SET domain bifurcated histone lysine methyltransferase 1 regulates histone modification and DNA damage response during zygotic genome activation in pigs
- 1Department of Animal Science, Chungbuk National University, Cheongju, Chungbuk 28644, Republic of Korea
- 2Primate Resources Center (PRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Jeongeup-si, Jeollabuk-do 56216, Republic of Korea
Abstract
SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) is a key epigenetic regulator that catalyzes histone H3 lysine 9 trimethylation (H3K9me3), a mark essential for transcriptional repression and heterochromatin formation. Here, we investigated the role of SETDB1 during zygotic genome activation (ZGA) in porcine embryos. SETDB1 knockdown (KD) was induced by microinjecting double-stranded RNA (dsRNA), and its impact on early embryonic development was evaluated. SETDB1 KD decreased H3K9me3 levels, markedly increased H3K9ac, and downregulated ZGA-associated genes. These epigenetic alterations were accompanied by impaired cleavage, reduced blastocyst formation, and a lower total cell number. Upon etoposide-induced DNA double-strand breaks, SETDB1 KD embryos showed reduced expression of key DNA repair proteins, failed to efficiently restore DNA integrity, and exhibited increased apoptosis, indicating a compromised DNA damage response and repair process. SETDB1 KD also reduced HDAC3 expression, suggesting that SETDB1 may regulate HDAC3 to maintain histone acetylation balance. Consistently, HDAC3 inhibition increased H3K9ac, decreased H3K9me3, and reduced SETDB1 protein levels, supporting a reciprocal regulatory relationship. Together, these findings indicate that SETDB1 is important for porcine embryonic development by coordinating histone modifications and safeguarding genomic integrity during ZGA, and they suggest that the interplay between SETDB1 and HDAC3 constitutes a potentially important epigenetic axis for proper histone modification dynamics and developmental competence.
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BibTeX
@article{song2026domain,
title = {{SET domain bifurcated histone lysine methyltransferase 1 regulates histone modification and DNA damage response during zygotic genome activation in pigs}},
author = {Hyeon-Ji Song and Song-Hee Lee and Cheng-Lin Zhan and Qin-Yue Lu and Gyu-Hyun Lee and Jae-Min Sim and Yu-Jin Jo and Ji-Su Kim and Xiang-Shun Cui},
journal = {Zoological Research},
year = {2026},
month = sep,
doi = {10.24272/j.issn.2095-8137.2025.322},
url = {https://doi.org/10.24272/j.issn.2095-8137.2025.322},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - SET domain bifurcated histone lysine methyltransferase 1 regulates histone modification and DNA damage response during zygotic genome activation in pigs
AU - Hyeon-Ji Song
AU - Song-Hee Lee
AU - Cheng-Lin Zhan
AU - Qin-Yue Lu
AU - Gyu-Hyun Lee
AU - Jae-Min Sim
AU - Yu-Jin Jo
AU - Ji-Su Kim
AU - Xiang-Shun Cui
PY - 2026
DA - 2026/09/18
JO - Zoological Research
DO - 10.24272/j.issn.2095-8137.2025.322
UR - https://doi.org/10.24272/j.issn.2095-8137.2025.322
AB - SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) is a key epigenetic regulator that catalyzes histone H3 lysine 9 trimethylation (H3K9me3), a mark essential for transcriptional repression and heterochromatin formation. Here, we investigated the role of SETDB1 during zygotic genome activation (ZGA) in porcine embryos. SETDB1 knockdown (KD) was induced by microinjecting double-stranded RNA (dsRNA), and its impact on early embryonic development was evaluated. SETDB1 KD decreased H3K9me3 levels, markedly increased H3K9ac, and downregulated ZGA-associated genes. These epigenetic alterations were accompanied by impaired cleavage, reduced blastocyst formation, and a lower total cell number. Upon etoposide-induced DNA double-strand breaks, SETDB1 KD embryos showed reduced expression of key DNA repair proteins, failed to efficiently restore DNA integrity, and exhibited increased apoptosis, indicating a compromised DNA damage response and repair process. SETDB1 KD also reduced HDAC3 expression, suggesting that SETDB1 may regulate HDAC3 to maintain histone acetylation balance. Consistently, HDAC3 inhibition increased H3K9ac, decreased H3K9me3, and reduced SETDB1 protein levels, supporting a reciprocal regulatory relationship. Together, these findings indicate that SETDB1 is important for porcine embryonic development by coordinating histone modifications and safeguarding genomic integrity during ZGA, and they suggest that the interplay between SETDB1 and HDAC3 constitutes a potentially important epigenetic axis for proper histone modification dynamics and developmental competence.
SN - 2095-8137
ER -