Epigenetic factors regulating immune responses and microbiota-crosstalk in the colon

Nathalia Araujo¹, Kashaf Javed¹, Vinicius Nirello¹, Mariane Font Fernandes¹, Marco Aurelio Ramirez Vinolo¹, and Patrick Varga-Weisz^1,2

¹ Institute of Biology, University of Campinas, Campinas, Brazil,

² School of Life Sciences, University of Essex, Colchester, UK

[email protected]

Epigenetic mechanisms are important in the regulation of inflammatory processes, but mechanisms are poorly explored. Previously, we have published that ATP-dependent chromatin remodelling factor SMARCAD1 is required for inflammatory responses in the gut. Recently we discovered that Death-associated protein 6 (DAXX) is a chromatin-associated protein that functions in the opposite direction, curtailing inflammatory processes and regulating key genes in an opposite manner compared to SMARCAD1. DAXX functions as a histone chaperone for the histone H3.3 variant and has been implicated in cancer. 

In an acute colitis model, intestinal epithelium specific DAXX knockout mice displayed significantly increased pathology compared to wild-type animals. Transcriptome and microbiome analysis show that DAXX deletion alone predisposes mice to intestinal inflammation and changes of the microbiome. Interestingly, DAXX-knockout females are more susceptible to induced colitis compared to males and exhibit more pronounced transcriptome disturbance. Consistent with the increased colitis susceptibility, chromatin analysis (ATAC-Seq) of colon epithelial cells in steady-state revealed an overall increase in chromatin accessibility of DAXX-deleted colon epithelial cells compared to control over genes linked to innate immunity in a microbiota-dependent manner. Altogether, this study connects DAXX and histone H3 variant H3.3 to regulation of host-microbiota interactions and uncovers un-expected sex-dependent responses. Our work reveals a highly conserved epigenetic pathways critical for innate immunity.