Structural and functional analysis of chromatin compaction

染色质紧凑是细胞内的一个关键过程，它调控着许多生物反应，如基因表达、染色质附着在核孔上、端粒稳定性和DNA修复。虽然潜在的机制还不是很清楚，但人们认为染色质调节因子的结合限制了多种因子对DNA的访问。涉及染色质压缩的因素的作用与癌症和神经疾病等疾病有关。目前，SPECK实验室的工作重点是阐明染色质压缩过程中的结构变化及其后果。这个博士项目的目的是通过对重组染色质的冷冻-EM分析，全面阐明一组特定的染色质调节因子对染色质压缩的分子机制，并推断这一过程是如何受到连接子组蛋白的调控的。生物物理技术将被用来研究染色质及其紧凑形式的动力学。一组与疾病相关的染色质压缩因子突变将被评估，以调查这些突变如何影响染色质结构。在PHD项目的过程中，各种DNA序列将被用作染色质组装的模板，包括在人类基因组的异染色质区域中发现的序列，或者与疾病相关的序列。这个项目将有助于对染色质的结构了解，特别是描述异染色质的构象图景。

Chromatin compaction is a key process in the cell, modulating many biological reactions such as gene expression, chromatin attachment to the nuclear pore, telomere stability and DNA repair. Although the underlying mechanisms are not well known, it is thought that the binding of chromatin regulators restricts access of a variety of factors to DNA. The role of factors involved in chromatin compaction is linked to diseases such as cancer and neurological disorders. Currently, work in the Speck lab has been focussing on elucidating the structural changes during chromatin compaction and their consequences. This PhD project will aim to fully elucidate the molecular mechanisms of chromatin compaction by a specific set of chromatin regulators using cryo-EM analysis of reconstituted chromatin, and to deduce how this process is modulated by linker histones. Biophysical techniques will be employed to investigate the dynamics of chromatin and its compacted form. A cohort of disease-associated mutants of chromatin compaction factors will be assessed in order to investigate how these mutants impact on chromatin architecture. During the course of the PhD project various DNA sequences will be used as a template for chromatin assembly, including sequences found in heterochromatic regions of the human genome, or sequences related to disease. This project will help to provide a structural understanding of chromatin and describe in particular the conformational landscape of hetero-chromatin.