Aging-like Spontaneous Epigenetic Silencing Facilitates Wnt Activation, Stemness, and BrafV600E-Induced Tumorigenesis

Tao, Yong; Kang, Byunghak; Petkovich, Daniel A.; Bhandari, Yuba R.; In, Julie; Stein-O’Brien, Genevieve; Kong, Xiangqian; Xie, Wenbing; Zachos, Nicholas C.; Maegawa, Satoru; Vaidya, Himani; Brown, Stephen M.; Yen, Ray Whay Chiu; Shao, Xiaojian; Thakor, Jai; Lü, Zhihao; Cai, Yi; Zhang, Yuezheng; Mallona, Izaskun; Peinado, Miguel A.; Zahnow, Cynthia A.; Ahuja, Nita; Fertig, Elana J.; Issa, Jean Pierre J.; Baylin, Stephen B.; Easwaran, Hariharan

doi:10.1016/j.ccell.2019.01.005

Cited by 117 publications

(141 citation statements)

References 74 publications

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“…Critically, increased or sustained Wnt pathway activity contributes to colorectal cancers, complicating the path to restoration of regenerative capacity if Wnt signaling activity is in fact reduced in old crypts (181). Accordingly, a connection between age-related molecular changes and the increased propensity for colorectal cancer has recently been described in the colon: In colonderived organoids from old mice, spontaneous epigenetic silencing by promoter hypermethylation (which mimics human aging-like phenotypes) leads to activation of the Wnt pathway, causing a stem-like state and differentiation defects and resulting in higher sensitivity to transformation by Braf V600E compared to organoids from young mice (182).…”

Section: Aging In the Mammalian Intestinementioning

confidence: 99%

Intestinal Stem Cell Aging: Origins and Interventions

Jasper¹

2020

Annu. Rev. Physiol.

109

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Regenerative processes that maintain the function of the gastrointestinal (GI) epithelium are critical for health and survival of multicellular organisms. In insects and vertebrates, intestinal stem cells (ISCs) regenerate the GI epithelium. ISC function is regulated by intrinsic, local, and systemic stimuli to adjust regeneration to tissue demands. These control mechanisms decline with age, resulting in significant perturbation of intestinal homeostasis. Processes that lead to this decline have been explored intensively in Drosophila melanogaster in recent years and are now starting to be characterized in mammalian models. This review presents a model for age-related regenerative decline in the fly intestine and discusses recent findings that start to establish molecular mechanisms of age-related decline of mammalian ISC function. 203 Annu. Rev. Physiol. 2020.82:203-226. Downloaded from www.annualreviews.org Access provided by 44.224.250.200 on 07/08/20. For personal use only.

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Section: Aging In the Mammalian Intestinementioning

confidence: 99%

Intestinal Stem Cell Aging: Origins and Interventions

Jasper¹

2020

Annu. Rev. Physiol.

109

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“…7 In addition, mouse colon organoids aged in vitro show global methylation changes similar to those seen in the aging mouse colon. 8 However, although there is potential for organoids to be used as models for aging, 9 the degree to which organoids faithfully recapitulate aging has yet to be determined.…”

mentioning

confidence: 99%

DNA Methylation Analysis Validates Organoids as a Viable Model for Studying Human Intestinal Aging

Lewis

Nachun

Martı́n

et al. 2020

Cellular and Molecular Gastroenterology and Hepatology

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We found that human intestinal organoids maintain the age of the patient from whom they are derived, as measured by the epigenetic clock. Unexpectedly, we found that crypts and spheroids derived from small intestine showed striking epigenetic age reduction, relative to the colon. BACKGROUND & AIMS:The epithelia of the intestine and colon turn over rapidly and are maintained by adult stem cells at the base of crypts. Although the small intestine and colon have distinct, well-characterized physiological functions, it remains unclear if there are fundamental regional differences in stem cell behavior or region-dependent degenerative changes during aging. Mesenchyme-free organoids provide useful tools for investigating intestinal stem cell biology in vitro and have started to be used for investigating agerelated changes in stem cell function. However, it is unknown whether organoids maintain hallmarks of age in the absence of an aging niche. We tested whether stem cell-enriched organoids preserved the DNA methylationbased aging profiles associated with the tissues and crypts from which they were derived. METHODS:To address this, we used standard human methylation arrays and the human epigenetic clock as a biomarker of age to analyze in vitro-derived, 3-dimensional, stem cell-enriched intestinal organoids. RESULTS:We found that human stem cell-enriched organoids maintained segmental differences in methylation patterns and that age, as measured by the epigenetic clock, also was maintained in vitro. Surprisingly, we found that stem cell-enriched organoids derived from the small intestine showed striking epigenetic age reduction relative to organoids derived from colon. CONCLUSIONS:Our data validate the use of organoids as a model for studying human intestinal aging and introduce methods that can be used when modeling aging or age-onset diseases in vitro. (Cell Mol Gastroenterol Hepatol 2020;9:527-541; https://doi.

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“…Consistent with this model, in a mouse model of BrafV600E-driven colon cancer, escape from senescence and tumor progression was linked to increased expression of Dnmt3b and methylation and silencing of p16 (Carragher et al, 2010). According to this model, although activated BRAFV600E can increase the selective pressure that favors CIMP, methylation is not directly caused by BRAFV600E but has an inherent tendency to encroach on unmethylated CpG islands during aging (Skvortsova et al, 2019;Ushijima and Suzuki, 2019;Tao et al, 2019). In another model that more directly links oncogenic signaling and CIMP, it has been proposed that BRAFV600E signaling recruits DNMT3B to genes silenced by CIMP via the transcriptional repressor, MAFG, thereby directly promoting CIMP (Fang et al, 2014(Fang et al, , 2016.…”

Section: Introductionmentioning

confidence: 57%

DNMT3B Oncogenic Activity in Human Intestinal Cancer Is Not Linked to CIMP or BRAFV600E Mutation

et al. 2020

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Approximately 10% of human colorectal cancer (CRC) are associated with activated BRAFV600E mutation, typically in absence of APC mutation and often associated with a CpG island methylator (CIMP) phenotype. To protect from cancer, normal intestinal epithelial cells respond to oncogenic BRAFV600E by activation of intrinsic p53 and p16-dependent tumor suppressor mechanisms, such as cellular senescence. Conversely, CIMP is thought to contribute to bypass of these tumor suppressor mechanisms, e.g. via epigenetic silencing of tumor suppressor genes, such as p16. It has been repeatedly proposed that DNMT3B is responsible for BRAFV600E-induced CIMP in human CRC. Here we set out to test this by in silico, in vitro, and in vivo approaches. We conclude that although both BRAFV600E and DNMT3B harbor oncogenic potential in vitro and in vivo and show some evidence of cooperation in tumor promotion, they do not frequently cooperate to promote CIMP and human intestinal cancer.

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Aging-like Spontaneous Epigenetic Silencing Facilitates Wnt Activation, Stemness, and BrafV600E-Induced Tumorigenesis

Cited by 117 publications

References 74 publications

Intestinal Stem Cell Aging: Origins and Interventions

Intestinal Stem Cell Aging: Origins and Interventions

DNA Methylation Analysis Validates Organoids as a Viable Model for Studying Human Intestinal Aging

DNMT3B Oncogenic Activity in Human Intestinal Cancer Is Not Linked to CIMP or BRAFV600E Mutation

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