Epigenetics in Intestinal Epithelial Cell Renewal

Roostaee, Alireza; Benoit, Yannick D.; Boudjadi, Salah; Beaulieu, Jean‐François

doi:10.1002/jcp.25401

Cited by 34 publications

(29 citation statements)

References 82 publications

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“…13 Similar to butyrate, we found that βHB, acting as an endogenous inhibitor of HDACs, induces p21 Waf1 expression and inhibits intestinal cell proliferation associated with the induction of differentiation. Given the extensive gene regulation by HDACs and the important role of HDACs in regulating intestinal cell differentiation, 38,39 βHB likely induces intestinal cell differentiation through inhibition of HDACs.…”

Section: Discussionmentioning

confidence: 99%

Ketogenesis contributes to intestinal cell differentiation

et al. 2016

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The intestinal epithelium undergoes a continual process of proliferation, differentiation and apoptosis. Previously, we have shown that the PI3K/Akt/mTOR pathway has a critical role in intestinal homeostasis. However, the downstream targets mediating the effects of mTOR in intestinal cells are not known. Here, we show that the ketone body β-hydroxybutyrate (βHB), an endogenous inhibitor of histone deacetylases (HDACs) induces intestinal cell differentiation as noted by the increased expression of differentiation markers (Mucin2 (MUC2), lysozyme, IAP, sucrase-isomaltase, KRT20, villin, Caudal-related homeobox transcription factor 2 (CDX2) and p21 Waf1 ). Conversely, knockdown of the ketogenic mitochondrial enzyme hydroxymethylglutaryl CoA synthase 2 (HMGCS2) attenuated spontaneous differentiation in the human colon cancer cell line Caco-2. Overexpression of HMGCS2, which we found is localized specifically in the more differentiated portions of the intestinal mucosa, increased the expression of CDX2, thus further suggesting the contributory role of HMGCS2 in intestinal differentiation. In addition, mice fed a ketogenic diet demonstrated increased differentiation of intestinal cells as noted by an increase in the enterocyte, goblet and Paneth cell lineages. Moreover, we showed that either knockdown of mTOR or inhibition of mTORC1 with rapamycin increases the expression of HMGCS2 in intestinal cells in vitro and in vivo, suggesting a possible cross-talk between mTOR and HMGCS2/βHB signaling in intestinal cells. In contrast, treatment of intestinal cells with βHB or feeding mice with a ketogenic diet inhibits mTOR signaling in intestinal cells. Together, we provide evidence showing that HMGCS2/βHB contributes to intestinal cell differentiation. Our results suggest that mTOR acts cooperatively with HMGCS2/βHB to maintain intestinal homeostasis.

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Section: Discussionmentioning

confidence: 99%

Ketogenesis contributes to intestinal cell differentiation

et al. 2016

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“…Through milk, the infant may benefit from these bioactive molecules, which may act as key regulators to set up important processes during the maturation of organs, such as the GI tract. The epithelium of the GI system is continuously renewed and dynamically regulated by epigenetic modifications and transcription factors, which influence intestinal cells throughout the crypt-villus axis [97]. Histone methylation and acetylation are crucial in controlling proliferation and differentiation of intestinal cells of the crypts [97].…”

Section: Breast Milk Mirna: Possible Key Regulators and Noninvasivmentioning

confidence: 99%

“…The epithelium of the GI system is continuously renewed and dynamically regulated by epigenetic modifications and transcription factors, which influence intestinal cells throughout the crypt-villus axis [97]. Histone methylation and acetylation are crucial in controlling proliferation and differentiation of intestinal cells of the crypts [97]. DNA methylation sites are key regulators of postnatal epigenetic changes in intestinal stem cells [98].…”

Section: Breast Milk Mirna: Possible Key Regulators and Noninvasivmentioning

confidence: 99%

Roles of MicroRNA across Prenatal and Postnatal Periods

Floris

Kraft

Altosaar

2016

IJMS

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Communication between mother and offspring in mammals starts at implantation via the maternal–placental–fetal axis, and continues postpartum via milk targeted to the intestinal mucosa. MicroRNAs (miRNAs), short, noncoding single-stranded RNAs, of about 22 nucleotides in length, are actively involved in many developmental and physiological processes. Here we highlight the role of miRNA in the dynamic signaling that guides infant development, starting from implantation of conceptus and persisting through the prenatal and postnatal periods. miRNAs in body fluids, particularly in amniotic fluid, umbilical cord blood, and breast milk may offer new opportunities to investigate physiological and/or pathological molecular mechanisms that portend to open novel research avenues for the identification of noninvasive biomarkers.

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“…Very recent data advances the hypotheses that intestinal stem cells might be involved in the inflammatory paths discussed in IBS [84,88]. Due to their properties, stem cells not only are able to respond to pathogens but also may modulate the spectrum of answers by their secretory functions [84,89].…”

Section: New Hypothesesmentioning

confidence: 93%

Inflammation as a Potential Therapeutic Target in IBS

Chira¹,

Chira²,

Dumitraşcu³

2016

Irritable Bowel Syndrome - Novel Concepts for Research and Treatment

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The pathogenesis of irritable bowel syndrome (IBS) has been intensively researched, and despite a long journey for unraveling all the structures and the pathways involved, it still remains partially obscure. Inflammation was the first to be hypothesized as a potential pathway for the pathogenesis of IBS. It remains a keystone in the complex machinery of the pathogenesis that is currently considered multifactorial. Elucidating the pathogenesis of IBS is crucial for a targeted therapy of the disease. In this chapter, we review information regarding gut inflammation in IBS, underlining some of the newest data or the cornerstones. Additionally, our aim was also to review treatment currently available and future perspectives regarding anti-inflammatory treatments for IBS. Newer techniques allow detection and research of mediators involved in inflammation, as well as their potential role to be targeted by pharmacological agents. Recent data supports not only further research of the newer agents that are currently being developed but also some of the available ones that do not have sufficient evidence. Emerging therapies that target inflammation are under evaluation, in trials. A multidrug or a multidisciplinary approach needs to be considered in some cases that fail to respond to current treatment.

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Epigenetics in Intestinal Epithelial Cell Renewal

Cited by 34 publications

References 82 publications

Ketogenesis contributes to intestinal cell differentiation

Ketogenesis contributes to intestinal cell differentiation

Roles of MicroRNA across Prenatal and Postnatal Periods

Inflammation as a Potential Therapeutic Target in IBS

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