Zhao, J. Y. | bioRxiv Science

bioRxiv2020

LongGeneDB: a data hub for long genes

The human genome contains more than 4000 genes that are longer than 100 kb. These long genes require more time and resources to make a transcript than shorter genes do. Long genes have also been linked to various human diseases. Specific mechanisms are utilized by long genes to facilitate their transcription and co-transcriptional processes. This results in unique features in their multi-omics profiles. Although these unique profiles are important to understand long genes, a database that provides an integrated view and easy access to the multi-omics profiles of long genes does not exist. We leveraged the publicly accessible multi-omics data and systematically analyzed the genomic conservation, histone modifications, chromatin organization, tissue-specific transcriptome, and single cell transcriptome of 992 protein-coding genes that are longer than 200 kb in the mouse genome. We also examined the evolution history of their gene lengths in 15 species that belong to six Classes and 11 Orders. To share the multi-omics profiles of long genes, we developed a user-friendly and easy-to-use database, LongGeneDB (https://longgenedb.org), for users to search, browse, and download these profiles. LongGeneDB will be a useful data hub for the biomedical research community to understand long genes.

bioinformatics↗

bioRxiv2020

Histone deacetylase inhibition by gut microbe-generated short chain fatty acids entrains intestinal epithelial circadian rhythms

Background and aimsThe circadian clock orchestrates ~24-hour oscillations of gastrointestinal (GI) epithelial structure and function that drive diurnal rhythms in the composition, localization, and metabolism of gut microbiota. Here, we use experimental and computational approaches in enteroids to reveal reciprocal effects of microbial metabolites on intestinal epithelial timekeeping by an epigenetic mechanism. MethodsWe cultured 3D PER2::LUCIFERASE and Bmal1-ELuciferase jejunal enteroids in media supplemented with sterile supernatants from the altered Schaedler Flora (ASF), a defined murine microbiota. Circadian oscillations of bioluminescent PER2 and Bmal1 were measured in enteroids cultured in the presence or absence of individual ASF supernatants. Separately, we applied machine learning to ASF metabolic profiles to identify phase-shifting metabolites. ResultsFiltrates from 3 of 7 ASF species (ASF360 Lactobacillus intestinalis, ASF361 Ligilactobacillus murinus, ASF502 Clostridium spp.) induced minimal alterations in circadian rhythms, whereas 4 ASF species (ASF356 Clostridium spp., ASF492 Eubacterium plexicaudatum, ASF500 Pseudoflavonifactor spp., ASF519 Parabacteroides goldsteinii) induced profound, concentration-dependent phase delays. Random forest classification identified short chain fatty acids (SCFA: butyrate, propionate, acetate, and isovalerate) production as a discriminating feature of "shifters", i.e., ASF taxa whose metabolites induce phase delay. Experiments with SCFAs confirmed machine learning predictions, with a median phase delay of 6.2 hours. Pharmacological or botanical HDAC inhibitors generated similar phase delays. Further, mithramycin A, an inhibitor of HDAC inhibition, abrogated SCFA-induced phase delays by 20% (P<0.05). Key findings were reproducible in human Bmal1-luciferase enteroids. ConclusionsGut microbe-generated SCFAs entrain intestinal epithelial circadian rhythms, in part, by an HDACi-dependent mechanism, with critical implications for understanding microbial and circadian network regulation of intestinal epithelial homeostasis.

cell biology↗