The role of 3D genome organization in development and cell differentiation


In eukaryotes, the genome does not exist as a linear molecule but instead is hierarchically packaged inside the nucleus. This complex genome organization includes multiscale structural units of chromosome territories, compartments, topologically associating domains, which are often demarcated by architectural proteins such as CTCF and cohesin, and chromatin loops. The 3D organization of chromatin modulates biological processes such as transcription, DNA replication, cell division and meiosis, which are crucial for cell differentiation and animal development. In this Review, we discuss recent progress in our understanding of the general principles of chromatin folding, its regulation and its functions in mammalian development. Specifically, we discuss the dynamics of 3D chromatin and genome organization during gametogenesis, embryonic development, lineage commitment and stem cell differentiation, and focus on the functions of chromatin architecture in transcription regulation. Finally, we discuss the role of 3D genome alterations in the aetiology of developmental disorders and human diseases.

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Fig. 1: The hierarchical organization of the 3D genome.
Fig. 2: Chromatin architecture dynamics during mammalian gamete development.
Fig. 3: Chromatin architecture dynamics during early development in mammals.
Fig. 4: Different modes of interactions among cis-regulatory elements in development.
Fig. 5: Misregulation of the 3D genome in human diseases.


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The authors thank B. Ren and J. Xu for careful reading of the manuscript. The authors thank Z. Du, Y. Wang, Y. Zhang and other members of the Xie laboratory for valuable comments. This Review included only selected studies as an illustration of the recent progress of our understanding of the 3D genome in development; the authors apologize to researchers whose studies could not be cited owing to space limitations. The work was supported by the National Key R&D Program of China (2016YFC0900300 to W.X.), the National Basic Research Program of China (2015CB856201 to W.X.), the National Natural Science Foundation of China (31725018 and 31830047 to W.X.), the Beijing Municipal Science & Technology Commission (Z181100001318006 to W.X.), the THU–PKU Center for Life Sciences, and Beijing Advanced Innovation Center for Structural Biology (W.X.). H.Z. is supported by a postdoctoral fellowship from the THU–PKU Center for Life Sciences. W.X. is a recipient of HHMI International Research Scholar.

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Nature Reviews Molecular Cell Biology thanks P. Fraser and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Both authors equally contributed to researching data for the article, the discussion of content, writing of the manuscript and its editing before submission.

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Correspondence to Wei Xie.

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The process in which diploid gamete-precursor cells undergo meiotic division and differentiation to form mature sperm and oocytes.

Primordial germ cells

(PGCs). The germline ancestor cells of both sperm and oocytes. PGCs are diploid and are first found in the primary ectoderm of the epiblast.


Small, arginine-rich nuclear proteins that are specifically found in the haploid phase of mature sperm and that largely replace histones as the DNA-packaging proteins.


A stage of prophase in meiosis I. During diplotene, the synaptonemal complex degrades and two homologous chromosomes separate from each other and uncoil.


A totipotent cell has the capacity to divide and produce all the differentiated cells of both embryonic and extraembryonic tissues.

Zygotic genome activation

(ZGA). The activation of gene transcription from the zygote genome after fertilization.


A process of early embryonic development during which the single-layer blastula is reorganized to form a multilayer structure known as the gastrula.


A condensed form of chromatin in which gene activity is usually repressed.

Nuclear lamina

A mesh structure just inside the nuclear membrane that is composed of lamins and lamin-associated proteins.

Nuclear speckles

Also known as splicing speckles, these are nuclear domains enriched in pre-mRNA splicing factors and located in interchromatin regions of the nucleoplasm.


Genomic regions comprising multiple enhancers that are collectively bound by multiple transcription factors to drive gene transcription.

Synaptonemal complex

A structure that forms between homologous chromosomes during meiosis and functions in mediating chromosome pairing, synapsis and recombination.


A stage of prophase in meiosis I during which the paired chromosomes shorten and thicken. Homologous recombination occurs during this stage.

Meiotic sex chromosome inactivation

In spermatogenesis, the transcriptional silencing of the X and Y chromosomes during meiotic pachytene.

Maternal-to-zygotic transition

The stage in early embryonic development when the zygotic genome takes control of development from the maternal genome. This transition requires zygotic genome activation and the degradation of maternal RNA and proteins.

Germinal vesicle oocytes

Growing or grown oocytes arrested in prophase of meiosis I before ovulation. The germinal vesicle refers to their nucleus, which is clearly visible under the microscope.


The paternal and maternal nuclei just after fertilization, when they are still physically separated in the zygote.

Somatic cell nuclear transfer

A technique for creating a viable embryo by transferring a donor nucleus of a somatic cell to an enucleated oocyte.

Naive pluripotency

In preimplantation embryos, pluripotent stem cells in the epiblast are in a ‘naive’ state. They become ‘primed’ during postimplantation development.


cis-regulatory elements that can block the function of enhancers or the spreading of gene silencing. The word can also refer to the protein complexes that bind to these elements, such as CTCF.

2i ground-state pluripotent mouse ESCs

Mouse embryonic stem cells cultured in the presence of MEK and glycogen synthase kinase 3 inhibitors and thought to be in a naive ground state.

Primed-like pluripotent state

Mouse embryonic stem cells cultured in serum that are thought to be epigenetically more restricted and developmentally primed than 2i ground-state pluripotent mouse embryonic stem cells and are similar to cells in the postimplantation epiblast.

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Zheng, H., Xie, W. The role of 3D genome organization in development and cell differentiation. Nat Rev Mol Cell Biol 20, 535–550 (2019).

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