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Setd2 overexpression rescues bivalent gene expression during SCNT-mediated ZGA
Xiaolei Zhang1,2, Ruimin Xu1,2, Yuyan Zhao1,2
1Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Clinical and Translation Research Center, Shanghai First Maternity and Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
Protein & Cell
|February 13, 2025
Summary
Overcoming epigenetic barriers in cloning is key. Enhancing H3K36me3 levels in cloned embryos resolves aberrant epigenetic marks, significantly improving cloning efficiency.
Area of Science:
- Epigenetics
- Developmental Biology
- Reproductive Science
Background:
- Somatic cell nuclear transfer (SCNT) cloning is hindered by epigenetic reprogramming obstacles.
- Histone modifications, specifically H3K4me3 and H3K27me3, are implicated in these SCNT challenges.
- The precise mechanisms by which these epigenetic marks impede cloning remain largely undefined.
Purpose of the Study:
- To investigate the genome-wide distribution of H3K4me3 and H3K27me3 in mouse pre-implantation cloned embryos.
- To elucidate the role of aberrant epigenetic marks in SCNT-mediated developmental errors.
- To identify strategies for enhancing cloning efficiency by manipulating epigenetic landscapes.
Main Methods:
- Generation of genome-wide H3K4me3 and H3K27me3 maps in mouse cloned (NT) and naturally fertilized (NF) embryos.
- Quantitative analysis of histone mark distribution and bivalent promoter states.
- Overexpression of the H3K36me3 methyltransferase, Setd2, in cloned embryos.
Main Results:
- Cloned embryos exhibit increased bivalent marks (H3K4me3/H3K27me3) at gene promoters compared to NF embryos, linked to reduced H3K36me3.
- Setd2 overexpression normalized H3K36me3 levels, corrected aberrant H3K4me3 and H3K27me3 patterns, and restored ZGA gene expression.
- Restoration of H3K36me3 at gene bodies reduced bivalent promoter marks, thereby improving cloning outcomes.
Conclusions:
- Excessive bivalent promoter states represent a significant barrier to successful SCNT cloning.
- Targeted manipulation of H3K36me3, such as through Setd2, can resolve these epigenetic barriers.
- Enhancing H3K36me3 is a promising strategy to improve the efficiency of somatic cell nuclear transfer cloning.
