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Wei Xie¡¯s group at School of Life Sciences at Tsinghua University published a research paper in Nature, reporting the dynamics of 3D chromatin architecture in mammalian preimplantation embryos

Research groups of Prof. Wei Xie at Tsinghua University published a research paper in Nature on July 13th, entitled “Allelic reprogramming of 3D chromatin architecture during early mammalian development”. This study reported the dynamics of 3D chromatin organization during mammalian preimplantation development.


In eukaryotes, the linear DNA is compactly packaged in the nucleus through hierarchical organization. The proper three-dimensional folding of chromatin fiber is crucial for many biological processes including gene regulation, DNA replication and recombination. For example, cis-regulatory elements such as enhancers can activate promoters over long distances through chromatin looping. By employing chromosome conformation capture based methods, such as Hi-C, the global chromatin structure has been determined in various cell types from different species in recent years, revealing key principles for 3D genome packaging. For instance, topologically associated domains (TADs) were discovered as possibly one of the fundamental units of higher-order chromatin folding. TADs are largely invariant among different cell types and developmental stages, and are highly conserved among species. On the other hand, chromatin is highly compartmentalized as different regions that are far away from one another can display similar chromatin states and preferential interactions. Two major compartments A and B are frequently observed. Compartment A typically corresponds to mega-base domains that show open chromatin, high levels of gene density and transcription. Compartment B is usually associated with closed chromatin, gene deserts and low levels of transcription. However, owing to the limited experimental materials, how chromatin structure reprogrammed in mammalian early development remains poorly understood. To address this question, Wei Xie’s group developed a low-input Hi-C method termed sisHi-C (small-scale in situ Hi-C). By applying this method on mouse gametes and preimplantation embryos, the authors characterized the allelic reprogramming of chromatin organization during mouse early development.


Wei Xie’s group found sperm shows canonical higher order chromatin structure including TADs and compartments. By contrast, oocytes in metaphase II show homogeneous chromatin folding that lacks detectable topologically associating domains (TADs) and chromatin compartments. Strikingly, chromatin shows greatly diminished higher-order structure after fertilization. Unexpectedly, the subsequent establishment of chromatin organization is a prolonged process that extends through preimplantation development, as characterized by slow consolidation of TADs and segregation of chromatin compartments. The two sets of parental chromosomes are spatially separated from each other and display distinct compartmentalization in zygotes. Such allele separation and allelic compartmentalization can be found as late as the 8-cell stage. Finally, investigators show that chromatin compaction in preimplantation embryos can partially proceed in the absence of zygotic transcription and is a multi-level hierarchical process. Taken together, this work suggests that chromatin may exist in a markedly relaxed state after fertilization, followed by progressive maturation of higher-order chromatin architecture during early development.

Figure 1. A schematic model showing the reprogramming of chromatin organization in early mouse development.

Investigator Wei Xie from School of Life Sciences at Tsinghua University is the corresponding author of this work. Zhenhai Du from CLS program of School of Life Sciences at Tsinghua University is the first author of this work. Dr. Hui Zheng from the CLS program of School of Life Sciences at Tsinghua University, Dr. Bo Huang from CLS program of Academy for Advanced Interdisciplinary Studies of Peking University, and Rui Ma from Institute for Interdisciplinary Information Sciences at Tsinghua University made great contributions to this work. Dr Jingyi Wu from PTN program of School of Life Sciences at Tsinghua University and Xianglin Zhang from Department of Automation were also involved in this work. Collaborators include Jianyang Zeng’s group from Institute for Interdisciplinary Information Sciences at Tsinghua University, Michael Q. Zhang’s group, Xiaowo Wang’s group from Department of Automation at Tsinghua University, Jesse Dixon’s group from Salk Institute for Biological Studies in USA, the animal facility and the sequencing facility at Tsinghua University. This work is supported by the funding provided by the National Key R&D Program of China, National Basic Research Program of China (973 program), the National Natural Science Foundation of China, the National Basic Research Program of China, the funding from the THU-PKU Center for Life Sciences, the Youth Thousand Scholar Program of China, TNLIST Cross-discipline Foundation and the NIH and Beijing Advanced Innovation Center for Structural Biology.


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