Structure and functional studies of HDAC complexes

1类组蛋白脱乙酰酶(HDACs 1、2、3)是存在于所有哺乳动物细胞核中的重要酶，它们作为多蛋白共抑制物(Sin3A/B、NuRD、Corest、MIDAC和NCoR/SMRT)的催化成分，帮助调节染色质的结构。这些复合体中的每一个都被特定的转录因子招募到靶向基因来调节转录。结合到特定的复合体是HDAC 1、2和3功能的基础，因为这既指导底物特异性，也调节HDAC的酶活性。组蛋白脱乙酰酶(HDAC)通常被认为是通过从组蛋白尾部的赖氨酸残基中去除乙酰基来调节基因表达的，从而导致染色质凝聚和基因抑制，尽管基因图谱表明HDAC主要位于活性基因，这表明HDAC在几轮转录之间重新设置染色质的作用。这个博士项目将涉及使用结构生物学技术来研究NuRD和Corest复合体的组装和染色质相互作用，以期确定它们的详细作用机制。这项研究将涉及结构和功能两方面的方法，并将利用X射线结晶学、低温电子显微镜以及生物物理和细胞生物学技术。

Class-1 histone deacetylases (HDACs 1, 2, 3) are essential enzymes present in the nucleus of all mammalian cells, where they help regulate chromatin structure as the catalytic component of large multi-protein co-repressor complexes such as Sin3A/B, NuRD, CoREST, MIDAC and NCoR/SMRT. Each of these complexes is recruited to target genes by specific transcription factors to regulate transcription. Incorporation into specific complexes is fundamental to HDAC 1, 2 and 3 function since this directs both substrate specificity as well as regulating the enzymatic activity of the HDAC. Histone deacetylase enzymes (HDACs) are generally thought to regulate gene expression by removing acetyl groups from lysine residues in histone tails resulting in chromatin condensation and gene repression, although gene profiling has shown HDACs are predominately located at active genes, suggesting a role in resetting chromatin between rounds of transcription.This PhD project will involve using structural biology techniques to investigate the assembly and chromatin interactions of the NuRD and CoREST complexes with a view to determining their detailed mechanism of action. The research will involve both structural and functional approaches and will utilise X-ray crystallography, cryo-electron microscopy as well as biophysical and cell biology techniques.