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ORIGINAL ARTICLES

Dynamic nucleosome organization after fertilization reveals regulatory factors for mouse zygotic genome activation

Chenfei Wang1,2,† , Chuan Chen1,3,† , Xiaoyu Liu1,4,† , Chong Li5,† , Qiu Wu5 , Xiaolan Chen1,4 , Lingyue Yang5 , Xiaochen Kou5 , Yanhong Zhao5 , Hong Wang5 , Yawei Gao1,4,* , Yong Zhang1,4,* , Shaorong Gao1,4,5,*

1Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
2Department of Urology, Tongji Hospital, Frontier Science Center for Stem Cells, School of Life Science and Technology, Tongji University, Shanghai, China
3Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
4Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China
5Clinical and Translation Research Center of Shanghai First Maternity & Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
These authors contributed equally: Chenfei Wang, Chuan Chen, Xiaoyu Liu, Chong Li
* Correspondence: Yawei Gao(gaoyawei@tongji.edu.cn)Yong Zhang(yzhang@tongji.edu.cn)Shaorong Gao(gaoshaorong@tongji.edu.cn)

Chromatin remodeling is essential for epigenome reprogramming after fertilization. However, the underlying mechanisms of chromatin remodeling remain to be explored. Here, we investigated the dynamic changes in nucleosome occupancy and positioning in pronucleus-stage zygotes using ultra low-input MNase-seq. We observed distinct features of inheritance and reconstruction of nucleosome positioning in both paternal and maternal genomes. Genome-wide de novo nucleosome occupancy in the paternal genome was observed as early as 1 h after the injection of sperm into ooplasm. The nucleosome positioning pattern was continually rebuilt to form nucleosome-depleted regions (NDRs) at promoters and transcription factor (TF) binding sites with differential dynamics in paternal and maternal genomes. NDRs formed more quickly on the promoters of genes involved in zygotic genome activation (ZGA), and this formation is closely linked to histone acetylation, but not transcription elongation or DNA replication. Importantly, we found that NDR establishment on the binding motifs of specific TFs might be associated with their potential pioneer functions in ZGA. Further investigations suggested that the predicted factors MLX and RFX1 played important roles in regulating minor and major ZGA, respectively. Our data not only elucidate the nucleosome positioning dynamics in both male and female pronuclei following fertilization, but also provide an efficient method for identifying key transcription regulators during development.

https://doi.org/10.1038/s41422-022-00652-8

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