Chromatin Remodeling Complex in the spreading of silent heterochromatin

描述（由申请人提供）：衰老，无论是自然的还是疾病驱动的，都伴随着全球表观遗传变化，包括沉默的异染色质的破坏。最近，在细胞老化时发生的染色质变化与NuRD染色质重塑复合体之间建立了物理和功能上的联系。NuRD是一种独特的染色质修饰复合物，它具有组蛋白去乙酰化酶和核小体重塑活性的物理关联。虽然在出芽酵母中似乎不存在，但从裂变酵母S. pombe中纯化出了一种高度相似的复合物，SHREC，它似乎以一种类似于哺乳动物NuRD的方式调节异染色质。本研究旨在利用酵母遗传学和体外生物化学的可追溯性来研究异染色质依赖于SHREC扩散的分子和生化基础，目的是表征保守的染色质结合模块的重要性以及复合物在修饰核小体底物中的活性。

DESCRIPTION (provided by applicant): Ageing, either natural or disease-driven, is accompanied by global epigenetic changes including the disruption of silent heterochromatin. Recently, a physical and functional connection has been made between the chromatin changes that occur as cells age and the NuRD chromatin remodeling complex. NuRD is a unique chromatin modifying complex in that it harbors the physical association of histone deacetylase as well as nucleosome remodelling activity. While seemingly absent from budding yeast, a highly similar complex, SHREC, has been purified from the fission yeast S. pombe which appears to regulate heterochromatin in a manner similar to mammalian NuRD. This proposal seeks to investigate the molecular and biochemical basis for SHREC- dependent spreading of heterochromatin using the tractability of yeast genetics and in vitro biochemistry with the intent of characterizing the importance of conserved chromatin binding modules as well as activity of the complex in modifying nucleosomal substrates.