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Activating Signal Cointegrator-2 Is an Essential Adaptor to Recruit Histone H3 Lysine 4 Methyltransferases MLL3 and MLL4 to the Liver X Receptors

Departments of Molecular and Cellular Biology (S.L., S.-K.L., J.W.L.), Medicine-Division Diabetes, Endocrinology and Metabolism (J.L., J.W.L.), Molecular and Human Genetics (S.-K.L., J.W.L.), Neuroscience (S.-K.L.), The Huffington Center on Aging (S.-K.L.), and Program in Developmental Biology (S.-K.L.), Baylor College of Medicine, Houston, Texas 77030

Address all correspondence and requests for reprints to: Jae W. Lee, One Baylor Plaza N520.06, Houston, Texas 77030. E-mail: jwlee{at}bcm.edu.

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.

NURSA Molecule Pages Link:

Nuclear Receptors:   RARα  |  LXRβ  |  LXRα  |  ERα

Coregulators:   ASC-2

Ligands:   T0901317

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