MORC2 controls HIF-1α stability via an HDAC4-dependent mechanism to regulate erythropoiesis

• 成果类型: Article
• 署名作者: Tang, Yanfei; Zhang, Boqi; Xue, Tingting; Liu, Yunzhang; Li, Yun; Gu, Yuchao; Hao, Jiejie; Lu, Ling
• 署名单位: Ocean University of China; Qingdao University of Science & Technology
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2537114123
• 发表日期: 2026-08-04
• 页码: e2537114123
• 关键词: hypoxia; hif; MORC2; zebrafish; HDAC4; ERYTHROCYTOSIS

摘要

The hypoxia-inducible factor (HIF) signaling pathway is essential for cellular adaptation to low oxygen. Although the canonical PHD-pVHL pathway that mediates HIF-alpha degradation under normoxia is well established, alternative regulatory mechanisms remain poorly understood. Here, we identify Microrchidia family CW-type zinc-finger 2 (MORC2) as a negative regulator of HIF-alpha. In zebrafish, CRISPR/Cas9-generated morc2 mutants developed polycythemia, systemic hypoxia, and constitutive activation of the HIF pathway. Mechanistically, MORC2 counteracts histone deacetylase 4 (HDAC4) by competing for HIF-1 alpha binding. Loss of MORC2 enhances HDAC4 recruitment to HIF-1 alpha, reducing acetylation at lysine 629 and preventing proteasomal degradation of HIF-1 alpha. These results define a regulatory mechanism in which MORC2 modulates HIF-1 alpha stability via HDAC4 mediated deacetylation, shedding light on hematopoiesis and HIF-related disorders.