Crucial roles for interactions between MLL3/4 and INI1 in nuclear receptor transactivation.
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.
Lee
Seunghee
S
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Kim
Dae-Hwan
DH
Goo
Young Hwa
YH
Lee
Young Chul
YC
Lee
Soo-Kyung
SK
Lee
Jae W
JW
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*
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