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Novel Regulatory Role for Human Acf1 in Transcriptional Repression of Vitamin D3 Receptor-Regulated Genes

Department of Pharmacology (A.K.E., M.A., D.C.), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104; and Division of Reproductive Biology Research (D.C.), Department of Obstetrics and Gynecology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611

Address all correspondence and requests for reprints to: Debabrata Chakravarti, Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611. E-mail: debu{at}northwestern.edu.

Hormones and vitamins play integral roles in modulating transcriptional activity of members of the nuclear hormone receptor (NR) superfamily. The nuclear receptor corepressor protein (N-CoR) is essential for the transcriptional repression by unliganded NRs. In an attempt to isolate novel components of the hormone signaling pathway, we used a yeast two-hybrid screen and identified human ATP-utilizing chromatin assembly and remodeling factor 1 (hAcf1) as an N-CoR interacting protein. A previously unrecognized function of hAcf1 in the repression of euchromatic genes in mammalian cells was found: hAcf1 plays key roles in the hormone responsiveness and in the transcriptional repression of specific class II NR-regulated genes. First, hormone treatment causes a significant release of hAcf1 from its target gene promoters. Second, hAcf1 is crucial for stabilizing the endogenous vitamin D receptor-N-CoR repression complex and N-CoR itself, in the vitamin D3-regulated IGF binding protein 3 and receptor activator of nuclear factor-B ligand gene promoters, respectively. Third, RNA interference-mediated reduction of hAcf1 or vitamin D3 treatment differentially affects the histone modification profile and the histone occupancy in these genes. Together, these results establish that hAcf1 has a critical role in the transcriptional repression of specific NR-regulated genes and indicate that hAcf1 release and histone H3 and H4 eviction are novel mechanisms in hormone-induced gene activation.

NURSA Molecule Pages Link:

Nuclear Receptors:   VDR

Coregulators:   WSTF  |  NCOR  |  SMRT

Ligands:   all-trans-Retinoic acid  |  Calcitriol  |  Thyroid hormone