Dux-Mediated Corrections of Aberrant H3K9ac during 2-Cell Genome Activation Optimize Efficiency of Somatic Cell Nuclear Transfer

Guang Yang; Linfeng Zhang; Wenqiang Liu; Zhibin Qiao; Shijun Shen; Qianshu Zhu; Rui Gao; Mengting Wang; Mingzhu Wang; Chong Li; Meng Liu; Jin Sun; Liping Wang; Wenju Liu; Xinyu Cui; Kun Zhao; Ruge Zang; Mo Chen; Zehang Liang; Lu Wang; Xiaochen Kou; Yanhong Zhao; Hong Wang; Yixuan Wang; Shaorong Gao; Jiayu Chen; Cizhong Jiang

doi:10.1016/j.stem.2020.09.006

Dux-Mediated Corrections of Aberrant H3K9ac during 2-Cell Genome Activation Optimize Efficiency of Somatic Cell Nuclear Transfer

Cell Stem Cell. 2021 Jan 7;28(1):150-163.e5. doi: 10.1016/j.stem.2020.09.006. Epub 2020 Oct 12.

Authors

Guang Yang¹, Linfeng Zhang², Wenqiang Liu², Zhibin Qiao³, Shijun Shen⁴, Qianshu Zhu⁴, Rui Gao², Mengting Wang², Mingzhu Wang², Chong Li², Meng Liu⁴, Jin Sun⁴, Liping Wang⁴, Wenju Liu⁴, Xinyu Cui⁴, Kun Zhao², Ruge Zang², Mo Chen², Zehang Liang⁴, Lu Wang⁴, Xiaochen Kou², Yanhong Zhao², Hong Wang², Yixuan Wang⁵, Shaorong Gao⁶, Jiayu Chen⁷, Cizhong Jiang⁸

Affiliations

¹ Clinical and Translation Research Center of Shanghai First Maternity & Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China; Frontier Science Center for Stem Cell Research, Tongji University, Shanghai 200092, China; Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, Tongji University, Shanghai 200065, China.
² Clinical and Translation Research Center of Shanghai First Maternity & Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China; Frontier Science Center for Stem Cell Research, Tongji University, Shanghai 200092, China.
³ Clinical and Translation Research Center of Shanghai First Maternity & Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China; Frontier Science Center for Stem Cell Research, Tongji University, Shanghai 200092, China; Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P.R. China.
⁴ Frontier Science Center for Stem Cell Research, Tongji University, Shanghai 200092, China; Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, Tongji University, Shanghai 200065, China.
⁵ Frontier Science Center for Stem Cell Research, Tongji University, Shanghai 200092, China; Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P.R. China.
⁶ Clinical and Translation Research Center of Shanghai First Maternity & Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China; Frontier Science Center for Stem Cell Research, Tongji University, Shanghai 200092, China; Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P.R. China. Electronic address: gaoshaorong@tongji.edu.cn.
⁷ Clinical and Translation Research Center of Shanghai First Maternity & Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China; Frontier Science Center for Stem Cell Research, Tongji University, Shanghai 200092, China. Electronic address: chenjiayu@tongji.edu.cn.
⁸ Frontier Science Center for Stem Cell Research, Tongji University, Shanghai 200092, China; Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, Tongji University, Shanghai 200065, China. Electronic address: czjiang@tongji.edu.cn.

PMID: 33049217
DOI: 10.1016/j.stem.2020.09.006

Abstract

Differentiated somatic cells can be reprogrammed to totipotent embryos through somatic cell nuclear transfer (SCNT) with low efficiency. The histone deacetylase inhibitor trichostatin A (TSA) has been found to improve SCNT efficiency, but the underlying mechanism remains undetermined. Here, we examined genome-wide H3K9ac during SCNT embryo development and found that aberrant H3K9ac regions resulted in reduced 2-cell genome activation. TSA treatment largely corrects aberrant acetylation in SCNT embryos with an efficiency that is dictated by the native epigenetic environment. We further identified that the overexpression of Dux greatly improves SCNT efficiency by correcting the aberrant H3K9ac signal at its target sites, ensuring appropriate 2-cell genome activation. Intriguingly, the improvement in development mediated by TSA and Kdm4b is impeded by Dux knockout in SCNT embryos. Together, our study reveals that reprogramming of H3K9ac is important for optimal SCNT efficiency and identifies Dux as a crucial transcription factor in this process.

Keywords: Dux; H3K9ac; H3K9me3; Kdm4; SCNT; TSA; epigenetic barrier; reprogramming.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Blastocyst*
Cloning, Organism
Embryo, Mammalian*
Embryonic Development
Histone Deacetylase Inhibitors / pharmacology
Histones
Hydroxamic Acids / pharmacology
Nuclear Transfer Techniques

Substances

Histone Deacetylase Inhibitors
Histones
Hydroxamic Acids