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Peer-reviewedCC BY-NC-ND 4.0Communications Biology

ALKBH5 is required to maintain proper SETDB1 protein levels associated with meiotic sex chromosome inactivation

  • Qingqing Chen1,2
  • Yu Xiang1,2
  • Yang Song1,2
  • Sisi Wang1,2
  • Qingwen Wu1,2
  • Zhekun Li1,2
  • Qichao Chen1,2
  • Min Zhang1,2
  • Yimin Zhu1,2,3,4
  • Long Bai1,2,3,4
4 affiliations
  1. 1Key Laboratory of Reproductive Genetics (Ministry of Education), Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
  2. 2Department of Reproductive Endocrinology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, China
  3. 3Institute of Medical Genetics and Development, Zhejiang University, Hangzhou, China
  4. 4Zhejiang Key Laboratory of Maternal and Infant Health, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Abstract

N6-methyladenosine (m6A) is the most abundant RNA modification in eukaryotes. ALKBH5 is an m6A demethylase that is essential for spermatogenesis. However, its function in meiotic prophase remains elusive. Here, we report that Alkbh5-knockout spermatocytes exhibit normal double-strand break (DSB) formation, homologous recombination and synapsis on autosomes but impaired synapsis between sex chromosomes. ALKBH5 depletion causes a significantly upregulated transcriptome on sex chromosomes and meiotic sex chromosome inactivation (MSCI) defects in spermatocytes at the pachytene stage. Mechanistically, ALKBH5 regulates SETDB1 expression in a post-transcriptional manner. Alkbh5 knockout inhibits SETDB1 protein expression, leading to the decreased SETDB1 signals on sex chromosomes and subsequently inhibiting H3K9me3 to form heterochromatin and silence transcriptional activity. Taken together, our findings identify ALKBH5 as a critical regulator of male meiosis by demonstrating that it is required to maintain proper SETDB1 protein levels, which in turn ensures the faithful execution of MSCI.

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Cite

BibTeXRIS
BibTeX
@article{chen2026alkbh5,
  title = {{ALKBH5 is required to maintain proper SETDB1 protein levels associated with meiotic sex chromosome inactivation}},
  author = {Qingqing Chen and Yu Xiang and Yang Song and Sisi Wang and Qingwen Wu and Zhekun Li and Qichao Chen and Min Zhang and Yimin Zhu and Long Bai},
  journal = {Communications Biology},
  year = {2026},
  month = jul,
  doi = {10.1038/s42003-026-10636-8},
  url = {https://doi.org/10.1038/s42003-026-10636-8},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - ALKBH5 is required to maintain proper SETDB1 protein levels associated with meiotic sex chromosome inactivation
AU  - Qingqing Chen
AU  - Yu Xiang
AU  - Yang Song
AU  - Sisi Wang
AU  - Qingwen Wu
AU  - Zhekun Li
AU  - Qichao Chen
AU  - Min Zhang
AU  - Yimin Zhu
AU  - Long Bai
PY  - 2026
DA  - 2026/07/13
JO  - Communications Biology
DO  - 10.1038/s42003-026-10636-8
UR  - https://doi.org/10.1038/s42003-026-10636-8
AB  - N6-methyladenosine (m6A) is the most abundant RNA modification in eukaryotes. ALKBH5 is an m6A demethylase that is essential for spermatogenesis. However, its function in meiotic prophase remains elusive. Here, we report that Alkbh5-knockout spermatocytes exhibit normal double-strand break (DSB) formation, homologous recombination and synapsis on autosomes but impaired synapsis between sex chromosomes. ALKBH5 depletion causes a significantly upregulated transcriptome on sex chromosomes and meiotic sex chromosome inactivation (MSCI) defects in spermatocytes at the pachytene stage. Mechanistically, ALKBH5 regulates SETDB1 expression in a post-transcriptional manner. Alkbh5 knockout inhibits SETDB1 protein expression, leading to the decreased SETDB1 signals on sex chromosomes and subsequently inhibiting H3K9me3 to form heterochromatin and silence transcriptional activity. Taken together, our findings identify ALKBH5 as a critical regulator of male meiosis by demonstrating that it is required to maintain proper SETDB1 protein levels, which in turn ensures the faithful execution of MSCI.
SN  - 2399-3642
ER  -