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 is an essential adaptor to recruit histone H3 lysine 4 methyltransferases MLL3 and MLL4 to the liver X receptors
复制标题
DOI：
10.1210/me.2008-0012
复制
发表时间：
2008-06-01
影响因子：
--
通讯作者：
Lee, Jae W.
中科院分区：
文献类型：
--
作者：
Lee, Seunghee;Lee, Jeongkyung;Lee, Jae W.
激活信号共整合子-2（ASC-2）是多种核受体和转录因子（包括肝脏X受体（LXR））的共激活子，与组蛋白H3赖氨酸4（H3 K4）甲基转移酶（H3 K4 MT）MLL 3或其paraminase MLL 4形成稳态复合物ASCOM（ASC-2复合物）。ASCOM属于Set 1-like复合物，一个保守的H3 K4 MT相关复合物家族。ASC-2通过其两个LXXLL基序以配体依赖性方式与许多核受体结合。特别是，第二个基序已经显示出特异性识别LXR。然而，ASC-2和MLL 3/4在LXR反式激活中的确切作用都没有明确定义。在这里，我们表明ASC-2在LXR反式激活中的关键功能是将MLL 3和MLL 4呈递给LXR。因此，ASC-2是配体诱导的MLL 3和MLL 4向LXR的募集所必需的，并且LXR配体T1317不仅诱导LXR靶基因的表达，而且诱导它们的H3 K4-三甲基化。引人注目的是，这两种配体效应在ASC-2缺失细胞中被消除，但在表达酶失活突变体MLL 3的细胞中仅被部分抑制。我们的研究结果还表明，LXR的反式激活似乎不需要其他Set 1样复合物。综上所述，这些结果表明，ASCOM-MLL 3和ASCOM-MLL 4在配体依赖性H3 K4三甲基化和LXR靶基因表达中发挥冗余但重要的作用，并且ASC-2可能是LXR通过ASCOM而不是其他Set 1样复合物发挥功能的关键决定因素。
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.