Epigenetic factors Dnmt1 and Uhrf1 coordinate intestinal development

Ganz, Julia; Melançon, Ellie; Wilson, Catherine; Amores, Angel; Batzel, Peter; Strader, Marie E.; Braasch, Ingo; Diba, Parham; Kuhlman, Julie A.; Postlethwait, John H.; Eisen, Judith S

doi:10.1016/j.ydbio.2019.08.002

Cited by 19 publications

(16 citation statements)

References 78 publications

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“…Unlike mouse embryos where uhrf1 deletion is embryonic lethal (12), uhrf1 mutant zebrafish embryos survive past the early embryonic stages due to maternal supplies (11)(12)(13). Loss of either uhrf1 or dnmt1 in zebrafish causes profound developmental defects leading to premature death by 8 days post fertilization (dpf) (13)(14)(15)(16). uhrf1 is essential for cell proliferation and development of the eye (17), intestine (8,16), and liver (14,15).…”

Section: Introductionmentioning

confidence: 99%

uhrf1 and dnmt1 Loss Induces an Immune Response in Zebrafish Livers Due to Viral Mimicry by Transposable Elements

et al. 2021

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Activation of transposable elements (TEs) can cause cellular damage. Cytoplasmic nucleic acid sensing pathways evolved to detect pathogens, but can also serve to cull cells with inappropriate TE activation as TEs can be viral mimetics. Epigenetic silencing of TEs is mediated in part by DNA methylation, but it is not clear if TE activation or the immune system contribute to the cellular damage caused by loss of DNA methylation. Here, we provide mechanistic insight into the observation of an activated interferon response in the liver of zebrafish larvae with deletion in critical components of the DNA methylation machinery, uhrf1 and dnmt1. We focus on dissecting the relationship between DNA methylation, TE activation and induction of an immune response through cytoplasmic DNA and double stranded RNA sensing pathways and identify tnfa as a mediator of cell death in the liver of these mutants. Integrated RNAseq and methylome analysis identified LTR transposons as the most upregulated in these mutants and also the most methylated in control larvae, indicating a direct role of DNA methylation in suppressing this TE subclass. RNAseq analysis from these same samples revealed expression signatures of a type-I interferon response and of tnfa activation, mimicking the pattern of gene expression in virally infected cells. CRISPR/Cas9 mediated depletion of the cellular antiviral sensors sting and mavs reduced expression of interferon response genes and tnfa depletion dramatically reduced cell death in uhrf1 mutant livers. This suggests that the antiviral response induced by DNA hypomethylation and TE activation in the liver is mediated by the signaling pathways activated by both cytoplasmic double stranded RNA and DNA and that tnfa mediates cell death as a potential mechanism to eliminate these damaged cells.

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Section: Introductionmentioning

confidence: 99%

uhrf1 and dnmt1 Loss Induces an Immune Response in Zebrafish Livers Due to Viral Mimicry by Transposable Elements

et al. 2021

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“…Such role has recently been confirmed by showing that, EZH2 is involved in intestinal immune response and is even associated to inflammatory bowel disease (Zhou et al, 2019 ). Another study has shown that loss of genes coding for the ubiquitin-like protein containing PHD and RING finger domains 1 (Uhrf1), and DNA methyltransferase 1 (Dnmt1) reduced the number of enteric neurons and disrupted intestinal smooth muscle in zebrafish (Ganz et al, 2019 ). Although epigenetic mechanisms, including hypomethylation, have been suggested as a disease mechanism for HSCR [reviewed in Torroglosa et al ( 2019 )], this was the first report of a genetic animal model of aberrant methylation, that showed an effect on ENS development in vivo (Ganz et al, 2019 ).…”

Section: Genetic Modifications In Zebrafish To Study Ens Developmentmentioning

confidence: 99%

“…Another study has shown that loss of genes coding for the ubiquitin-like protein containing PHD and RING finger domains 1 (Uhrf1), and DNA methyltransferase 1 (Dnmt1) reduced the number of enteric neurons and disrupted intestinal smooth muscle in zebrafish (Ganz et al, 2019 ). Although epigenetic mechanisms, including hypomethylation, have been suggested as a disease mechanism for HSCR [reviewed in Torroglosa et al ( 2019 )], this was the first report of a genetic animal model of aberrant methylation, that showed an effect on ENS development in vivo (Ganz et al, 2019 ). It would be of high interest to investigate the downstream transcriptional consequences of hypomethylation in enteric neurons, to further expand our understanding on HSCR pathogenicity.…”

Section: Genetic Modifications In Zebrafish To Study Ens Developmentmentioning

confidence: 99%

“…As mentioned earlier, transplantation of wildtype ENS progenitors in sox10 zebrafish mutants could rescue the ENS (Rolig et al, 2017 ). In the uhrf1 mutant fish, ENS progenitor transplantation from wildtype donors was used to test cell autonomous effects (Ganz et al, 2019 ). Interestingly, transplanted wildtype cells were absent from the distal-most region in the mutants, showing that Uhrf1 function is necessary in non-neuronal cells in the intestine, for ENS progenitors to migrate to the far end of the intestine (Ganz et al, 2019 ).…”

Section: Identification Of Drugs That Stimulate Ens Developmentmentioning

confidence: 99%

“…In the uhrf1 mutant fish, ENS progenitor transplantation from wildtype donors was used to test cell autonomous effects (Ganz et al, 2019 ). Interestingly, transplanted wildtype cells were absent from the distal-most region in the mutants, showing that Uhrf1 function is necessary in non-neuronal cells in the intestine, for ENS progenitors to migrate to the far end of the intestine (Ganz et al, 2019 ). In mammalian HSCR models a lot of progress has been made in optimizing transplantation therapy.…”

Section: Identification Of Drugs That Stimulate Ens Developmentmentioning

confidence: 99%

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Zebrafish: A Model Organism for Studying Enteric Nervous System Development and Disease

Kuil¹,

Chauhan²,

Cheng³

et al. 2021

Front. Cell Dev. Biol.

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The Enteric Nervous System (ENS) is a large network of enteric neurons and glia that regulates various processes in the gastrointestinal tract including motility, local blood flow, mucosal transport and secretion. The ENS is derived from stem cells coming from the neural crest that migrate into and along the primitive gut. Defects in ENS establishment cause enteric neuropathies, including Hirschsprung disease (HSCR), which is characterized by an absence of enteric neural crest cells in the distal part of the colon. In this review, we discuss the use of zebrafish as a model organism to study the development of the ENS. The accessibility of the rapidly developing gut in zebrafish embryos and larvae, enables in vivo visualization of ENS development, peristalsis and gut transit. These properties make the zebrafish a highly suitable model to bring new insights into ENS development, as well as in HSCR pathogenesis. Zebrafish have already proven fruitful in studying ENS functionality and in the validation of novel HSCR risk genes. With the rapid advancements in gene editing techniques and their unique properties, research using zebrafish as a disease model, will further increase our understanding on the genetics underlying HSCR, as well as possible treatment options for this disease.

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Aberrant expression of LINC00346 regulates cell migration and proliferation via competitively binding to miRNA-148a-3p/Dnmt1 in Hirschsprung’s disease

Wang

et al. 2022

Pediatr Surg Int

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Epigenetic factors Dnmt1 and Uhrf1 coordinate intestinal development

Cited by 19 publications

References 78 publications

uhrf1 and dnmt1 Loss Induces an Immune Response in Zebrafish Livers Due to Viral Mimicry by Transposable Elements

uhrf1 and dnmt1 Loss Induces an Immune Response in Zebrafish Livers Due to Viral Mimicry by Transposable Elements

Zebrafish: A Model Organism for Studying Enteric Nervous System Development and Disease

Aberrant expression of LINC00346 regulates cell migration and proliferation via competitively binding to miRNA-148a-3p/Dnmt1 in Hirschsprung’s disease

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