Transcriptional activation is a function of a """"""""coactivator code"""""""" in which multiple coactivators function in a combinatorial manner dictated by the context of the individual target gene and cell type. We have recently purified and characterized a novel transcriptional coactivator complex called ASCOM (for the ASC-2 complex), and this proposal focuses on the detailed molecular mechanisms by which ASCOM mediates transcriptional activation by nuclear receptors (NRs). The ASC-2 component of this complex is an NR coactivator protein independently isolated in this and at least five other laboratories. ASCOM also contains ALR-1/MLL2 (Trx/ALL-1/MLLl-related protein) and its splicing isoform ALR-2, ALR-like protein HALR (MLL3), ASH2, the Rb binding protein RBQ-3 and others. ALRol/ALR-2 and HALR exhibit histone methyltransferase (HMT) activity, and ASCOM represents the first NR coactivator complex associated with this important histone modification function. The central hypothesis of this proposal is that ASCOM, along with other complexes such as SRC/CBP, TRAP/DRIP, Swi/Snf and N-CoR/SMRT/HDAC, serves as a key mediator of transcriptional activation by NRs. Studies are proposed to test 1) the detailed biochemical function of different constituents of ASCOM during NR transcriptional activation and 2) the combinatorial coactivator code of ASCOM with other coactivators in NR transactivation, with an emphasis on Swi/Snf and CBP/p300. Our recent characterization of the biological functions of ASC-2 using transgenic mice has identified potential roles in many important processes, including metabolic regulation of lipid and cholesterol homeostasis. Gene-amplification as well as alterations of expression of ASC-2 and other ASCOM components in several human cancers also suggest a role in tumorigenesis. Thus, we believe that the studies proposed here will not only provide an important step toward fully understanding the molecular mechanisms by which NRs regulate transcription but could also lead to novel therapeutic approaches to the treatment of important human diseases.

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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Endocrinology Study Section (END)
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Margolis, Ronald N
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Baylor College of Medicine
Internal Medicine/Medicine
Schools of Medicine
United States
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Cargnin, Francesca; Kwon, Ji-Sun; Katzman, Sol et al. (2018) FOXG1 Orchestrates Neocortical Organization and Cortico-Cortical Connections. Neuron 100:1083-1096.e5
Kim, Janghyun; Lee, Bora; Kim, Dae-Hwan et al. (2018) UBE3A suppresses overnutrition-induced expression of the steatosis target genes of MLL4 by degrading MLL4. Hepatology :
Erb, Madalynn; Lee, Bora; Yeon Seo, So et al. (2017) The Isl1-Lhx3 Complex Promotes Motor Neuron Specification by Activating Transcriptional Pathways that Enhance Its Own Expression and Formation. eNeuro 4:
Kim, Dae-Hwan; Kim, Janghyun; Kwon, Ji-Sun et al. (2016) Critical Roles of the Histone Methyltransferase MLL4/KMT2D in Murine Hepatic Steatosis Directed by ABL1 and PPAR?2. Cell Rep 17:1671-1682
Lee, Bora; Lee, Seunghee; Agulnick, Alan D et al. (2016) Single-stranded DNA binding proteins are required for LIM complexes to induce transcriptionally active chromatin and specify spinal neuronal identities. Development 143:1721-31
Clovis, Yoanne M; Seo, So Yeon; Kwon, Ji-Sun et al. (2016) Chx10 Consolidates V2a Interneuron Identity through Two Distinct Gene Repression Modes. Cell Rep 16:1642-1652
Lee, Bora; Lee, Seunghee; Lee, Soo-Kyung et al. (2016) The LIM-homeobox transcription factor Isl1 plays crucial roles in the development of multiple arcuate nucleus neurons. Development 143:3763-3773
Kim, Dae-Hwan; Rhee, Jennifer Chiyeon; Yeo, Sujeong et al. (2015) Crucial roles of mixed-lineage leukemia 3 and 4 as epigenetic switches of the hepatic circadian clock controlling bile acid homeostasis in mice. Hepatology 61:1012-23
Thiebes, Karen P; Nam, Heejin; Cambronne, Xiaolu A et al. (2015) miR-218 is essential to establish motor neuron fate as a downstream effector of Isl1-Lhx3. Nat Commun 6:7718
Roh, Jae-Il; Cheong, Cheolho; Sung, Young Hoon et al. (2014) Perturbation of NCOA6 leads to dilated cardiomyopathy. Cell Rep 8:991-8

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