The tumor-suppressor BAP1 promotes differentiation during embryonic development

KUZNETSOV, JEFFIM N.; KING, MARY LOU; AGÜERO, TRISTAN; KURTENBACH, STEFAN; OWENS, DAWN A.; HARBOUR, WILIAM JAMES

Congreso; Latinamerican Society for Developmental Biology; 2019

The tumor suppressor BAP1 is involved in many biologicalprocesses including transcriptional regulation, chromatin modification togetherwith the polycomb repressive complex 1 and 2, and DNA repair. Loss-of-functionmutations in BAP1 are strongly associated with human cancers, includingmelanoma and mesothelioma. In mice, Bap1 mutant embryos die in utero preventinga proper developmental analysis. To overcome this impossibility, we use Xenopusto analyze the role of Bap1 in the context of a whole embryo. Bap1 is a monodeubiquitinase, highly conserved across species. Interestingly, most known BAP1interacting proteins are developmental epigenetic regulators such as Asxl1/2,Cbx1/3, and Kdm1b. Depletion of Bap1 protein in Xenopus embryos leads todefects in gastrulation, neural crest specification, and loss ofdifferentiation of ectodermal and mesodermal derivatives. Down regulation ofdifferentiation markers resembles key results found in melanoma cell cultures. Remarkably,all embryonic defects were rescued by the replacement of human or Xenopus Bap1RNA. We found evidence that BAP1 functions at the chromatin level interactingwith the polycomb complex since all defects were restored by the inhibition ofdeacetylases. BAP1 is a key regulator of multiple developmental lineages,including the neural crest from which melanomas arises, and results obtained fromXenopus embryos can be used to screen for novel therapeutic compounds thatreverse the phenotypic effects of BAP1 loss.