Activating signal cointegrator-2 is an essential adaptor to recruit histone H3 lysine 4 methyltransferases MLL3 and MLL4 to the liver X receptors.
Activating signal cointegrator-2 (ASC-2), a coactivator of multiple nuclear receptors and transcription factors, including the liver X receptors (LXRs), is associated with histone H3 lysine 4 (H3K4) methyltransferase (H3K4MT) MLL3 or its paralogue MLL4 in a steady-state complex named ASCOM (ASC-2 complex). ASCOM belongs to Set1-like complexes, a conserved family of related H3K4MT complexes. ASC-2 binds to many nuclear receptors in a ligand-dependent manner through its two LXXLL motifs. In particular, the second motif has been shown to specifically recognize LXRs. However, the exact role for neither ASC-2 nor MLL3/4 in LXR transactivation is clearly defined. Here, we show that the key function of ASC-2 in transactivation by LXRs is to present MLL3 and MLL4 to LXRs. Thus, ASC-2 is required for ligand-induced recruitment of MLL3 and MLL4 to LXRs, and LXR ligand T1317 induces not only expression of LXR-target genes but also their H3K4-trimethylation. Strikingly, both of these ligand effects are ablated in ASC-2-null cells but only partially suppressed in cells expressing an enzymatically inactivated mutant MLL3. Our results also reveal that transactivation by LXRs does not appear to require other Set1-like complexes. Taken together, these results suggest that ASCOM-MLL3 and ASCOM-MLL4 play redundant but essential roles in ligand-dependent H3K4 trimethylation and expression of LXR-target genes, and that ASC-2 is likely a key determinant for LXRs to function through ASCOM but not other Set1-like complexes.
Lee
Seunghee
S
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Lee
Jeongkyung
J
Lee
Soo-Kyung
SK
Lee
Jae W
JW
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism* / Q000502:physiology; D004622:Embryo, Mammalian; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism* / Q000502:physiology; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism* / Q000502:physiology*; D000071518:Liver X Receptors; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D056918:Nuclear Receptor Coactivators; D057093:Orphan Nuclear Receptors; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism* / Q000502:physiology; D015533:Transcriptional Activation
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D000071518:Liver X Receptors; C484898:Men1 protein, mouse; C405683:Ncoa6 protein, mouse; D056918:Nuclear Receptor Coactivators; D057093:Orphan Nuclear Receptors; D011518:Proto-Oncogene Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D011495:Histone-Lysine N-Methyltransferase; C510652:Kmt2c protein, mouse; C516439:MLL4 protein, mouse; D008239:Lysine