Cholesterol dysregulation contributes to hematopoietic failure in parn-mutant zebrafish with implications for dyskeratosis congenita

ABSTRACT: Germline mutations in PARN cause dyskeratosis congenita (DC), an inherited bone marrow failure syndrome characterized by multilineage cytopenia and progression to myeloid disease. The mechanisms underlying this malignant transformation have not been fully elucidated. Here we show, using a loss-of-function CRISPR-Cas9 zebrafish parn mutant, hematopoietic stem and progenitor (HSPC) expansion and reduced mature hematopoietic cells across various lineages. Cholesterol biosynthesis was transcriptionally activated; a finding recapitulated in patient-derived iPSCs with PARN mutations. Inhibiting cholesterol biosynthesis rescued HSPC expansion and anemia in parn mutants. Concurrent myeloid differentiation therapy or Wnt inhibition reduced HSPCs to varying degrees. We further demonstrate a role for activated Erk signaling in impairing erythrocyte differentiation and show robust rescue with trametinib treatment. Overall, our findings uncover unrecognized roles for Parn in regulating cholesterol metabolism and Erk signaling and provide preclinical evidence for targeting these pathways to restore hematopoiesis in DC.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse-phase, Liquid Chromatography MS - positive - reverse-phase

PROVIDER: MTBLS15863 | MetaboLights | 2026-09-29

REPOSITORIES: MetaboLights