Histone modifications reflect gene activity, but the relationship between cause and consequence of transcriptional control is heavily debated. Recent developments in rewriting local histone codes of endogenous genes elucidated instructiveness of certain marks in regulating gene expression. Maintenance of such repressive epigenome editing is controversial, while stable reactivation is still largely unexplored. Here we demonstrate sustained gene re-expression using two types of engineered DNA-binding domains fused to a H3K4 methyltransferase. Local induction of H3K4me3 is sufficient to allow re-expression of silenced target genes in various cell types. Maintenance of the re-expression is achieved, but strongly depends on the chromatin microenvironment (that is, DNA methylation status). We further identify H3K79me to be essential in allowing stable gene re-expression, confirming its role in epigenetic crosstalk for stable reactivation. Our approach uncovers potent epigenetic modifications to be directly written onto genomic loci to stably activate any given gene.

ScopeLactic acid bacteria (LAB) are recognized to promote gastrointestinal health by mechanisms that are not fully understood. LABs might modulate the mucus and thereby enhance intestinal barrier function. Herein, we investigate effects of different LAB strains and species on goblet cell genes involved in mucus synthesis.Methods and resultsGene expression profiles of goblet‐cell‐associated products (mucin MUC2, trefoil factor 3, resistin‐like molecule β, carbohydrate sulfotransferase 5, and galactose‐3‐O‐sulfotransferase 2) induced by LAB or their derived conditioned medium in human goblet cell line LS174T are studied. Effects of LAB on gene transcription are assessed with or without exposure to TNF‐α, IL‐13, or the mucus damaging agent tunicamycin. LAB do impact the related genes in a species‐ and strain‐specific fashion and their effects are different in the presence of the cytokines and tunicamycin. Bioactive factors secreted by some strains are also found to regulate goblet cell‐related genes.ConclusionOur findings provide novel insights in differences in modulatory efficacy on mucus genes between LAB species and strains. This study further unravels direct interactions between LAB and intestinal goblet cells, and highlights the importance of rationally selecting appropriate LAB candidates to achieve specific benefits in the gut.

These results suggest that TLR4 and Dectin-1 are synergistically activated by particulate β-glucans, wherein TLR4 activates an immune regulatory pathway in human dendritic cells. Our data suggest that β-glucan is an immune regulatory ligand for TLR4.