DNA methyltransferase 1 functions through C/ebpa to maintain hematopoietic stem and progenitor cells in zebrafish

Liu, Xiaohui; Jia, Xiaoe; Yuan, Hao; Ma, Ke; Chen, Yi; Jin, Y.; Deng, Min; Pan, Weijun; Chen, Sai‐Juan; Chen, Zhu; Thé, Hugues de; Zon, Leonard I.; Zhou, Yi; Zhou, Jun; Zhu, Jun

doi:10.1186/s13045-015-0115-7

Cited by 40 publications

(34 citation statements)

References 59 publications

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“…Dnmt1 serves as a maintenance methyltransferase, copying the methylation pattern from parent to daughter strand during DNA replication and its function is required for cell cycle progression [24][25][26] . Loss of Dnmt1 function results in genomic hypomethylation 27-29 and in developmental contexts and specific organ systems, this often compromises progenitor cell maintenance 24,27,[30][31][32][33] through numerous cellular mechanisms. These include: inducing cell cycle arrest 34,35 , retroelement activation 36-39 , inflammatory responses 33,37,40 , aberrant differentiation 28,31,41-44 and/or p53-mediated apoptosis 34,35 .Utilizing the dnmt1 s872 mutant zebrafish allele 30 , we establish an in vivo requirement for dnmt1 in RSCs.…”

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confidence: 99%

dnmt1function is required to maintain retinal stem cells within the ciliary marginal zone of the zebrafish eye

Angileri

Gross

2020

Preprint

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The ciliary marginal zone (CMZ) of the zebrafish retina contains a population of actively proliferating resident stem cells, which generate retinal neurons throughout life. The maintenance methyltransferase, dnmt1, is expressed within the CMZ. Loss of dnmt1 function results in gene misregulation and cell death in a variety of developmental contexts, however, its role in retinal stem cell (RSC) maintenance is currently unknown. Here, we demonstrate that zebrafish dnmt1 s872 mutants possess severe defects in RSC maintenance within the CMZ. Using a combination of immunohistochemistry, in situ hybridization, and a transgenic reporter assay, our results demonstrate a requirement for dnmt1 activity in the regulation of RSC proliferation, gene expression and in the repression of endogenous retroelements (REs). Ultimately, cell death is elevated in the dnmt1 -/-CMZ, but in a p53-independent manner. Using a transgenic reporter for RE transposition activity, we demonstrate increased transposition in the dnmt1 -/-CMZ. Taken together our data identify a critical role for dnmt1 function in RSC maintenance in the vertebrate eye. Introduction:The distal region of the vertebrate retina, termed the ciliary marginal zone (CMZ), contains a population of resident retinal stem cells (RSCs). The CMZ remains proliferative throughout the life of fish, but it proliferates to a more limited extent during the lifetime of amphibians and birds 1-6 . Whether an analogous structure exists in mammals is debated, but there are distinct, progenitor-like cells in the periphery of the retina that are active during embryogenesis 7-9 . Mammalian RSCs can also be isolated from the adult ciliary margin, cultured in vitro, and stimulated to produce retinal neurons 10-13 .However, this activity has not been demonstrated in the mature mammalian retinae in vivo.Studies of the CMZ have primarily focused on zebrafish and Xenopus models to determine genetic pathways required for RSC identity 2,14-16 and to characterize the epigenetic networks which regulate RSC function 17,18 . By comparison, the mechanisms mediating RSC maintenance in vivo remain unknown. In studies of RSCs, the zebrafish has been advantageous given that it possesses a highly active RSC population and is tractable for genetic and pharmacological manipulations, transgenesis and in vivo imaging 19,20 .DNA methylation, a frequently studied epigenetic modification, is the process through which a methyl group is added to the fifth carbon of cytosine nucleotides and is commonly found at CpG dinucleotide sequences 21 . Members of the family of DNA methyltransferase (Dnmt) enzymes 22,23 catalyze this epigenetic modification. Dnmt1 serves as a maintenance methyltransferase, copying the methylation pattern from parent to daughter strand during DNA replication and its function is required for cell cycle progression [24][25][26] . Loss of Dnmt1 function results in genomic hypomethylation 27-29 and in developmental contexts and specific organ systems, this often compromises progenitor cell maintenance 24...

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confidence: 99%

dnmt1function is required to maintain retinal stem cells within the ciliary marginal zone of the zebrafish eye

Angileri

Gross

2020

Preprint

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“…The inability of rnf4 SIMs mutants to rescue granulopoiesis suggested that an undefined SUMOylated negative regulator of c/ebpa might contribute to the defective phenotype. Our previous work has reported that c/ebpa expression is negatively regulated by DNMT1 through promoter methylation in zebrafish HSPC development (20). It is also well known that SUMOylation can significantly enhance DNMT1 activity (17).…”

Section: Dnmt1-c/ebpa Axis Is Impaired In Primitive and Definitive Grmentioning

confidence: 98%

“…A large number of these TFs, such as GATA1, CCAAT/enhancer-binding protein a (C/ EBPa), and IKAROS, have been characterized as SUMO targets (13)(14)(15)(16). Furthermore, SUMOylation of a series of epigenetic modifiers, including DNA methyltransferase (DNMT) family members (17), have been shown to be crucial in normal and malignant hematopoiesis (18)(19)(20)(21)(22).…”

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confidence: 99%

RNF4 regulates zebrafish granulopoiesis through the DNMT1‐C/EBPα axis

et al. 2018

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RING finger protein 4 (RNF4) is a multifunctional small ubiquitin-related modifier (SUMO)-targeted ubiquitin E3 ligase (STUbL) ubiquitously expressed in all tissues, and which mainly participates in DNA repair and in chromatin and transcriptional regulation. Although RNF4 has been implicated in hematopoietic disorders, its ontogenic role during hematopoietic development remains undiscovered. We generated a zebrafish rnf4 knockout line by using transcription activator-like effector nucleases technology to address the impact of rnf4 during hematopoiesis. Rnf4-deficient zebrafish embryos exhibited sharply decreased neutrophils numbers during both primitive and definitive hematopoiesis. Mechanistic studies revealed that repression of the key granulocytic activator, CCAAT/enhancer-binding protein α ( c/ebpα), via promoter hypermethylation by SUMOylated DNA methyltransferase 1 (DNMT1) was the main cause of impaired granulopoiesis in rnf4-deficient zebrafish. In addition, for the first time, we identified DNMT1 as a potential new STUbL substrate of RNF4, with knockdown of dnmt1 largely restoring primitive and definitive granulopoiesis in rnf4-deficient zebrafish. Collectively, RNF4 is indispensable for zebrafish granulopoiesis through regulation of the DNMT1-C/EBPα functional axis.-Wang, L., Liu, X., Wang, H., Yuan, H., Chen, S., Chen, Z., de The, H., Zhou, J., Zhu, J. RNF4 regulates zebrafish granulopoiesis through the DNMT1-C/EBPα axis.

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“…Uhrf1 is necessary to recruit Dnmt1 to unmethylated DNA during replication (Bostick et al, 2007;Muto et al, 2002;Sharif et al, 2007), and Dnmt1 is necessary to maintain intestinal epithelial progenitor cells . Given this interaction, and that expression of Dnmt1 has been documented in zebrafish embryos in developing endoderm (Liu et al, 2015;Rai et al, 2006), we wondered whether Dnmt1 protein is also expressed in EPCs and surrounding intestinal cell types. To address this question, we immunostained transverse sections of phox2b:EGFP-expressing embryos at 34 and 36 hpf with a Dnmt1 antibody.…”

Section: Enteric Progenitors and Surrounding Intestinal Cells Expressmentioning

confidence: 99%

Epigenetic factors coordinate intestinal development

Ganz

Melançon

Wilson

et al. 2018

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This work provides evidence that DNA methylation factors are important in all cell types that contribute to development of a functional intestine. AbstractIntestinal epithelium development depends on epigenetic modifications, but whether that is also the case for other intestinal tract cell types remains unclear. We found that functional loss of a DNA methylation machinery component, ubiquitin-like protein containing PHD and RING finger domains 1 (uhrf1), leads to reduced enteric neuron number, changes in neuronal morphology, and severe intestinal smooth muscle disruption. Genetic chimeras revealed that Uhrf1 functions both cell-autonomously in enteric neuron progenitors and cell-non-autonomously in surrounding intestinal cells. Uhrf1 recruits the DNA methyltransferase Dnmt1 to unmethylated DNA during replication. Dnmt1 is also expressed in enteric neuron and smooth muscle progenitors. dnmt1 mutants show a strong reduction in enteric neuron number and disrupted intestinal smooth muscle. Because dnmt1;uhrf1 double mutants have a similar phenotype to dnmt1 and uhrf1 single mutants, Dnmt1 and Uhrf1 must function together during enteric neuron and intestinal muscle development. This work shows that genes controlling epigenetic modifications are important in coordinating intestinal tract development, provides the first demonstration that these genes are important in ENS development, and advances uhrf1 and dnmt1 as potential new Hirschsprung disease candidates. We thank Doug Turnbull and the University of Oregon Genomics and Cell Characterization Core Facility for their expertise in Illumina sequencing and bioinformatics, Poh Kheng Loi for histology, Adam Christensen, John Dowd and the UO Zebrafish Facility staff for assistance with zebrafish husbandry.

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DNA methyltransferase 1 functions through C/ebpa to maintain hematopoietic stem and progenitor cells in zebrafish

Cited by 40 publications

References 59 publications

dnmt1function is required to maintain retinal stem cells within the ciliary marginal zone of the zebrafish eye

dnmt1function is required to maintain retinal stem cells within the ciliary marginal zone of the zebrafish eye

RNF4 regulates zebrafish granulopoiesis through the DNMT1‐C/EBPα axis

Epigenetic factors coordinate intestinal development

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