Defective chromatin architectures in embryonic stem cells derived from somatic cell nuclear transfer impair their differentiation potentials

Cheng Peng,Qiao-Ran Sun,Xinxin Li,Tian Xu,Yi-Liang Miao,Xia Zhang,Guo-Wei Bu,Bingbing Luo,Han Luo,Cheng-Li Dou,Haitao Fu,Bin-Guang Ma,Hainan He,Dan-Ya Wu

doi:10.1038/s41419-021-04384-2

Cheng Peng, Qiao-Ran Sun + Show 12 more

Open Access

https://doi.org/10.1038/s41419-021-04384-2

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Abstract

Nuclear transfer embryonic stem cells (ntESCs) hold enormous promise for individual-specific regenerative medicine. However, the chromatin states of ntESCs remain poorly characterized. In this study, we employed ATAC-seq and Hi-C techniques to explore the chromatin accessibility and three-dimensional (3D) genome organization of ntESCs. The results show that the chromatin accessibility and genome structures of somatic cells are re-arranged to ESC-like states overall in ntESCs, including compartments, topologically associating domains (TADs) and chromatin loops. However, compared to fertilized ESCs (fESCs), ntESCs show some abnormal openness and structures that have not been reprogrammed completely, which impair the differentiation potential of ntESCs. The histone modification H3K9me3 may be involved in abnormal structures in ntESCs, including incorrect compartment switches and incomplete TAD rebuilding. Moreover, ntESCs and iPSCs show high similarity in 3D genome structures, while a few differences are detected due to different somatic cell origins and reprogramming mechanisms. Through systematic analyses, our study provides a global view of chromatin accessibility and 3D genome organization in ntESCs, which can further facilitate the understanding of the similarities and differences between ntESCs and fESCs.

Highlights

Nuclear transfer embryonic stem cells provide a resource of patient-matched cells for personalized therapies and disease models with less teratogenic, which hold enormous promise for regenerative medicine [1, 2]
The results show that the chromatin accessibility and genome structures of somatic cells are re-arranged to ESC-like states overall in Nuclear transfer embryonic stem cells (ntESCs), including compartments, topologically associating domains (TADs) and chromatin loops
Our study provides a global view of chromatin accessibility and 3D genome organization in ntESCs, which can further facilitate the understanding of the similarities and differences between ntESCs and fertilized ESCs (fESCs)

Summary

Introduction

Nuclear transfer embryonic stem cells (ntESCs) provide a resource of patient-matched cells for personalized therapies and disease models with less teratogenic, which hold enormous promise for regenerative medicine [1, 2]. Both fertilized ESCs (fESCs) and ntESCs have similar developmental potentials, such as teratoma formation and full-term development of tetraploid complemented embryos [3,4,5]. In addition to ntESCs, induced pluripotent stem cells (iPSCs) are another pluripotent stem cells derived by somatic cell reprogramming and provide potential medical applications [14, 15] They have unique differences in their genetic and epigenetic [16, 17]

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