KMT2A and KMT2B Mediate Memory Function by Affecting Distinct Genomic Regions

Kmt2a and Kmt2b are H3K4 methyltransferases of the Set1/Trithorax class. We have recently shown the importance of Kmt2b for learning and memory. Here, we report that Kmt2a is also important in memory formation. We compare the decrease in H3K4 methylation and de-regulation of gene expression in hippocampal neurons of mice with knockdown of either Kmt2a or Kmt2b. Kmt2a and Kmt2b control largely distinct genomic regions and different molecular pathways linked to neuronal plasticity. Finally, we show that the decrease in H3K4 methylation resulting from Kmt2a knockdown partially recapitulates the pattern previously reported in CK-p25 mice, a model for neurodegeneration and memory impairment. Our findings point to the distinct functions of even closely related histone-modifying enzymes and provide essential insight for the development of more efficient and specific epigenetic therapies against brain diseases.Beca Ramón y CajalGAIN- Agencia Gallega de Innovació

Microbiota derived short chain fatty acids promote histone crotonylation in the colon through histone deacetylases

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

Enduring Behavioral Effects Induced by Birth by Caesarean Section in the Mouse

Birth by Caesarean (C)-section impacts early gut microbiota colonization and is associated with an increased risk of developing immune and metabolic disorders. Moreover, alterations of the microbiome have been shown to affect neurodevelopmental trajectories. However, the long-term effects of C-section on neurobehavioral processes remain unknown. Here, we demonstrated that birth by C-section results in marked but transient changes in microbiome composition in the mouse, in particular, the abundance of Bifidobacterium spp. was depleted in early life. Mice born by C-section had enduring social, cognitive, and anxiety deficits in early life and adulthood. Interestingly, we found that these specific behavioral alterations induced by the mode of birth were also partially corrected by co-housing with vaginally born mice. Finally, we showed that supplementation from birth with a Bifidobacterium breve strain, or with a dietary prebiotic mixture that stimulates the growth of bifidobacteria, reverses selective behavioral alterations in C-section mice. Taken together, our data link the gut microbiota to behavioral alterations in C-section-born mice and suggest the possibility of developing adjunctive microbiota-targeted therapies that may help to avert long-term negative consequences on behavior associated with C-section birth mode

KMT2A and KMT2B Mediate Memory Function by Affecting Distinct Genomic Regions

Kmt2a and Kmt2b are H3K4 methyltransferases of the Set1/Trithorax class. We have recently shown the importance of Kmt2b for learning and memory. Here, we report that Kmt2a is also important in memory formation. We compare the decrease in H3K4 methylation and de-regulation of gene expression in hippocampal neurons of mice with knockdown of either Kmt2a or Kmt2b. Kmt2a and Kmt2b control largely distinct genomic regions and different molecular pathways linked to neuronal plasticity. Finally, we show that the decrease in H3K4 methylation resulting from Kmt2a knockdown partially recapitulates the pattern previously reported in CK-p25 mice, a model for neurodegeneration and memory impairment. Our findings point to the distinct functions of even closely related histone-modifying enzymes and provide essential insight for the development of more efficient and specific epigenetic therapies against brain diseases