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The histone acetyltransferase Mst2 prevents epigenetic silencing via specific acetylation of the ubiquitin ligase Brl1 [NGS data]

ABSTRACT: Faithful propagation of distinct chromatin states is crucial to maintain cellular identity. Whereas mechanisms that sustain repressed states have been intensely studied, regulatory circuits that protect active chromatin from inactivating signals are not well understood. Here we report the discovery of a self-reinforcing feedback loop that preserves the transcription-competent state of RNA polymerase II transcribed genes. We found that the chromatin reader Pdp3 recruits the histone acetyltransferase Mst2 to H3K36me3 marked chromatin. Thereby, Mst2 binds to all transcriptionally active regions genome-wide. Besides histone H3K14, Mst2 specifically acetylates Brl1, a component of the histone H2B ubiquitin ligase complex (HULC). Brl1 acetylation results in increased histone H2B ubiquitination, which together with H3K14ac positively feeds back on transcription and prevents assembly of ectopic heterochromatin. Our work uncovers a molecular pathway that secures epigenome integrity and highlights the importance of opposing feedback loops for the partitioning of chromatin into transcriptionally active and inactive states.

ORGANISM(S): Schizosaccharomyces pombe

PROVIDER: GSE93432 | GEO | 2017/06/22

SECONDARY ACCESSION(S): PRJNA361034

REPOSITORIES: GEO

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Project description:Metastatic malignant melanoma is the deadliest skin cancer type, and it is characterized by its high resistance to apoptosis. The main driving mutations in melanoma cause hyperactivation of genes within the ERK pathway, with BRAF mutations being the most frequent ones, followed by NRAS, NF1 and MEK mutations. Increasing evidence shows that the MST2/Hippo pathway is also deregulated in this cancer type. While mutations are rare, MST2/Hippo pathway core proteins expression levels are often dysregulated in melanoma. The expression of the tumour suppressor RASSF1A, a bona fide activator of the pro-apoptotic MST2 pathway, is silenced by promoter methylation in over half of melanomas and correlates with poor prognosis. Here, using mass spectrometry-based interaction proteomics we identified Second Mitochondria-derived Activator of Caspases (SMAC) as a novel LATS1 interactor. We show that RASSF1A-dependent activation of the pro-apoptotic MST2 pathway promotes LATS1-SMAC interaction and negatively regulates the anti-apoptotic signal mediated by the members of the IAP family. Moreover, proteomic experiments identified a common cluster of the apoptotic regulator that bind to SMAC and LATS1. Mechanistic analysis show that the LATS1-SMAC complex promotes XIAP ubiquitination and its subsequent degradation which ultimately results apoptosis. Importantly, we show that the oncogenic BRAFV600E mutant prevents the pro-apoptotic signal mediated by the LAST1-SMAC complex while treatment of melanoma cell lines with BRAF inhibitors promotes this complex, indicating that inhibition of the LATS1-SMAC might be necessary for BRAFV600E-driven melanoma. Finally, we show that LATS1-SMAC interaction is regulated by the SMAC mimetic Birinapant which requires the inhibition of C-IAP1 and the degradation of XIAP, indicating that the MST2/Hippo pathway is part of the mechanism of action of Birinapant. Overall, the current work shows SMAC-dependent apoptosis is regulated by the LATS1 tumour suppressor and supports the idea that LATS1 is a signalling hub that regulates the crosstalk between the MST2 pathway, the apoptotic network and the RAF/ERK pathway.

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The histone acetyltransferase Mst2 prevents epigenetic silencing via specific acetylation of the ubiquitin ligase Brl1 [NGS data]

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