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Review
. 2022 Dec 21;11(1):42.
doi: 10.1186/s13619-022-00145-4.

The dynamics of three-dimensional chromatin organization and phase separation in cell fate transitions and diseases

Xiaoru Ling #  1   2   3 , Xinyi Liu #  1   2   3 , Shaoshuai Jiang  1   2   3 , Lili Fan  4 , Junjun Ding  5   6   7   8   9
Affiliations
Review

The dynamics of three-dimensional chromatin organization and phase separation in cell fate transitions and diseases

Xiaoru Ling et al. Cell Regen. .

Abstract

Cell fate transition is a fascinating process involving complex dynamics of three-dimensional (3D) chromatin organization and phase separation, which play an essential role in cell fate decision by regulating gene expression. Phase separation is increasingly being considered a driving force of chromatin folding. In this review, we have summarized the dynamic features of 3D chromatin and phase separation during physiological and pathological cell fate transitions and systematically analyzed recent evidence of phase separation facilitating the chromatin structure. In addition, we discuss current advances in understanding how phase separation contributes to physical and functional enhancer-promoter contacts. We highlight the functional roles of 3D chromatin organization and phase separation in cell fate transitions, and more explorations are required to study the regulatory relationship between 3D chromatin organization and phase separation. 3D chromatin organization (shown by Hi-C contact map) and phase separation are highly dynamic and play functional roles during early embryonic development, cell differentiation, somatic reprogramming, cell transdifferentiation and pathogenetic process. Phase separation can regulate 3D chromatin organization directly, but whether 3D chromatin organization regulates phase separation remains unclear.

Keywords: 3D chromatin organization; Cell fate transitions; Disease; Phase separation.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Dynamics of 3D chromatin organization during different cell fate transitions and diseases. A During early embryogenesis, compartments, TADs and chromatin loops are reestablished at species-specific stage; frequently interacting regions (FIREs) are identified as well, within which super-enhancers are enriched. B During cell differentiation, A-to-B compartment shift and interactions within B compartments increase; TAD number decreases and TAD size increases; tissue-specific E-P interactions are established consistent with cell-specific gene expression; increased centromere and telomere clusters (Rabl configuration) are formed. C During somatic cell reprogramming, the proportion of A compartments are slightly increased; TAD dynamics are opposed to that in cell differentiation; long-range pluripotency contacts and 3D enhancer hubs are formed. D During pathogenetic process, compartments undergo muti-directional and complex dynamics in different diseases; TAD boundary disruption are mainly caused by structural variations at boundary loci; loss of CTCF binding lead to loop disassembly; Lamin-associated domains are reorganized, such as abnormal reduction in HGPS fibroblast cells
Fig. 2
Fig. 2
Dynamics of phase separation during different cell fate transitions. A Typical phase separation dynamics during early embryogenesis. (1) In C.elegans zygote, P granules are initially distributed in the cytoplasm evenly, and become enriched in the posterior by asymmetric cell division. (2) During C.elegans germline blastomere-to-germ cell transition, Z granule (green) separates from P granule (yellow) near the nucleus. (3) At the onset of ZGA in mice, nucleolus (purple), Cajal bodies (green) and HLB bodies (orange) are assembled at rRNA gene locus, snRNA gene locus and histone gene locus respectively. B Typical phase separation dynamics during cell differentiation. (1) During Drosophila oogenesis, polar granules aggregate at the posterior pole of oocytes initiated by mRNA transport from the nurse cells. (2) During Xenopus/zebrafish oogenesis, the Balbiani body is a large condensate consisting of germ granules and mitochondria near the nucleus, and disperses to vegetal hemisphere during oocyte growth. (3) During mouse spermatogenesis, piP-body locates adjacent to pi-bodies in prospermatogonia firstly, and then fuses with pro-chromatoid body to form mature chromatoid body before round spermatid stage. C During skin barrier formation, keratohyalin granules are gradually formed, and then dissolved due to the dramatic pH decrease
Fig. 3
Fig. 3
Research strategies for studying the relationship between 3D chromatin organization and phase separation. A Artificially induce condensates at specific genomic loci to form chromatin loops by the combination of light induction, CRISPR-Cas9, and IDR-induced phase separation in CasDrop system. B Globally damage phase separation in the nucleus by 1.5% 1,6-HD treatment for 2 min, which leads to strengthened compartment segregation, homogenized A-A interactions, B-A compartment switching, TAD reorganization and weakened long-range interactions. C Disrupt distinct nuclear condensates by key phase-separating protein mutations and rescue them through IDR fusion to observe 3D chromatin reorganization
Fig. 4
Fig. 4
Coordinated or independent roles of 3D chromatin organization and phase separation in cell fate regulation. A Phase separation affects cell type-specific gene expression to regulate cell fate by regulating 3D chromatin structure at different hierarchies. B Specific chromatin structure recruits different phase separations and affects cell type-specific gene expression to regulate cell fate. C Phase separation and 3D chromatin structure affect cell type-specific gene expression to regulate cell fate without interfering with each other
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