bims-instec 2023-09-03 papers

Sci Rep. 2023 08 26. 13(1): 13964

Mutational landscape of intestinal crypt cells after long-term in vivo exposure to high fat diet.

Mathilde Meyenberg, Anna Hakobyan, Nikolina Papac-Milicevic, Laura Göderle, Franziska L Langner, Mateo Markovic, Ji-Hyun Lee, Bon-Kyoung Koo, Georg A Busslinger, Israel Tojal da Silva, Christoph J Binder, Jörg Menche, Joanna I Loizou.

Obesity is a modifiable risk factor in cancer development, especially for gastrointestinal cancer. While the etiology of colorectal cancer is well characterized by the adenoma-carcinoma sequence, it remains unclear how obesity influences colorectal cancer development. Dietary components of a high fat diet along with obesity have been shown to modulate the cancer risk by perturbing the homeostasis of intestinal stem cells, yet how adiposity impacts the development of genomic instability has not been studied. Mutational signatures are a powerful way to understand how a complex biological response impacts genomic stability. We utilized a mouse model of diet-induced obesity to study the mutational landscape of intestinal crypt cells after a 48-week exposure to an experimental high fat diet in vivo. By clonally enriching single crypt derived cells in organoid culture and obtaining whole genome sequences, we analyzed and compared the mutational landscape of intestinal epithelial cells from normal diet and high fat diet mice. Single nucleotide substitution signatures and indel signatures present in our cohort are found equally active in both diet groups and reflect biological processes of normal aging, cellular replication, and oxidative stress induced during organoid culturing. Thus, we demonstrate that in the absence of activating mutations or chemical exposure, high fat diet alone is not sufficient to increase genomic instability.

DOI: https://doi.org/10.1038/s41598-023-41123-3

Sci Adv. 2023 Sep;9(35): eadh5016

Inhibiting sorting nexin 10 promotes mucosal healing through SREBP2-mediated stemness restoration of intestinal stem cells.

Intestinal stem cell (ISC) is a promising therapeutic target for inflammatory bowel disease. Cholesterol availability is critical for ISC stemness. Low plasma cholesterol is a typical feature of Crohn's disease (CD); however, its impact on mucosal healing remains unclear. Here, we identified an essential role of sorting nexin 10 (SNX10) in maintaining the stemness of ISCs. SNX10 expression in intestinal tissues positively correlates with the severity of human CD and mouse colitis. Conditional SNX10 knockout in intestinal epithelial cells or ISCs promotes intestinal mucosal repair by maintaining the ISC population associated with increased intracellular cholesterol synthesis. Disassociation of ERLIN2 with SCAP by SNX10 deletion enhances the activation of SREBP2, resulting in increased cholesterol biosynthesis. DC-SX029, a small-molecule inhibitor of SNX10, was used to verify the druggable potential of SNX10 for the treatment of patients with CD. Our study provides a strategy for mucosal healing through SREBP2-mediated stemness restoration of ISCs.

DOI: https://doi.org/10.1126/sciadv.adh5016

J Clin Invest. 2023 Aug 29. pii: e163591. [Epub ahead of print]

Epithelial TNF controls cell differentiation and CFTR activity to maintain intestinal mucin homeostasis.

Efren A Reyes, David Castillo-Azofeifa, Jérémie Rispal, Tomas Wald, Rachel K Zwick, Brisa Palikuqi, Angela Mujukian, Shervin Rabizadeh, Alexander R Gupta, James M Gardner, Dario Boffelli, Zev J Gartner, Ophir D Klein.

The gastrointestinal tract relies on the production, maturation, and transit of mucin to protect against pathogens and to lubricate the epithelial lining. Although the molecular and cellular mechanisms that regulate mucin production and movement are beginning to be understood, the upstream epithelial signals that contribute to mucin regulation remain unclear. Here, we report that the inflammatory cytokine tumor necrosis factor (TNF), generated by the epithelium, contributes to mucin homeostasis by regulating both cell differentiation and cystic fibrosis transmembrane conductance regulator (CFTR) activity. We used genetic mouse models and non-inflamed samples from Inflammatory Bowel Disease (IBD) patients undergoing anti-TNF therapy to assess the effect of in vivo perturbation of TNF. We found that inhibition of epithelial TNF promotes the differentiation of secretory progenitor cells into mucus-producing goblet cells. Furthermore, TNF treatment and CFTR inhibition in intestinal organoids demonstrated that TNF promotes ion transport and luminal flow via CFTR. The absence of TNF led to slower gut transit times, which we propose results from increased mucus accumulation coupled with decreased luminal fluid pumping. These findings point to a TNF-CFTR signaling axis in the adult intestine and identify epithelial-derived TNF as an upstream regulator of mucin homeostasis.

Keywords: Cytokines; Epithelial transport of ions and water; Gastroenterology; Molecular genetics

DOI: https://doi.org/10.1172/JCI163591

Cell Death Dis. 2023 Sep 01. 14(9): 581

IGF2BP3 promotes the progression of colorectal cancer and mediates cetuximab resistance by stabilizing EGFR mRNA in an m6A-dependent manner.

Li-Jie Chen, Hui-Ye Liu, Zhi-Yuan Xiao, Ting Qiu, Dan Zhang, Ling-Jie Zhang, Fang-Yi Han, Guo-Jun Chen, Xue-Mei Xu, Jiong-Hua Zhu, Yan-Qing Ding, Shu-Yang Wang, Ya-Ping Ye, Hong-Li Jiao.

Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), an RNA-binding protein, is associated with tumorigenesis and progression. However, the exact molecular mechanisms of IGF2BP3 in colorectal cancer (CRC) oncogenesis, progression, and drug resistance remain unclear. This study found that IGF2BP3 was upregulated in CRC tissues. Clinically, the elevated IGF2BP3 level is predictive of a poor prognosis. Functionally, IGF2BP3 enhances CRC tumorigenesis and progression both in vitro and in vivo. Mechanistically, IGF2BP3 promotes epidermal growth factor receptor (EGFR) mRNA stability and translation and further activates the EGFR pathway by serving as a reader in an N6-methyladenosine (m6A)-dependent manner by cooperating with METTL14. Furthermore, IGF2BP3 increases the drug resistance of CRC cells to the EGFR-targeted antibody cetuximab. Taken together, our results demonstrated that IGF2BP3 was a functional and clinical oncogene of CRC. Targeting IGF2BP3 and m6A modification may therefore offer rational therapeutic targets for patients with CRC.

DOI: https://doi.org/10.1038/s41419-023-06099-y

Front Endocrinol (Lausanne). 2023 ;14 1232569

Multiple roles and regulatory mechanisms of the transcription factor HNF4 in the intestine.

Kiranmayi Vemuri, Sarah H Radi, Frances M Sladek, Michael P Verzi.

Hepatocyte nuclear factor 4-alpha (HNF4α) drives a complex array of transcriptional programs across multiple organs. Beyond its previously documented function in the liver, HNF4α has crucial roles in the kidney, intestine, and pancreas. In the intestine, a multitude of functions have been attributed to HNF4 and its accessory transcription factors, including but not limited to, intestinal maturation, differentiation, regeneration, and stem cell renewal. Functional redundancy between HNF4α and its intestine-restricted paralog HNF4γ, and co-regulation with other transcription factors drive these functions. Dysregulated expression of HNF4 results in a wide range of disease manifestations, including the development of a chronic inflammatory state in the intestine. In this review, we focus on the multiple molecular mechanisms of HNF4 in the intestine and explore translational opportunities. We aim to introduce new perspectives in understanding intestinal genetics and the complexity of gastrointestinal disorders through the lens of HNF4 transcription factors.

Keywords: HNF4; colon cancer; inflammatory bowel disease; intestinal differentiation; intestinal regeneration; intestine; redundancy; transcription factor

DOI: https://doi.org/10.3389/fendo.2023.1232569