Transcription factor dynamics, oscillation, and functions in human enteroendocrine cell differentiation

Singh, Pratik N. P.; Gu, Wei; Madha, Shariq; Lynch, Allen W.; Cejas, Paloma; He, Ruiyang; Bhattacharya, Swarnabh; Gomez, Miguel M.; Oser, Matthew G.; Brown, Myles; Long, Henry W.; Meyer, Clifford A.; Zhou, Qiao; Shivdasani, Ramesh A.

doi:10.1101/2024.01.09.574746

Cited by 3 publications

References 109 publications

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Epigenetic investigation of multifocal small intestinal neuroendocrine tumours reveals accelerated ageing of tumours and epigenetic alteration of metabolic genes

Webster,

Mäkinen,

Mensah

et al. 2024

Preprint

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Background: Small intestinal neuroendocrine tumours (SI-NETs) are the most common malignancy of the small intestine and around 50% of patients present in clinic with multifocal disease. Recent investigations into the genomic architecture of multifocal SI-NETs have found evidence that these synchronous primary tumours evolve independently of each other. They also have extremely low mutational burden and few known driver genes, suggesting that epigenetic dysregulation may be driving tumorigenesis. Very little is known about epigenetic gene regulation, metabolism and ageing in these tumours, and how these traits differ across multiple tumours within individual patients. Methods: In this study, we performed the first investigation of genome-wide DNA methylation in multifocal SI-NETs, assessing multiple primary tumours within each patient (n=79 primary tumours from 14 patients) alongside matched metastatic tumours (n=12) and normal intestinal epithelial tissue (n=9). We assessed multifocal SI-NET differential methylation using a novel method, comparing primary tumours with matched normal epithelial tissue and an enterochromaffin-enriched cell line to enrich for tumour-specific effects. This method reduced the identification of 'false positive' methylation differences driven by cell composition differences between tumour and normal epithelial tissue. We also assessed tumour ageing using epigenetic clocks and applied metabolic predictors in the dataset to assess methylation variation across key metabolic genes. Results: We have identified 12,392 tumour-specific differentially methylated positions (Bonferroni corrected p<0.05) which were enriched for neural pathways. The expression levels of the genes associated with top sites were also found to be significantly altered in SI-NETs. Age acceleration was observed across SI-NETs and a variability in epigenetic 'age' of tumours within each patient, which we believe is reflecting the 'order' in which tumours have developed. This is supported by the correlation of age acceleration with somatic mutational count in the tumours. We have identified SI-NET associated alterations to the methylation patterns in key metabolic genes compared to matched normal tissue, which is more pronounced in metastatic tumours and tumours harbouring chromosome 18 loss of heterozygosity, indicating metabolic differences in these tumour subtypes. Conclusions: We have identified accelerated ageing and changes to regulation of metabolic genes, alongside an epigenetic signature of multifocal SI-NETs. These findings add to our understanding of multifocal SI-NET biology and their molecular differences which may be instrumental in the development of these elusive tumours.

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Epigenetic investigation of multifocal small intestinal neuroendocrine tumours reveals accelerated ageing of tumours and epigenetic alteration of metabolic genes

Webster,

Mäkinen,

Mensah

et al. 2024

Preprint

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Protein arginine methyltransferase 1 regulates mouse enteroendocrine cell development and homeostasis

Peng,

Bao,

Iben

et al. 2024

Cell Biosci

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Background The adult intestinal epithelium is a complex, self-renewing tissue composed of specialized cell types with diverse functions. Intestinal stem cells (ISCs) located at the bottom of crypts, where they divide to either self-renew, or move to the transit amplifying zone to divide and differentiate into absorptive and secretory cells as they move along the crypt-villus axis. Enteroendocrine cells (EECs), one type of secretory cells, are the most abundant hormone-producing cells in mammals and involved in the control of energy homeostasis. However, regulation of EEC development and homeostasis is still unclear or controversial. We have previously shown that protein arginine methyltransferase (PRMT) 1, a histone methyltransferase and transcription co-activator, is important for adult intestinal epithelial homeostasis. Results To investigate how PRMT1 affects adult intestinal epithelial homeostasis, we performed RNA-Seq on small intestinal crypts of tamoxifen-induced intestinal epithelium-specific PRMT1 knockout and PRMT1fl/fl adult mice. We found that PRMT1fl/fl and PRMT1-deficient small intestinal crypts exhibited markedly different mRNA profiles. Surprisingly, GO terms and KEGG pathway analyses showed that the topmost significantly enriched pathways among the genes upregulated in PRMT1 knockout crypts were associated with EECs. In particular, genes encoding enteroendocrine-specific hormones and transcription factors were upregulated in PRMT1-deficient small intestine. Moreover, a marked increase in the number of EECs was found in the PRMT1 knockout small intestine. Concomitantly, Neurogenin 3-positive enteroendocrine progenitor cells was also increased in the small intestinal crypts of the knockout mice, accompanied by the upregulation of the expression levels of downstream targets of Neurogenin 3, including Neuod1, Pax4, Insm1, in PRMT1-deficient crypts. Conclusions Our finding for the first time revealed that the epigenetic enzyme PRMT1 controls mouse enteroendocrine cell development, most likely via inhibition of Neurogenin 3-mediated commitment to EEC lineage. It further suggests a potential role of PRMT1 as a critical transcriptional cofactor in EECs specification and homeostasis to affect metabolism and metabolic diseases.

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Functional Analysis of TAAR1 Expression in the Intestine Wall and the Effect of Its Gene Knockout on the Gut Microbiota in Mice

Vaganova,

Zhukov,

Shemiakova

et al. 2024

IJMS

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Currently, the TAAR1 receptor has been identified in various cell groups in the intestinal wall. It recognizes biogenic amine compounds like phenylethylamine or tyramine, which are products of decarboxylation of phenylalanine and tyrosine by endogenous or bacterial decarboxylases. Since several gut bacteria produce these amines, TAAR1 is suggested to be involved in the interaction between the host and gut microbiota. The purpose of this present study was to clarify the TAAR1 function in the intestinal wall and estimate the TAAR1 gene knockout effect on gut microbiota composition. By analyzing public transcriptomic data of the GEO repository, we identified TAAR1 expression in enterocytes, enteroendocrine cells, tuft cells, and myenteric neurons in mice. The analysis of genes co-expressed with TAAR1 in enteroendocrine cells allows us to suggest the TAAR1 involvement in enteroendocrine cell maturation. Also, in myenteric neurons, we identified the co-expression of TAAR1 with calbindin, which is specific for sensory neurons. The 16S rRNA gene-based analysis of fecal microbiota revealed a slight but significant impact of TAAR1 gene knockout in mice on the gut microbial community, which manifests in the higher diversity, accompanied by low between-sample variability and reorganization of the microbial co-occurrence network.

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Transcription factor dynamics, oscillation, and functions in human enteroendocrine cell differentiation

Cited by 3 publications

References 109 publications

Epigenetic investigation of multifocal small intestinal neuroendocrine tumours reveals accelerated ageing of tumours and epigenetic alteration of metabolic genes

Epigenetic investigation of multifocal small intestinal neuroendocrine tumours reveals accelerated ageing of tumours and epigenetic alteration of metabolic genes

Protein arginine methyltransferase 1 regulates mouse enteroendocrine cell development and homeostasis

Functional Analysis of TAAR1 Expression in the Intestine Wall and the Effect of Its Gene Knockout on the Gut Microbiota in Mice

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