Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium

Abstract

Background: How intestinal epithelial cells interact with the microbiota and how this is regulated at the gene expression level are critical questions. Smarcad1 is a conserved chromatin remodeling factor with a poorly understood tissue function. As this factor is highly expressed in the stem and proliferative zones of the intestinal epithelium, we explore its role in this tissue. Results: Specific deletion of Smarcad1 in the mouse intestinal epithelium leads to colitis resistance and substantial changes in gene expression, including a striking increase of expression of several genes linked to innate immunity. Absence of Smarcad1 leads to changes in chromatin accessibility and significant changes in histone H3K9me3 over many sites, including genes that are differentially regulated upon Smarcad1 deletion. We identify candidate members of the gut microbiome that elicit a Smarcad1-dependent colitis response, including members of the poorly understood TM7 phylum. Conclusions: Our study sheds light onto the role of the chromatin remodeling machinery in intestinal epithelial cells in the colitis response and shows how a highly conserved chromatin remodeling factor has a distinct role in anti-microbial defense. This work highlights the importance of the intestinal epithelium in the colitis response and the potential of microbial species as pharmacological and probiotic targets in the context of inflammatory diseases. Background The intestinal epithelium is a highly dynamic tissue that is constantly renewed within a few days, driven by intestinal stem cells that reside at the base of intestinal crypts [1, 2]. Intestinal stem cells and their derivatives express many factors involved in DNA replication, DNA repair, chromatin packaging, and chromatin remodeling, including ATP-dependent remodeling factors [3]. The roles of these factors in genomic and epigenomic stability of this tissue are likely of great importance. Understanding epithelial biology is complicated by the fact that this tissue is in close proximity to the gut microbiota, which normally is either innocuous or even beneficial to the host, but can become pathogenic. How intestinal epithelial cells interact with the host immune system and the microbiota and how this is regulated at the gene expression level are critical questions.

Arabidopsis CHROMATIN REMODELING 19 acts as a transcriptional repressor and contributes to plant pathogen resistance

“…In the present study, we extended the previous finding of Drosophila SMARCAD1 is a transcriptional activator that enhances H2A acetylation by the histone acetylase CBP in an ATP-dependent manner, and SMARCAD1 is recruited by CBP to regulate gene expression (Doiguchi et al, 2016). Knockout of SMARCAD1 in mouse results in increased H3K9me3 levels within the broader coding regions of multiple genes, as well as decreased expression levels of some target genes, suggesting that SMARCAD1 prevents the spread of repressive machineries or activities (Kazakevych et al, 2020). The present findings for CHR19 indicate that Fun30/SMARCAD1 homologs do not play an evolutionarily conserved role in transcriptional regulation, similar to the above-mentioned CUE domain-mediated DNA damage response.…”

Metagenomics studies for the diagnosis and treatment of prostate cancer

“…Several experiments have shown dramatic changes in gene expression upon the introduction of microbial communities in laboratory animals. These findings indicate the potential influence of microbiota on the genetic and epigenetic modulation of the host, which can alter the efficiency of the immune system response 91 . In a healthy person, the prostate gland is normally free of pathogenic microbes that cause cancer.…”

“…These findings indicate the potential influence of microbiota on the genetic and epigenetic modulation of the host, which can alter the efficiency of the immune system response. 91 In a healthy person, the prostate gland is normally free of pathogenic microbes that cause cancer. It is well-known that the commensal microbes of other organs and systems have somehow interfered with PC development, therapy, and systemic inflammation.…”

Loss of smarcad1a accelerates tumorigenesis of malignant peripheral nerve sheath tumors in zebrafish

“…Altogether, these data suggest that SMARCAD1 may be an evolutionarily conserved tumor suppressor gene in vertebrates. Future conditional knockout mouse models will be helpful to address whether Smarcad1 is also involved in mouse MPNSTs since the new conditional mice were just created recently 76 …”