Roles of MLL histone methyalses in estrogen mediated regulation of HDLR-SRB1

MLL 组蛋白甲基化在雌激素介导的 HDLR-SRB1 调节中的作用

• 批准号: 7882188
• 负责人: Subhrangsu S Mandal
• 金额: $ 21.9万
• 依托单位: UNIVERSITY OF TEXAS ARLINGTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2010-04-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7882188
• 关键词: Alternative Splicing; Binding; Biochemical; Blood; Bone Development; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cell Cycle Regulation; Cell Line; Cells; Cholesterol; Cholesterol Homeostasis; Collaborations; Complex; Decision Making; Disease; Environment; Enzymes; Epigenetic Process; Estradiol; Estrogen Receptors; Estrogens; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Histone H3; Histones; Hormonal; Hormones; Human; Laboratories; Link; Lysine; MLL2 gene; Malignant Neoplasms; Mediating; Nuclear Hormone Receptors; Play; Process; Protein Family; Proteins; RNA Splicing; Regulation; Role; Signal Transduction; Testing; Tissues; Transcription Factor AP-1; Transcriptional Activation; Transferase; Variant; base; biological adaptation to stress; cancer therapy; estrophilin; experience; high density lipoprotein receptor; histone methyltransferase; knock-down; leukemia; mRNA Precursor; member; novel; promoter; public health relevance; reproductive; research study; scavenger receptor; transcription factor; uptake

DESCRIPTION (provided by applicant): The estrogen receptors (ERs) are key players in estrogen signaling. In addition to their crucial roles in mediating hormonal effects in reproductive tissues, ERs play important roles in bone development, normal cardiovascular functions, cardiovascular disease (CVD), and in cancer. ER mediated gene regulation and signaling is a complex process which involves many transcription factors and coregulators. Mixed Lineage Leukemias (MLLs) are human histone methyl-transferases that play critical roles in gene expression, epigenetics, and cancer. In human, there are several MLL families of proteins such as MLL1, MLL2, MLL3, MLL4, etc. Recent studies demonstrated that several MLLs act as coactivators for ER in regulation of estrogen responsive genes. Although, the importance of MLLs in gene expression, hormone signaling, and disease is well recognized their mechanism of actions and any roles associated with CVD are largely unknown. Our preliminary studies demonstrated that human HDLR-SRB1 (high density lipoprotein receptor scavenger receptor type B1, or SRB1), a protein that is critical for maintaining blood cholesterol, is transcriptionally activated by estrogen. Estrogen also induced differential splicing of SRB1 pre-mRNA. Interestingly, knock down of either MLL1 or MLL2 down regulated the estrogen mediated activation of SRB1 and also modulated the alternative splicing of SRB1 variants, suggesting their critical roles in these processes. Importantly, knock down of MLL1 and MLL2 also significantly decreased the cholesterol uptake efficiencies of steroidogenic cells indicating their critical roles in cholesterol uptake. Herein, experiments are proposed to elucidate the biochemical roles of different MLL histone methylases and their collaboration with ERs in estrogen mediated activation and alternate splicing of HDLR-SRB1 and related genes. Experiments are also proposed to understand the roles of MLLs and ERs in cholesterol transport in steroidogenic cells. These studies will reveal novel functions of MLL histone methylating enzymes in estrogen signaling, cholesterol transport and hence in CVD. Furthermore, as estrogen signaling is closely associated with cancer and cardiovascular disease, these studies will advance our understanding about these diseases and eventually will open up new avenues for cardiovascular and cancer therapy. 1 PUBLIC HEALTH RELEVANCE: The estrogen receptors (ERs) are key players in mediating hormonal effects in reproductive tissues, in bone development, and in diseases including cardiovascular disease (CVD) and cancer. Herein experiments are proposed to understand the biochemical mechanism of estrogen signaling associated with cholesterol homeostasis. Completion of these studies will advance our understanding about CVD and cancer and will open up new avenues for potential therapy. 1

描述（由申请人提供）：雌激素受体（ER）是雌激素信号传导的关键参与者。除了在生殖组织中介导激素效应的关键作用外，ER在骨发育、正常心血管功能、心血管疾病（CVD）和癌症中发挥重要作用。ER介导的基因调控和信号转导是一个复杂的过程，涉及许多转录因子和辅调节因子。混合谱系白血病（MLL）是人类组蛋白甲基转移酶，在基因表达、表观遗传学和癌症中起关键作用。在人类中，有几个MLL家族的蛋白质，如MLL 1，MLL 2，MLL 3，MLL 4等。最近的研究表明，几个MLL作为共激活剂的ER在调节雌激素反应基因。尽管MLL在基因表达、激素信号传导和疾病中的重要性已被充分认识，但其作用机制和与CVD相关的任何作用在很大程度上仍未知。我们的初步研究表明，人类HDLR-SRB 1（高密度脂蛋白受体清道夫受体B1型，或SRB 1），一种对维持血液胆固醇至关重要的蛋白质，被雌激素转录激活。雌激素还诱导SRB 1前体mRNA的差异剪接。有趣的是，MLL 1或MLL 2的敲低下调了雌激素介导的SRB 1激活，也调节了SRB 1变体的选择性剪接，表明它们在这些过程中的关键作用。重要的是，MLL 1和MLL 2的敲低也显著降低类固醇生成细胞的胆固醇摄取效率，表明它们在胆固醇摄取中的关键作用。在此，实验提出了阐明不同的MLL组蛋白甲基化酶的生化作用，并与雌激素介导的激活和选择性剪接的HDLR-SRB 1和相关基因的ER的合作。实验也提出了了解的作用，MLL和ER的胆固醇运输类固醇细胞。这些研究将揭示MLL组蛋白甲基化酶在雌激素信号传导、胆固醇转运和CVD中的新功能。此外，由于雌激素信号与癌症和心血管疾病密切相关，这些研究将促进我们对这些疾病的理解，并最终为心血管和癌症治疗开辟新的途径。1 公共卫生相关性：雌激素受体（ER）是介导生殖组织、骨发育和包括心血管疾病（CVD）和癌症在内的疾病中的激素效应的关键参与者。在此，提出实验来了解与胆固醇稳态相关的雌激素信号转导的生化机制。这些研究的完成将促进我们对CVD和癌症的理解，并将为潜在的治疗开辟新的途径。1