Chromatin Remodeling Complex in the spreading of silent heterochromatin

描述(申请人提供)：衰老，无论是自然的还是疾病驱动的，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，随着细胞年龄的增长，染色质的变化与NuRD染色质重塑复合体之间存在着物理和功能上的联系。NuRD是一种独特的染色质修饰复合体，因为它包含组蛋白脱乙酰酶的物理结合以及核小体重塑活性。虽然似乎不存在于萌芽酵母中，但从分裂酵母S.pombe中纯化出了一种高度相似的复合体SHREC，它似乎以类似于哺乳动物NuRD的方式调节异染色质。这项建议试图利用酵母遗传学和体外生物化学的易操纵性来研究SHREC依赖的异染色质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体在修饰核小体底物方面的活性。

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.