC2 and HDAC 8. Efficient deletion of the floxed alleles
was obtained by using either a self-deleting lentiviral CRE or a Tamoxifen-inducible CRE.
We found that deletion of any single HDAC did not lead to a block in adipogenesis.
However deletion of both HDAC1 and HDAC2 completely blocked adipocyte
differentiation without being detrimental to cell survival. A detailed molecular analysis
indicated that this phenotype was due to defective chromatin remodelling during the
differentiation process as well as to perturbed post-translational modifications of
adipogenic transcription factors. Deletion of HDAC1 and HDAC2 in vivo using aP2-CRE
HDAC1/2 double-conditional mice indicated that histone deacetylases are required for
homeostasis of adipose tissue in animals.
contact:
Dr. Michael Haberland
UT Southwestern Medical School
Department of Molecular Biology
michael.haberland@utsouthwestern.edu
5323 Harry Hines BLVD
75390 Dallas, TX (USA)