The role of JADE in HBO complexes

项目摘要 JADE是主要的人赖氨酸乙酰转移酶（KAT）HBO复合物的核心亚基， 在转录和发育程序的调节中至关重要，并与 血液学异常JADE是HBO复合体正常运行所必需的， 然而，其在复合体中的作用仍不清楚。JADE包含三个相邻的锌指， 可以具有集成功能。无论是功能关系还是结构组织， JADE锌指的成分是已知的。我们最近的研究表明， JADE的手指识别组蛋白尾部和DNA，揭示了HBO- 介导的乙酰化和染色质上的复合物组装。我们的主要假设是 JADE的锌指的染色质结合活性是桥接HBO复合物所必需的 活性转录基因的启动子和复合物的KAT选择性。我们寻求 确定了JADE的分子机理、结构基础和功能意义 与染色质结合。我们将使用体外和体内互补的组合， 方法，整合结构，生物化学，分子生物学和细胞生物学工具， JADE锌指盒在HBO复合物生物学功能中的作用。 这项研究对于理解表观遗传机制具有重要意义。 乙酰转移酶刺激的转录激活。阐明了 JADE/HBO-染色质相互作用对于更好地理解肿瘤的病因也是必不可少的。 异常乙酰化引起的血液学疾病，并可能为 开发新的疗法来治疗或预防这些疾病。

Project Summary JADE is a core subunit of the major human lysine acetyltransferase (KAT) HBO complexes, essential in the regulation of transcriptional and developmental programs and linked to haematological abnormalities. JADE is required for proper functioning of the HBO complexes, however its role in the complexes remains unclear. JADE contains three adjacent zinc fingers that may have an integrated function. Neither the functional relationship nor structural organization of components of the JADE zinc fingers are known. Our recent studies demonstrate that the zinc fingers of JADE recognize both histone tails and DNA, revealing a novel link between HBO- mediated acetylation and the complex assembly on chromatin. Our major hypothesis is that the chromatin-binding activity of the zinc fingers of JADE is necessary to bridge the HBO complexes to promoters of actively transcribed genes and for the KAT selectivity of the complex. We seek to determine the molecular mechanism, the structural basis and functional significance of the JADE engagement with chromatin. We will use a combination of complementary in vitro and in vivo approaches, integrating structural, biochemical, molecular biology, and cell biology tools to gain insight into the role of the JADE zinc finger cassette in biological functions of the HBO complexes. This study is of fundamental importance for understanding the epigenetic mechanisms of acetyltransferase-stimulated transcriptional activation. Elucidating the molecular basis of the JADE/HBO-chromatin interaction is also essential to better understand the etiology of haematological diseases caused by aberrant acetylation and may pave the way for the development of novel therapies to treat or prevent these diseases.