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Crucial Roles for Interactions between MLL3/4 and INI1 in Nuclear Receptor Transactivation

Departments of Molecular and Cellular Biology (S.L., D.-H.K., Y.H.G., S.-K.L.), Molecular and Human Genetics (S.-K.L., J.W.L.), and Neuroscience (S.-K.L.) and Program in Developmental Biology (S.-K.L.), Baylor College of Medicine, Houston, Texas 77030; and Hormone Research Center (Y.C.L.), School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Korea

Address all correspondence and requests for reprints to: Jae W. Lee, Ph.D., Baylor College of Medicine, Department of Molecular and Human Genetics, One Baylor Plaza T826, Houston, Texas 77030. E-mail: jwlee{at}bcm.edu.

Nuclear receptor (NR) transactivation involves multiple coactivators, and the molecular basis for how these are functionally integrated needs to be determined to fully understand the NR action. Activating signal cointegrator-2 (ASC-2), a transcriptional coactivator of many NRs and transcription factors, forms a steady-state complex, ASCOM (for ASC-2 complex), which contains histone H3-lysine-4 (H3K4) methyltransferase MLL3 or its paralog MLL4. Here, we show that ASCOM requires a functional cross talk with the ATPase-dependent chromatin remodeling complex Swi/Snf for efficient NR transactivation. Our results reveal that ASCOM and Swi/Snf are tightly colocalized in the nucleus and that ASCOM and Swi/Snf promote each other’s binding to NR target genes. We further show that the C-terminal SET domain of MLL3 and MLL4 directly interacts with INI1, an integral subunit of Swi/Snf. Our mutational analysis demonstrates that this interaction underlies the mutual facilitation of ASCOM and Swi/Snf recruitment to NR target genes. Importantly, this study uncovers a specific protein-protein interaction as a novel venue to couple two distinct enzymatic coactivator complexes during NR transactivation.

NURSA Molecule Pages Link:

Nuclear Receptors:   RARα  |  RARβ  |  GR  |  AR

Coregulators:   BRG1  |  ASC-2

Ligands:   all-trans-Retinoic acid  |  Dexamethasone  |  Dihydrotestosterone