title: Crucial roles for interactions between MLL3/4 and INI1 in nuclear receptor transactivation.
abstract: 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.
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Seunghee
authors.initials: S
authors.lastname: Lee
authors.forename: Dae-Hwan
authors.initials: DH
authors.lastname: Kim
authors.forename: Young Hwa
authors.initials: YH
authors.lastname: Goo
authors.forename: Young Chul
authors.initials: YC
authors.lastname: Lee
authors.forename: Soo-Kyung
authors.initials: SK
authors.lastname: Lee
authors.forename: Jae W
authors.initials: JW
authors.lastname: Lee
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D047369:Chromatin Immunoprecipitation; D002868:Chromosomal Proteins, Non-Histone / Q000737:chemistry / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D019084:Fluorescent Antibody Technique, Indirect; D006367:HeLa Cells; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D056918:Nuclear Receptor Coactivators; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071796:SMARCB1 Protein; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C452979:KMT2C protein, human; C486559:NCOA6 protein, human; D056918:Nuclear Receptor Coactivators; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human; C445179:SWI-SNF-B chromatin-remodeling complex; D014157:Transcription Factors; D011495:Histone-Lysine N-Methyltransferase; C530816:MLL4 protein, human