Department of Biochemistry and Biophysics, Graduate Program in Biochemistry and Molecular Biophysics, Penn Center for Genome Integrity, and Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, 98195, USA.
Exp Cell Res. 2020 Jun 15;391(2):111978. doi: 10.1016/j.yexcr.2020.111978. Epub 2020 Apr 1.
Centromeres are essential components of all eukaryotic chromosomes, including artificial/synthetic ones built in the laboratory. In humans, centromeres are typically located on repetitive α-satellite DNA, and these sequences are the "major ingredient" in first-generation human artificial chromosomes (HACs). Repetitive centromeric sequences present a major challenge for the design of synthetic mammalian chromosomes because they are difficult to synthesize, assemble, and characterize. Additionally, in most eukaryotes, centromeres are defined epigenetically. Here, we review the role of the genetic and epigenetic contributions to establishing centromere identity, highlighting recent work to hijack the epigenetic machinery to initiate centromere identity on a new generation of HACs built without α-satellite DNA. We also discuss the opportunities and challenges in developing useful unique sequence-based HACs.
着丝粒是所有真核染色体的基本组成部分，包括实验室中构建的人工/合成染色体。在人类中，着丝粒通常位于重复的α-卫星 DNA 上，这些序列是第一代人类人工染色体（HAC）的“主要成分”。重复的着丝粒序列给合成哺乳动物染色体的设计带来了重大挑战，因为它们难以合成、组装和表征。此外，在大多数真核生物中，着丝粒是通过表观遗传定义的。在这里，我们回顾了遗传和表观遗传对建立着丝粒身份的贡献，强调了最近利用表观遗传机制在新一代不含有α-卫星 DNA 的 HAC 上启动着丝粒身份的工作。我们还讨论了开发有用的基于独特序列的 HAC 的机会和挑战。
