The class IIa HDACs prevent degradation of RBFOX2 by Chaperone-Mediated Autophagy

By modulating the acetylation level of histones, histone deacetylases (HDACs) are enzymes playing a key role in the control of gene expression. In addition to histones, HDACs also have non-histone substrates, which may relate to potential roles for HDACs outside of gene regulation. Because HDACs are key regulators of major cellular processes such as cell division, apoptosis and differentiation, it is not surprising that these enzymes have emerged as attractive therapeutic targets for cancer. While the in vivo antitumoral activities of several small molecules HDACs inhibitors have generated a lot of hope, these molecules often showed dramatic side-effects. It is suspected that these side effects could be related to unknown functions of HDACs. The goal of this project is to identify novel, unsuspected functions of HDACs that will help developing more efficient and specific HDAC-based antitumoral therapies. To identify novel functions of HDACs, we used a high-throughput yeast two hybrid (Y2H) approach. This led to the first comprehensive interactomic map of class IIa HDACs that includes 84 protein partners. Among new HDACs partners, we identified several RNA-binding proteins (RBPs) involved in mRNA processing. In this work, we focused on one, the alternative splicing regulator RBFOX2, and investigated its regulation by class IIa HDACs. Through various approaches, we verified that HDAC7 interacts with RBFOX2. In addition, we found that silencing of HDAC7 correlates with a decrease in stability of RBFOX2. Because we identified a potential CMA-specific KFERQ motif in RBFOX2, we tested the possibility that RBFOX2 might be degraded through Chaperone-Mediated Autophagy (CMA). Supporting this hypothesis, we found that RBFOX2 interacts with the co-chaperone HSC70. RBFOX2 levels are sensitive to CMA inducers, including serum starvation and 6AN. Interestingly, we found that a lysine residue in the KFERQ motif of RBFOX2 is acetylated, suggesting that HDAC7 might control RBFOX2 degradation through reversible acetylation. Indeed, degradation of RBFOX2 following HDAC7 silencing was reverted with an inhibitor of autophagy, bafilomycin A1. Analysis of RNA splicing pattern in cells depleted for HDAC7 showed that absence of HDAC7 is associated with 159 alternative splicing events. These events mostly include exon skipping that is known to be the major splicing event in which RBFOX2 is involved. In addition, we observed a highly statistically overlap between splicing events associated with RBFOX2 and HDAC7 depletion.Class IIa HDACs interactome : Toward identification of new functions in RNA processin

Conflict of interest policies at Belgian medical faculties: Cross-sectional study indicates little oversight.

BackgroundMedical students encounter pharmaceutical promotion from the very start of their training. Medical schools have an important role to play in educating medical students regarding the interactions between healthcare professionals (HCPs) and industry and in protecting them from commercial influence and conflict of interest (COI). In 2019, medical student associations in Belgium and abroad called for more preparation in dealing with COI and for a more independent medical training. As little information is available on the situation in our country, we undertook an assessment of conflict of interest policies at Belgium's medical schools. We relied on a methodology already used in studies from USA, Canada, Australia, France and Germany and adapted it to the Belgian context.MethodsWe identified 10 medical schools in Belgium. We searched the website of each medical school in November 2019 with standardized keywords for COI policies and learning activities on COI in the curriculum. The deans of medicine were invited to participate by sending us information that we could have overlooked during our web-based searches. We also consulted personal contacts within faculties among students and teachers. Based on a list of 15 criteria adapted from North American and French studies, we calculated a total for each faculty of medicine with a maximum score of 30 points.ResultsBy December 2019, we had gathered a set of written documents for four faculties of medicine (40%) containing policies with varying degrees of precision and relevance to our survey. We found elements of the curriculum addressing the COI issue for one faculty (10%). In all cases, these policies consisted of "moderate" initiatives with little or no "restrictive" elements. Only one faculty showed interest in our study by providing us with relevant information (10%). Half of the faculty notified us of their refusal to participate in the study (50%) and the other faculties either did not respond or did not provide us with any information (40%). The maximum score obtained was 3 out of 30 points with six faculties scoring 0 (60%).ConclusionThere is little transparency regarding interactions between medical students and pharmaceutical companies at Belgian medical faculties, which may create COI issues. Initiatives to protect students from pharmaceutical promotion and to train them to manage their future interaction with pharmaceutical companies have a limited scope and are isolated. This is inconsistent with international recommendations from Health Action International, World Health Organization or the American Medical Students' Association. The Belgian government has legislated in favor of more transparency in the relation between HCPs and pharmaceutical industry. Indeed, it made the disclosure of benefits granted by the industry compulsory and limited their value. Our results show that there is still some way to go to ensure an independent medical training for future Belgian physicians

The transcription factor ERG recruits CCR4-NOT to control mRNA decay and mitotic progression

Control of mRNA levels, a fundamental aspect in the regulation of gene expression, is achieved through a balance between mRNA synthesis and decay. E26-related gene (Erg) proteins are canonical transcription factors whose previously described functions are confined to the control of mRNA synthesis. Here, we report that ERG also regulates gene expression by affecting mRNA stability and identify the molecular mechanisms underlying this function in human cells. ERG is recruited to mRNAs via interaction with the RNA-binding protein RBPMS, and it promotes mRNA decay by binding CNOT2, a component of the CCR4-NOT deadenylation complex. Transcriptome-wide mRNA stability analysis revealed that ERG controls the degradation of a subset of mRNAs highly connected to Aurora signaling, whose decay during S phase is necessary for mitotic progression. Our data indicate that control of gene expression by mammalian transcription factors may follow a more complex scheme than previously anticipated, integrating mRNA synthesis and degradation.status: publishe

The transcription factor ERG recruits CCR4-NOT to control mRNA decay and mitotic progression.

Control of mRNA levels, a fundamental aspect in the regulation of gene expression, is achieved through a balance between mRNA synthesis and decay. E26-related gene (Erg) proteins are canonical transcription factors whose previously described functions are confined to the control of mRNA synthesis. Here, we report that ERG also regulates gene expression by affecting mRNA stability and identify the molecular mechanisms underlying this function in human cells. ERG is recruited to mRNAs via interaction with the RNA-binding protein RBPMS, and it promotes mRNA decay by binding CNOT2, a component of the CCR4-NOT deadenylation complex. Transcriptome-wide mRNA stability analysis revealed that ERG controls the degradation of a subset of mRNAs highly connected to Aurora signaling, whose decay during S phase is necessary for mitotic progression. Our data indicate that control of gene expression by mammalian transcription factors may follow a more complex scheme than previously anticipated, integrating mRNA synthesis and degradation