ATF2 and ATF7 Are Critical Mediators of Intestinal Epithelial Repair

Abstract

We show that ATF2 and ATF7 are dispensable for homeostatic turnover of the intestinal epithelium but are critically required to sustain sufficient epithelial repair after damage. ATF2 and ATF7 couple surface epithelial loss to a proportionate proliferative response and a decrease in secretory goblet cells providing an epithelial protective layer. BACKGROUND & AIMS: Activation factor-1 transcription factor family members activating transcription factors 2 and 7 (ATF2 and ATF7) have highly redundant functions owing to highly homologous DNA binding sites. Their role in intestinal epithelial homeostasis and repair is unknown. Here, we assessed the role of these proteins in these conditions in an intestine-specific mouse model. METHODS: We performed in vivo and ex vivo experiments using Villin-Cre ERT2 Atf2 fl/fl Atf7 ko/ko mice. We investigated the effects of intestinal epithelium-specific deletion of the Atf2 DNA binding region in Atf7-/mice on cellular proliferation, differentiation, apoptosis, and epithelial barrier function under homeostatic conditions. Subsequently, we exposed mice to 2% dextran sulfate sodium (DSS) for 7 days and 12 Gy whole-body irradiation and assessed the response to epithelial damage. RESULTS: Activating phosphorylation of ATF2 and ATF7 was detected mainly in the crypts of the small intestine and the lower crypt region of the colonic epithelium. Under homeostatic conditions, no major phenotypic changes were detectable in the intestine of ATF mutant mice. However, on DSS exposure or whole-body irradiation, the intestinal epithelium showed a clearly impaired regenerative response. Mutant mice developed severe ulceration and inflammation associated with increased epithelial apoptosis on DSS exposure and were less able to regenerate colonic crypts on irradiation. In vitro, organoids derived from double-mutant epithelium had a growth disadvantage compared with wild-type organoids, impaired wound healing capacity in scratch assay, and increased sensitivity to tumor necrosis factor-a-induced damage. CONCLUSIONS: ATF2 and ATF7 are dispensable for epithelial homeostasis, but are required to maintain epithelial regenerative capacity and protect against cell death during intestinal epithelial damage and repair.

Single-cell profiling of environmental enteropathy reveals signatures of epithelial remodeling and immune activation in severe disease

“…S9. This is consistent with reduced IL-22 signaling (75) and altered goblet cell development (79)). In addition, STAT6, a key regulator of secretory lineage differentiation, was predicted to have lower activity in OLFM4 expressing stem cells and immature enterocytes (80).…”

Targeted Transcriptomic Analysis of C57BL/6 and BALB/c Mice During Progressive Chronic Toxoplasma gondii Infection Reveals Changes in Host and Parasite Gene Expression Relating to Neuropathology and Resolution

“…While previous work on PSMB8 has produced minimal data in relation to Toxoplasma infection ( Agarwal et al., 2010 ), further research specifically relating to chronic infection could elaborate on anti-parasitic functions in the CNS. In addition to regulating TNFα production, ATF2 is a cAMP- or activator protein-dependent transcription factor that regulates the transcription of various genes involved in anti-apoptosis, cell growth, and DNA damage response ( Falvo et al., 2000 ; Tsytsykova and Goldfeld, 2002 ; Watson et al., 2017 ; Meijer et al., 2020 ). While the effect of T. gondii infection on the transcription of TNFα has been studied in the past, the specific role of ATF2 in the context of chronic T. gondii infection in the CNS has not been elucidated, and this gene may play a vital role in regulating TNFα production specifically in the brain or by CNS-resident cells ( Leng et al., 2009 ).…”

Emerging roles of activating transcription factor (ATF) family members in tumourigenesis and immunity: Implications in cancer immunotherapy

“…In addition to participating in inflammation-related pathological processes, a recent study reported that ATF2 and ATF7 are essential for epithelial homeostasis, but in the process of intestinal epithelial injury and repair, they need to maintain epithelial regeneration and prevent cell death. 69 …”