Vitamin biosynthesis by human gut butyrate-producing bacteria and cross-feeding in synthetic microbial communities

ACKNOWLEDGMENTS This project was funded by Danone Nutricia Research. F.M.F., G.H., H.J.F., S.H.D., and P.L. receive support from the Scottish Government Rural and Environment Sciences and Analytical Services. Method development for coculture microbial analysis was partially supported by European 7th Framework grant (289517) “Dietary fibres supporting gut and immune function; from polysaccharide compound to health claim (Fibebiotics).” We thank Timo Kramer for his technical support with the in silico analyses. M.D., J.-M.F., H.J.F., S.H.D., and P.L. conceived and designed the study. E.C.S.-M., I.W., F.M.F., and M.C. acquired data and contributed to interpreting the results. G.H. performed statistical analysis. E.C.S.-M. and P.L. drafted the manuscript. All authors contributed to revising the manuscript and approved the final version.Peer reviewedPublisher PD

Rare germline heterozygous missense variants in BRCA1-associated protein 1, BAP1, cause a syndromic neurodevelopmental disorder

International audienceNuclear deubiquitinase BAP1 (BRCA1-associated protein 1) is a core component of multiprotein complexes that promote transcription by reversing the ubiquitination of histone 2A (H2A). BAP1 is a tumor suppressor whose germline loss-of-function variants predispose to cancer. To our knowledge, there are very rare examples of different germline variants in the same gene causing either a neurodevelopmental disorder (NDD) or a tumor predisposition syndrome. Here, we report a series of 11 de novo germline heterozygous missense BAP1 variants associated with a rare syndromic NDD. Functional analysis showed that most of the variants cannot rescue the consequences of BAP1 inactivation, suggesting a loss-of-function mechanism. In T cells isolated from two affected children, H2A deubiquitination was impaired. In matching peripheral blood mononuclear cells, histone H3 K27 acetylation ChIP-seq indicated that these BAP1 variants induced genome-wide chromatin state alterations, with enrichment for regulatory regions surrounding genes of the ubiquitin-proteasome system (UPS). Altogether, these results define a clinical syndrome caused by rare germline missense BAP1 variants that alter chromatin remodeling through abnormal histone ubiquitination and lead to transcriptional dysregulation of developmental genes