BAP1 regulates epigenetic switch from pluripotency to differentiation in developmental lineages giving rise to BAP1-mutant cancers

Kuznetsov, Jeffim N.; Agüero, Tristan; Owens, Dawn A.; Kurtenbach, Stefan; Field, Matthew G.; Durante, Michael A.; Rodriguez, Daniel A.; King, Mary Lou; Harbour, J. William

doi:10.1126/sciadv.aax1738

Cited by 62 publications

(72 citation statements)

References 39 publications

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“…Additionally, recent work by Kuznetsov et al noted a relationship between BAP1 loss and HDAC4, where BAP1 mutant UM cells showed a change in HDAC4 expression pattern from cytoplasmic to nuclear. It was hypothesized that this change was at least partially responsible for restricting the function of HDAC4 in these cells [ 51 ]. This furthers the idea that HDAC4 specifically might be an important histone deacetylase in UM progression.…”

Section: Discussionmentioning

confidence: 99%

Novel Methylation Patterns Predict Outcome in Uveal Melanoma

Ferrier

Burnier

2020

Life

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Uveal melanoma (UM) is the most common intraocular tumor in adults. Despite effective local treatments, 50% of patients develop metastasis. Better ways to determine prognosis are needed as well as new therapeutic targets. Epigenetic changes are important events driving cancer progression; however, few studies exist on methylation changes in UM. Our aim was to identify methylation events associated with UM prognosis. Matched clinical, genetic, and methylation data for 80 UM cases were obtained from The Cancer Genome Atlas (TCGA). Top differentially methylated loci were sorted through hierarchical clustering based on methylation patterns, and these patterns were compared to tumor characteristics, genomic aberrations, and patient outcome. Hierarchical clustering revealed two distinct groups. These classifications effectively separated high and low-risk cases, with significant differences between groups in patient survival (p < 0.0001) and correlation with known prognostic factors. Major differences in methylation of specific genes, notably NFIA, HDAC4, and IL12RB2, were also seen. The methylation patterns identified in this study indicate potential novel prognostic indicators of UM and highlight the power of methylation changes in predicting outcome. The methylation events enriched in the high-risk group suggest that epigenetic modulating drugs may be useful in reducing metastatic potential, and that specific differentially methylated loci could act as biomarkers of therapeutic response.

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Section: Discussionmentioning

confidence: 99%

Novel Methylation Patterns Predict Outcome in Uveal Melanoma

Ferrier

Burnier

2020

Life

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“…4). In addition to similar expression patterns of these genes, phenotypes including extensive apoptotic cells in head, neural tube, and tail, as well as decreased size of eyes and head have also been described in udu 6,19 , dnmt1 30,48 , bap1 49,50 , and thoc1 51 knockdown or mutant animals. In dnmt1 mutant zebrafish, defective lens with dysplasia have been observed 30 .…”

Section: Discussionmentioning

confidence: 85%

“…Additionally, inherited mutations in human DNMT1 have been associated with neurodegenerative syndromes that are characterized by degeneration of the cerebellum and of the acoustic and optic nerves 48 . In Xenopus, expression of bap1 is restricted in the neural crest cells in early stages, and loss of bap1 results in abnormal gastrulation and malformation of ocular structure 49 . Zebrafish embryos injected with bap1 morpholino exhibited necrotic CNS 50 .…”

Section: Discussionmentioning

confidence: 99%

Newly identified Gon4l/Udu-interacting proteins implicate novel functions

Tsai

Chu

Jiang

2020

Sci Rep

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Mutations of the Gon4l/udu gene in different organisms give rise to diverse phenotypes. Although the effects of Gon4l/Udu in transcriptional regulation have been demonstrated, they cannot solely explain the observed characteristics among species. To further understand the function of Gon4l/Udu, we used yeast two-hybrid (Y2H) screening to identify interacting proteins in zebrafish and mouse systems, confirmed the interactions by co-immunoprecipitation assay, and found four novel Gon4l-interacting proteins: BRCA1 associated protein-1 (Bap1), DNA methyltransferase 1 (Dnmt1), Tho complex 1 (Thoc1, also known as Tho1 or HPR1), and Cryptochrome circadian regulator 3a (Cry3a). Furthermore, all known Gon4l/Udu-interacting proteins-as found in this study, in previous reports, and in online resources-were investigated by Phenotype Enrichment Analysis. The most enriched phenotypes identified include increased embryonic tissue cell apoptosis, embryonic lethality, increased T cell derived lymphoma incidence, decreased cell proliferation, chromosome instability, and abnormal dopamine level, characteristics that largely resemble those observed in reported Gon4l/udu mutant animals. Similar to the expression pattern of udu, those of bap1, dnmt1, thoc1, and cry3a are also found in the brain region and other tissues. Thus, these findings indicate novel mechanisms of Gon4l/ Udu in regulating CpG methylation, histone expression/modification, DNA repair/genomic stability, and RNA binding/processing/export.

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“…It will be critical to investigate in more details the nature of the transcripts affected when rescuing with the phospho-mimic version. Furthermore, and similar to the strategy used for BAP1 depletion 85 , we envisage the use of histone deacetylases inhibitors during development when endogenous H3.3 is depleted to potentially overcome gastrulation defects by restoring H3K27ac levels. Importantly, MBT in Xenopus also leads to changes in cell cycle progression, including establishment of longer cell cycles (somatic type) with gap phases and acquisition of checkpoints 55,56 .…”

Section: Discussionmentioning

confidence: 99%

Histone variant H3.3 residue S31 is essential for Xenopus gastrulation regardless of the deposition pathway

et al. 2020

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Vertebrates exhibit specific requirements for replicative H3 and non-replicative H3.3 variants during development. To disentangle whether this involves distinct modes of deposition or unique functions once incorporated into chromatin, we combined studies in Xenopus early development with chromatin assays. Here we investigate the extent to which H3.3 mutated at residues that differ from H3.2 rescue developmental defects caused by H3.3 depletion. Regardless of the deposition pathway, only variants at residue 31-a serine that can become phosphorylated-failed to rescue endogenous H3.3 depletion. Although an alanine substitution fails to rescue H3.3 depletion, a phospho-mimic aspartate residue at position 31 rescues H3.3 function. To explore mechanisms involving H3.3 S31 phosphorylation, we identified factors attracted or repulsed by the presence of aspartate at position 31, along with modifications on neighboring residues. We propose that serine 31-phosphorylated H3.3 acts as a signaling module that stimulates the acetylation of K27, providing a chromatin state permissive to the embryonic development program.

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BAP1 regulates epigenetic switch from pluripotency to differentiation in developmental lineages giving rise to BAP1-mutant cancers

Cited by 62 publications

References 39 publications

Novel Methylation Patterns Predict Outcome in Uveal Melanoma

Novel Methylation Patterns Predict Outcome in Uveal Melanoma

Newly identified Gon4l/Udu-interacting proteins implicate novel functions

Histone variant H3.3 residue S31 is essential for Xenopus gastrulation regardless of the deposition pathway

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