Agradecimentos: We thank Drs. Simon Andrews, Anne Segonds-Pichon, and Felix Krueger, Babraham Bioinformatics, for help with data processing, statistical and bioinformatic analysis, Dr. Kristina Tabbada and Clare Murnane, Babraham Institute Next Generation Sequencing facility, for next-generation sequencing, Nicolas Le Novère for advice with the kinetic analysis, all the staff of Babraham Institute BSU for animal care, and Matthew Sale for HCT116 cells and help with the cell cycle experiments. P.V.-W. thanks Drs. Kazuyuki Ohbo, Yokohama City University, and Masataka Nakamura, Tokyo Medical and Dental University, for hosting him for 2 months in 2012 in Japan, during which time the idea for this work was conceived. This work was funded by the UK Biotechnology and Biological Sciences Research Council (BBSRC), the UK Medical Research Council through project grant MR/N009398/1 to P.V.-W. and M.V., a Brazil-BBSRC Pump-priming award (BB/N013565/1) to P.V.-W. and M.A.R.V. and funding by the Science Policy Committee, Babraham Institute to P.V.-W. and M.V., Grants from NC3R (NC/L001217/1) to M.V. and FAPESP (2012/10653-9, 2015/50379-1 and 2015/14105-4) to M.A.R.V., grants from the Italian Association for Cancer Research (AIRC), the Italian Ministry of Health (RF-GR2011) and the EPIGEN flagship project grant to T.B. R.M., S.B., Z.H., M.S., C.M., and H.P. were funded through the Erasmus+ programme and H.B. through a BBSRC studentship Ver menos

Abstract: The recently discovered histone post-translational modification crotonylation connects cellular metabolism to gene regulation. Its regulation and tissue-specific functions are poorly understood. We characterize histone crotonylation in intestinal epithelia and find that histone H3 crotonylation at lysine 18 is a surprisingly abundant modification in the small intestine crypt and colon, and is linked to gene regulation. We show that this modification is highly dynamic and regulated during the cell cycle. We identify class I histone deacetylases, HDAC1, HDAC2, and HDAC3, as major executors of histone decrotonylation. We show that known HDAC inhibitors, including the gut microbiota-derived butyrate, affect histone decrotonylation. Consistent with this, we find that depletion of the gut microbiota leads to a global change in histone crotonylation in the colon. Our results suggest that histone crotonylation connects chromatin to the gut microbiota, at least in part, via short-chain fatty acids and HDACs Ver menos