Arid1a is essential for intestinal stem cells through Sox9 regulation

Abstract

Inactivating mutations of Arid1a, a subunit of the Switch/sucrose nonfermentable chromatin remodeling complex, have been reported in multiple human cancers. Intestinal deletion of Arid1a has been reported to induce colorectal cancer in mice; however, its functional role in intestinal homeostasis remains unclear. We investigated the functional role of Arid1a in intestinal homeostasis in mice. We found that intestinal deletion of Arid1a results in loss of intestinal stem cells (ISCs), decreased Paneth and goblet cells, disorganized crypt-villous structures, and increased apoptosis in adult mice. Spheroids did not develop from intestinal epithelial cells deficient for Arid1a. Lineage-tracing experiments revealed that Arid1a deletion in Lgr5+ ISCs leads to impaired self-renewal of Lgr5+ ISCs but does not perturb intestinal homeostasis. The Wnt signaling pathway, including Wnt agonists, receptors, and target genes, was strikingly down-regulated in Arid1a-deficient intestines. We found that Arid1a directly binds to the Sox9 promoter to support its expression. Remarkably, overexpression of Sox9 in intestinal epithelial cells abrogated the above phenotypes, although Sox9 overexpression in intestinal epithelial cells did not restore the expression levels of Wnt agonist and receptor genes. Furthermore, Sox9 overexpression permitted development of spheroids from Arid1a-deficient intestinal epithelial cells. In addition, deletion of Arid1a concomitant with Sox9 overexpression in Lgr5+ ISCs restores self-renewal in Arid1a-deleted Lgr5+ ISCs. These results indicate that Arid1a is indispensable for the maintenance of ISCs and intestinal homeostasis in mice. Mechanistically, this is mainly mediated by Sox9. Our data provide insights into the molecular mechanisms underlying maintenance of ISCs and intestinal homeostasis.

Transcriptional Regulation of Wnt/β-Catenin Pathway in Colorectal Cancer

“…The deficiency of ARID1A can drive CRC without APC mutations owing to the dysregulation of enhancer activity [ 206 ]. Subsequently, it has been reported that ARID1A is indispensable for intestinal homeostasis maintenance via regulating the Wnt pathway and SOX9 expression [ 207 ]. Lastly, in the context of neurodevelopment, ARID1B interacts with β-catenin via BRG1 to suppress Wnt-mediated downstream transcription.…”

Paradoxical role of AT-rich interactive domain 1A in restraining pancreatic carcinogenesis

“…Consistent with the published models, we found that Ptf1a-specific conditional loss of Arid1a in "AC" mice led to widespread pancreatitis and fatty replacement of post-mature parenchyma, suggesting that Arid1a is required for maintaining adult acinar homeostasis. This is comparable to conditional deletion of Arid1a leading to depletion of Lgr5-expressing mouse intestinal stem cells, disrupting intestinal homeostasis 46 . In mice with co-expression of mutant Kras G12D allele ("KAC"), the pancreas developed LG-IPMNs and LG-PanINs ubiquitously, with the former resembling gastric type IPMNs in patients, as has been previously reported 7,8 .…”

Chromatin Dynamics in Intestinal Epithelial Homeostasis: A Paradigm of Cell Fate Determination versus Cell Plasticity

“…The Brg1 KO likewise leads to a huge increase in secretory cell number, in a Math1-dependent manner [71]. In contrast, Arid1a KO diminishes secretory cell number via an uncharacterized mechanism [70]. Interestingly, these results show that Brg1 and Arid1a exert opposite roles on secretory lineage commitment.…”

“…Knock-out in the intestine of Arid1a, a subunit involved in DNA interaction, leads to loss of ISCs and thus to decreased tissue renewal. Indeed, ARID1a promotes expression of the gene encoding transcription factor SOX9, essential for ISC maintenance [70]. Deletion of the Brg1 gene, encoding the ATPase subunit, also causes a drastic decrease in expression of ISC marker genes (Lgr5, Olfm4, Ascl2…) [71].…”