MORC2 controls HIF-1α stability via an HDAC4-dependent mechanism to regulate erythropoiesis.
basic_science · Level V
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- Record sourced from PubMed, PMID 42507929.
- Also identified by DOI 10.1073/pnas.2537114123.
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Abstract
The hypoxia-inducible factor (HIF) signaling pathway is essential for cellular adaptation to low oxygen. Although the canonical PHD-pVHL pathway that mediates HIF-α 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-α. In zebrafish, CRISPR/Cas9-generated <i>morc2</i> mutants developed polycythemia, systemic hypoxia, and constitutive activation of the HIF pathway. Mechanistically, MORC2 counteracts histone deacetylase 4 (HDAC4) by competing for HIF-1α binding. Loss of MORC2 enhances HDAC4 recruitment to HIF-1α, reducing acetylation at lysine 629 and preventing proteasomal degradation of HIF-1α. These results define a regulatory mechanism in which MORC2 modulates HIF-1α stability via HDAC4 mediated deacetylation, shedding light on hematopoiesis and HIF-related disorders.