物理化学学报 >> 2020, Vol. 36 >> Issue (1): 1907010.doi: 10.3866/PKU.WHXB201907010

所属专题: 庆祝唐有祺院士百岁华诞特刊

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基于一维序列的三维染色质相分离:驱动力、过程与功能

刘思睿1,权慧1,田昊1,周瑞2,杨立江1,高毅勤1,2,*()   

  1. 1 北京大学化学与分子工程学院,北京 100871
    2 北京大学生物医学前沿创新中心(BIOPIC),北京 100871
  • 收稿日期:2019-07-01 录用日期:2019-08-30 发布日期:2019-09-06
  • 通讯作者: 高毅勤 E-mail:gaoyq@pku.edu.cn
  • 作者简介:高毅勤,1972年出生。1993年本科毕业于四川大学化学学院,1996年在中国科学院化学研究所获硕士学位,2001年在美国加州理工学院获得博士学位。2010年起任北京大学化学与分子工程学院教授,2013年起同时担任北京大学生物动态光学成像中心研究员。现为教育部长江学者特聘教授,国家杰出青年科学基金获得者,科技部“中青年科技创新领军人才”。主要从事生物物理化学/理论化学方面的基础研究,寻求复杂化学和生物体系的物理本质和分子机理
  • 基金资助:
    国家自然科学基金(21573006);国家自然科学基金(21821004);国家自然科学基金(21873007);国家重点研发计划(2017YFA0204702)

1D Sequence Based 3D Chromatin Phase Separation: Forces, Processes, and Functions

Sirui Liu1,Hui Quan1,Hao Tian1,Rui Zhou2,Lijiang Yang1,Yiqin Gao1,2,*()   

  1. 1 College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, P. R. China
    2 Biomedical Pioneering Innovation Center, Peking University, Beijing 100871, P. R. China
  • Received:2019-07-01 Accepted:2019-08-30 Published:2019-09-06
  • Contact: Yiqin Gao E-mail:gaoyq@pku.edu.cn
  • Supported by:
    the National Natural Science Foundation of China(21573006);the National Natural Science Foundation of China(21821004);the National Natural Science Foundation of China(21873007);the National Key R & D Program of China(2017YFA0204702)

摘要:

染色质高级结构在基因调控中起到不可忽视的作用,染色质结构的形成与调控机制受到广泛关注。“相分离”理论近年来受到较多关注,异染色质与转录因子在其中的作用引人瞩目。但是,目前的相分离模型更关注结合因子与表观遗传性质,对DNA序列自身的作用理解尚较不充分。许多物种基因组的序列分布均具有多尺度的不均一性,仅基于CpG岛(CpG island,CGI)密度差异这一序列性质,就可以划分出基因、表观遗传、结构和转录性质都截然不同的高CGI密度“森林”和低CGI密度“草原”两种序列区域,体现了基因组自身的马赛克性。本文聚焦染色质结构的序列依赖性,讨论了染色质结构模型的研究进展,关注在序列几乎相同的不同细胞类型中的序列-结构关系及其功能调控,对发育、分化、衰老、疾病等多种过程的染色质结构变化进行了系统分析。针对基于序列的染色质相分离模型,对其物理驱动力进行了讨论,并在该模型的框架下基于相分离的物理特性,对温度、序列不均一性等物理因素对染色质结构可能造成的影响进行了探讨。

关键词: 相分离, 序列马赛克性, CGI森林和草原, 发育与分化, 老化与疾病

Abstract:

The high-order chromatin structure plays a non-negligible role in gene regulation. The formation of chromatin structure and its regulatory mechanisms have been studied intensely. To analyze the high-order chromatin structures, both computational and physical models have been developed, including polymer physics models and molecular crowding models. Over the past few years, the phase separation theory has drawn a lot of research interest, and the effect of heterochromatin and transcriptional factors (TFs) on phase separation has attracted much attention. Existing phase separation models for chromatin focus on multivalent molecules or on epigenetic properties and does not adequately explore the dependence of chromatin structure organization and remodeling on DNA sequence. Genomes of a number of species are highly uneven at multiple scales. It can be divided purely based on sequential properties into two sequentially, epigenetically, and transcriptionally distinct regions, namely forest and prairie domains, demonstrating the intrinsic mosaicity in genome. Compared to prairies, forest domains are on average more gene-rich, accessible, transcriptionally active, higher in open-sea methylation level, and are enriched in RNA polymerase Ⅱ binding sites as well as active histone modifications. Moreover, different structural properties of these two types of sequential domains suggest that sequence may play a role in topologically associated domain (TAD) and compartment formation. The chromatin sequence-structural relationship and functional regulation in different cell types with almost identical sequences are discussed in this review. We try to describe the evolution of chromatin structure in multiple biological processes including early development, differentiation, and senescence in a unified framework. The forest and prairie domains with high and low CGI densities, respectively, show enhanced segregation from each other in development, differentiation, and senescence. Meanwhile the multiscale forest-prairie spatial intermingling is cell-type specific and increases upon differentiation, thereby helping to define cell identity. The consistency between chromatin structure and open-sea methylation level suggests that the latter is a promising indicator of structural segregation, deepening our understanding of epigenetic-structure relation. We further discuss the physical driving forces of phase separation as well as their biological implications. The phase separation of the uneven 1D sequence in 3D space serves as a potential driving force, and together with cell type specific epigenetic marks and transcription factors shapes the chromatin structure in different cell types. Transcriptional complex along with dynamic TFs and epigenetic marks may account for local structure formation and separation, regulating chromatin structure at a smaller spatial-temporal scale based on their sequential environment. Finally, role of physical factors like temperature and sequence unevenness in affecting chromatin structure have also been discussed.

Key words: Phase separation, Sequence mosaicity, Forest and prairie domains, Development and differentiation, Aging and disease

MSC2000: 

  • O641