FOXA2 controls the anti-oxidant response in FH-deficient cells independent of NRF2

ABSTRACT: Hereditary Leiomyomatosis and renal cell cancer (HLRCC) is caused by germline mutations of fumarate hydratase (FH) and subsequence accumulation of fumarate. Fumarate is known to activate the anti-oxidant response by KEAP1 succination and nuclear translocation of the transcription factor NRF2. The activation of the anti-oxidant response and is key for cellular survival in FH-deficient cells. To explore the global effects of FH loss and fumarate on the chromatin landscape, we performed unbiased multi-omic analyses. By integrating chromatin accessibility and histone ChIP-seq profiles, we identify additional transcription factor networks involved in the highly remodelled chromatin landscape of FH-deficient cells. Here, we implicate FOXA2 in the maintenance of FH-deficient cells by directly regulating anti-oxidant response genes and subsequent metabolic output. We also find that FOXA2 regulates anti-oxidant genes independent of the canonical anti-oxidant regulator NRF2. The identification of FOXA2 as an anti-oxidant regulator provide new insights into the molecular mechanisms behind cell responses to fumarate accumulation, and potentially provide new avenues for therapeutic intervention for HLRCC.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Joshua Kent  

LAB HEAD: Christian Frezza

PROVIDER: PXD034141 | Pride | 2026-07-20

REPOSITORIES: Pride