2. Academic Validation
  3. Maternal transcription factor OTX2 directly induces SETD1A and promotes embryonic genome activation in human pre-implantation embryos

Maternal transcription factor OTX2 directly induces SETD1A and promotes embryonic genome activation in human pre-implantation embryos

  • Sci China Life Sci. 2025 Jul;68(7):2058-2072. doi: 10.1007/s11427-024-2875-3.
Tianlei Zhang 1 2,  Ziyan Peng 2,  Fei Meng 1,  Zhuo Li 1,  Junru Chen 3,  Qinwei Zhou 1,  Lizhi Leng 1 4,  Hao Bo 1,  Guangxiu Lu 1 4,  Yun Deng 5 6,  Feng Gu 7 8,  Ge Lin 9 10 11
Affiliations

Affiliations

  • 1 Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, 410205, China.
  • 2 College of Life Sciences, Hunan Normal University, Changsha, 410081, China.
  • 3 State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, 999078, China.
  • 4 NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, School of Basic Medical Sciences, Central South University, Changsha, 410008, China.
  • 5 College of Life Sciences, Hunan Normal University, Changsha, 410081, China. dengyun@hunnu.edu.cn.
  • 6 Laboratory of Zebrafish Genetics, College of Life Sciences, Hunan Normal University, Changsha, 410081, China. dengyun@hunnu.edu.cn.
  • 7 Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, School of Medicine, Hunan Normal University, Engineering Research Center of Reproduction and Translational Medicine of Hunan Province, Changsha, 410013, China. fgu@hunnu.edu.cn.
  • 8 Guangxiu Hospital Affiliated with Hunan Normal University (Hunan Guangxiu Hospital), Changsha, 410017, China. fgu@hunnu.edu.cn.
  • 9 Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, 410205, China. 803191@csu.edu.cn.
  • 10 NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, School of Basic Medical Sciences, Central South University, Changsha, 410008, China. 803191@csu.edu.cn.
  • 11 Guangxiu Hospital Affiliated with Hunan Normal University (Hunan Guangxiu Hospital), Changsha, 410017, China. 803191@csu.edu.cn.
PMID: 40285911 DOI: 10.1007/s11427-024-2875-3
Abstract

Early embryonic development is controlled by maternal factors originating from mature oocytes. The zygotic genome is activated from a transcriptionally quiescent state through a process called embryonic genome activation (EGA), which involves the depletion and clearance of maternal factors. However, the mechanism by which maternal factors regulate EGA and embryonic development, particularly in humans, remains elusive. In this study, using tri-pronuclear (3PN) embryos and human embryonic stem cells (hESCs), we demonstrated that the maternal transcription factor Orthodenticle Homeobox 2 (OTX2), a paired-like homeobox gene, promotes EGA in human pre-implantation embryos. Knockdown of OTX2 through Trim-Away technology blocked embryonic development and minor EGA gene expression. Overexpression of OTX2 (OTX2OE) in hESCs increased transcript products, primarily at the 2-cell embryo stage genes, including genes encoding methyltransferase of histone H3K4. OTX2OE increased the level of H3K4me3 and increased the open chromatin region that co-occurs with the H3K4me3 region at the 4-cell stage in hESCs. Based on these findings in hESCs, we further verified that OTX2 directly induced the expression of SETD1A by binding to its promoter, leading to increased H3K4me3 levels in both hESCs and 3PN embryos. These findings suggest that the maternal transcription factor OTX2 regulates EGA and early embryogenesis via epigenetic mechanisms.

Keywords

SETD1A; OTX2; embryonic genome activation; maternal transcription factor.

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