Assembly and epigenetic inheritance of the human centromere

描述（由申请人提供）：着丝粒是一种独特的染色质结构域，由含有着丝粒蛋白a （CENP-A）的着丝粒特异性核小体的结合定义。着丝粒招募有丝分裂着丝点以确保有丝分裂期间染色体的均匀分离。着丝粒沿染色体的位置是由依赖于核小体的表观遗传机制决定的。新的CENP-A核小体在G1早期的一个离散时间内组装成分裂细胞的着丝粒。着丝粒的繁殖需要在DNA复制之前组装新的CENP-A核小体，以避免因连续稀释而丢失CENP-A核小体。先前我们确定Mis18复合体的募集是表观遗传的决定性步骤。本研究将探索新的CENP-A通过Mis18复合体的募集进入着丝粒的机制。典型组蛋白受到多种翻译后修饰（PTMs）的影响，这些修饰驱动染色质相关因子的募集并改变底层染色质的功能。我们将探索CENP-A尾部两个新发现的PTMs的功能，氨基端三甲基化和丝氨酸16和18的双磷酸化。本文提出的实验将极大地促进我们对着丝粒遗传的表观遗传机制的理解。此外，这项工作的影响将超越着丝粒，为乙酰化和甲基化或其他组蛋白变体编码的表观遗传信息的传播提供重要的见解。

DESCRIPTION (provided by applicant): The centromere is a unique chromatin domain defined by the incorporation of a centromere specific nucleosome containing centromere protein-A (CENP-A). The centromere recruits the mitotic kinetochore to ensure the equal segregation of chromosomes during mitosis. The location of the centromere along the chromosome is determined by an epigenetic mechanism that relies on the CENP-A nucleosome. New CENP-A nucleosomes are assembled into the centromeres of dividing cells during a discreet time in early G1. Propagation of the centromere requires assembly of new CENP-A nucleosomes prior to DNA replication to avoid the loss of CENP-A nucleosomes through their successive dilution. Previously we determined Mis18 complex recruitment is the defining step in epigenetic inheritance. This proposal will explore the mechanism by which new CENP-A is recruited to centromeres through the recruitment of the Mis18 complex. Canonical histones are subject to multiple posttranslational modifications (PTMs) that drive the recruitment of chromatin associated factors and modify the function of the underlying chromatin. We will explore the function of two newly identified PTMs of the CENP-A tail, amino-terminal trimethylation and dual phosphorylation of serine 16 and 18. The experiments proposed here will significantly advance our understanding of the epigenetic mechanism of centromere inheritance. Furthermore, the impact of this work will extend beyond the centromere to provide significant insight into the propagation of epigenetic information encoded by acetylation and methylation or other histone variants.