Dnmt1 is essential to maintain progenitors in the perinatal intestinal epithelium

Elliott, Ellen N.; Sheaffer, Karyn L.; Schug, Jonathan; Stappenbeck, Thaddeus S.; Kaestner, Klaus H.

doi:10.1242/dev.117341

Cited by 60 publications

(50 citation statements)

References 44 publications

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“…Recently, Kang et al (2015) also reported that Tet1-deficient C57BL/6 mice exhibit partial embryonic lethality and growth retardation; however, intestinal health was not examined in the prior study. Tet1 −/− mice exhibited shortened intestinal length and reduced proliferating cell number in the postnatal intestine, which is similar to the phenotype seen in mice with conditional deletion of Dnmt1 in the developing gut using Dnmt1 f/f ; VillinCre mice (Elliott et al 2015;Yu et al 2015).…”

Section: Discussionsupporting

confidence: 65%

Epigenetic regulation of intestinal stem cells by Tet1-mediated DNA hydroxymethylation

et al. 2016

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Methylated cytosines are associated with gene silencing. The ten-eleven translocation (TET) hydroxylases, which oxidize methylated cytosines to 5-hydroxymethylcytosine (5hmC), are essential for cytosine demethylation. Gene silencing and activation are critical for intestinal stem cell (ISC) maintenance and differentiation, but the potential role of TET hydroxylases in these processes has not yet been examined. Here, we generated genome-wide maps of the 5hmC mark in ISCs and their differentiated progeny. Genes with high levels of hydroxymethylation in ISCs are strongly associated with Wnt signaling and developmental processes. We found Tet1 to be the most abundantly expressed Tet gene in ISCs; therefore, we analyzed intestinal development in Tet1-deficient mice and determined that these mice are growth-retarded, exhibit partial postnatal lethality, and have significantly reduced numbers of proliferative cells in the intestinal epithelium. In addition, the Tet1-deficient intestine displays reduced organoidforming capacity. In the Tet1-deficient crypt, decreased expression of Wnt target genes such as Axin2 and Lgr5 correlates with lower 5hmC levels at their promoters. These data demonstrate that Tet1-mediated DNA hydroxymethylation plays a critical role in the epigenetic regulation of the Wnt pathway in intestinal stem and progenitor cells and consequently in the self-renewal of the intestinal epithelium.

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Section: Discussionsupporting

confidence: 65%

Epigenetic regulation of intestinal stem cells by Tet1-mediated DNA hydroxymethylation

et al. 2016

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“…Genome-wide examination of the postnatal methylome revealed microbiota-dependent increases in DNA methylation in intestinal stem cells within maturation-associated genes that positively correlated with increased gene expression [76]. IEC-specific deletion of the methyltransferase Dnmt1 resulted in global DNA hypomethylation, aberrant crypt formation and stunted colonic development [76,77]. While SCFAs and the epigenome have not been studied in vivo to the same extent as immune cells, recent work has demonstrated previously unrecognized differential effects of butyrate on differentiated versus stem cell IECs (Fig.…”

Section: Epigenomic Pathways Directed By the Microbiota Maintain Intementioning

confidence: 99%

Host–microbiota interactions: epigenomic regulation

Woo

Alenghat

2017

Current Opinion in Immunology

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The coevolution of mammalian hosts and their commensal microbiota has led to the development of complex symbiotic relationships between resident microbes and mammalian cells. Epigenomic modifications enable host cells to alter gene expression without modifying the genetic code, and therefore represent potent mechanisms by which mammalian cells can transcriptionally respond, transiently or stably, to environmental cues. Advances in genome-wide approaches are accelerating our appreciation of microbial influences on host physiology, and increasing evidence highlights that epigenomics represent a level of regulation by which the host integrates and responds to microbial signals. In particular, bacterial-derived short chain fatty acids have emerged as one clear link between how the microbiota intersects with host epigenomic pathways. Here we review recent findings describing crosstalk between the microbiota and epigenomic pathways in multiple mammalian cell populations. Further, we discuss interesting links that suggest that the scope of our understanding of epigenomic regulation in the host-microbiota relationship is still in its infancy.

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“…Importantly, cytosine methylation (5-mc) is preserved during mitosis through DNA methyltransferase 1 (DNMT), which recognizes hemi-methylated DNA during the S-phase of mitosis and copies this patern to the daughter strand [13][14][15]. This mechanism is essential to maintain tissue homogeneity and cell lineage in terminally diferentiated cells, and there are many publications that have established DNA methylation proiles speciic to certain tissues and additionally tissues or cells with similar functions have similar methylation proiles [16,17].…”

Section: Dna Methylationmentioning

confidence: 99%

Hydroxymethylation Influences on Intestinal Epithelial Cells in Health and Disease

Huff-Hardy¹,

Kwon²

2018

Gene Expression and Regulation in Mammalian Cells - Transcription Toward the Establishment of Novel Therapeutics

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Epigenetics describes modiications that afect gene expression that are not encoded within the DNA sequence. DNA methylation is the longest appreciated epigenetic modiication and has been accepted to play a critical role in maintaining euchromatin and silencing genes. Recently, a separate and distinct covalent modiication has been recognized; hydroxymethylation, which has been associated with increased gene expression as opposed to gene silencing. However, traditional methods to study DNA methylation also recognized hydroxymethylation and did not distinguish between these two distinct DNA covalent modiications. Furthermore, TET enzymes have been identiied to play a critical role in active hydroxymethylation of previously methylated cytosine residues and may further result in conversion to cytosine. TET1 plays a critical role in intestinal epithelial diferentiation and development, and this is also correlated with increased hydroxymethylation in terminally diferentiated epithelial cells. Colon cancer, which arises from the colonic epithelium, exhibits decreased hydroxymethylation and altered gene expression.

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Dnmt1 is essential to maintain progenitors in the perinatal intestinal epithelium

Cited by 60 publications

References 44 publications

Epigenetic regulation of intestinal stem cells by Tet1-mediated DNA hydroxymethylation

Epigenetic regulation of intestinal stem cells by Tet1-mediated DNA hydroxymethylation

Host–microbiota interactions: epigenomic regulation

Hydroxymethylation Influences on Intestinal Epithelial Cells in Health and Disease

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