MLL Histone Methylases Regulate Expression of HDLR-SR-B1 in Presence of Estrogen and Control Plasma Cholesterol in Vivo
MLL Histone Methylases Regulate Expression of HDLR-SR-B1 in Presence of Estrogen and Control Plasma Cholesterol in Vivo
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DOI：
10.1210/me.2012-1147
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发表时间：
2013-01-01
影响因子：
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通讯作者：
Mandal, Subhrangsu S.
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文献类型：
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作者：
Ansari, Khairul I.;Kasiri, Sahba;Mandal, Subhrangsu S.
高密度脂蛋白受体B型清道夫受体[HDLR-SR-B1(SR-B1)]是胆固醇逆向转运和维持血胆固醇的关键分子。我们在HepG2和JAR细胞中证明了17β-雌二醇(E2)在转录水平上激活了人SR-B1。SR-B1启动子含有多个雌激素反应元件(ERE半个位点)和一些Sp1结合位点。雌激素受体(ER)α和ERβ下调E2诱导的SR-B1表达。ER以E2依赖的方式与SR-B1启动子ERE结合。与ER一样，混合系白血病(MLL)组蛋白甲基酶，特别是MLL1和MLL2，在E2介导的SR-B1激活中起着关键作用。MLL1和MLL2以E2依赖的方式与SR-B1启动子结合，控制转录预启动复合体的组装和RNA聚合酶II(RNAPII)的募集。ERs和MLL在决定类固醇合成组织/细胞的胆固醇摄取中起关键作用，它们的敲除抑制了E2诱导的细胞胆固醇摄取效率。有趣的是，在小鼠体内，MLL2基因敲除导致血浆胆固醇水平增加33%，并降低了小鼠肝脏中SR-B1的表达，证明了其在体内控制血浆胆固醇的关键功能。(分子内分泌学27：92-105,2013)
High-density lipoprotein receptors scavenger receptor class B type I [HDLR-SR-B1 (SR-B1)] is a key player in reverse cholesterol transport and maintaining blood cholesterol. We demonstrated that human SR-B1 is transcriptionally activated by 17 beta-estradiol (E2) in HEPG2 and JAR cells. SR-B1 promoter contains multiple estrogen response elements (ERE half-sites) along with some Sp1 binding sites. Knockdown of estrogen receptor (ER)alpha and ER beta down-regulated E2-induced SR-B1 expression. ERs were bound to SR-B1 promoter EREs in an E2-dependent manner. Along with ERs, mixed-lineage leukemia (MLL) histone methylases, especially MLL1 and MLL2, play key roles in E2-mediated SR-B1 activation. MLL1 and MLL2 bind to SR-B1 promoter in an E2-dependent manner and control the assembly of transcription pre-initiation complex and RNA polymerase II (RNAPII) recruitment. ERs and MLLs play critical roles in determining the cholesterol uptake by steroidogenic tissues/cells, and their knockdown suppressed the E2-induced cholesterol uptake efficiencies of the cells. Intriguingly, MLL2 knockdown in mice resulted in a 33% increase in plasma cholesterol level and also reduced SR-B1 expression in mice liver, demonstrating its crucial functions in controlling plasma cholesterol in vivo. (Molecular Endocrinology 27: 92-105, 2013)