Maintenance of DNA methylation: Dnmt3b joins the dance

Walton, Emma Louise; Francastel, Claire; Velasco, Guillaume

doi:10.4161/epi.6.11.17978

Cited by 53 publications

(37 citation statements)

References 39 publications

(68 reference statements)

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“…We assessed profiles of gene expression focusing on the germline genes transcriptional signature that we previously established in a mouse model for ICF1 [23,24]. …”

Section: Resultsmentioning

confidence: 99%

“…Since the germline genes tested in this study are known to be repressed through DNA methylation in mice [23,24,28] we analyzed their methylation status on genomic DNA isolated from fresh whole blood samples (Figure 2A) or epithelial cells obtained from buccal swabs (Figure 2B), from ICF patients and healthy donors. Consistent with their expression only in blood cells from ICF1 patients (Figure 1), analysis of methylation at MAEL and SYCE1 revealed their hypomethylated state specifically in ICF1 patients since ICF2 and ICFX patients (except ICFX patient pN; discussed below) were methylated at values comparable to healthy controls (raw data and p values in Additional file 8).…”

Section: Resultsmentioning

confidence: 99%

“…In addition, our data suggested a new role for Dnmt3b in the protection of somatic cells against the promiscuous expression of the germ line program, playing the central role in both the establishment and maintenance of DNA methylation profiles at these genes [24]. Although the impact of their illicit expression on ICF phenotypes remains to be solved, their inherent repressed state in all somatic cells makes them good candidate biomarkers of molecular dysfunctions in ICF syndrome.…”

Section: Introductionmentioning

confidence: 99%

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Germline genes hypomethylation and expression define a molecular signature in peripheral blood of ICF patients: implications for diagnosis and etiology

Velasco

Walton

Sterlin

et al. 2014

Orphanet J Rare Dis

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BackgroundImmunodeficiency Centromeric Instability and Facial anomalies (ICF) is a rare autosomal recessive disease characterized by reduction in serum immunoglobulins with severe recurrent infections, facial dysmorphism, and more variable symptoms including mental retardation. ICF is directly related to a genomic methylation defect that mainly affects juxtacentromeric heterochromatin regions of certain chromosomes, leading to chromosomal rearrangements that constitute a hallmark of this syndrome upon cytogenetic testing. Mutations in the de novo DNA methyltransferase DNMT3B, the protein ZBTB24 of unknown function, or loci that remain to be identified, lie at its origin. Despite unifying features, common or distinguishing molecular signatures are still missing for this disease.MethodWe used the molecular signature that we identified in a mouse model for ICF1 to establish transcriptional biomarkers to facilitate diagnosis and understanding of etiology of the disease. We assayed the expression and methylation status of a set of genes whose expression is normally restricted to germ cells, directly in whole blood samples and epithelial cells of ICF patients.ResultsWe report that DNA hypomethylation and expression of MAEL and SYCE1 represent robust biomarkers, easily testable directly from uncultured cells to diagnose the most prevalent sub-type of the syndrome. In addition, we identified the first unifying molecular signatures for ICF patients. Of importance, we validated the use of our biomarkers to diagnose a baby born to a family with a sick child. Finally, our analysis revealed unsuspected complex molecular signatures in two ICF patients suggestive of a novel genetic etiology for the disease.ConclusionsEarly diagnosis of ICF syndrome is crucial since early immunoglobulin supplementation can improve the course of disease. However, ICF is probably underdiagnosed, especially in patients that present with incomplete phenotype or born to families with no affected relatives. The specific and robust biomarkers identified in this study could be introduced into routine clinical immunology or neurology departments to facilitate testing of patients with suspected ICF syndrome. In addition, as exemplified by two patients with a combination of molecular defects never described before, our data support the search for new types of mutations at the origin of ICF syndrome.

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“…We assessed profiles of gene expression focusing on the germline genes transcriptional signature that we previously established in a mouse model for ICF1 [23,24]. …”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Germline genes hypomethylation and expression define a molecular signature in peripheral blood of ICF patients: implications for diagnosis and etiology

Velasco

Walton

Sterlin

et al. 2014

Orphanet J Rare Dis

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“…four main DNMT isoforms are present in mammalian cells. DNMT1, the maintenance methyltransferase, is responsible for the conservation of methyl marks during DNA replication, while, DNMT3A and DNMT3B are contributed mainly to de novo DNA methylation, DNMT1, the catalytically inactive isoform, has a synergy with DNMT3A and DNMT3B (31), although a study appears to disagree with this rigid classification (32). These DNMTs play an important role in DNA methylation pattern of cellular processes, for example, differentiation of stem cells during embryonic development (33,34).…”

Section: Screening Mirnas Targeting Dnmts and Qrt-pcr Validationmentioning

confidence: 99%

Expression of DNA methyltransferases and target microRNAs in human tissue samples related to sporadic colorectal cancer

et al. 2016

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Abstract. Tissue microenvironment functions as a pivotal mediator in colorectal carcinogenesis, and its alteration can cause some important cellular responses including epigenetic events. The present study examined histologically altered tissue structure, DNA methyltransferases (DNMTs) and their corresponding expression of target microRNAs (miRNA). Tissues resected by surgery were from primary colorectal carcinoma. These samples were from three locations: and were ≥10, 5 and ≤2 cm away from the proximal lesion of colon cancer, and marked as no. 1, no. 2 and no. 3, respectively. Histological alteration was assessed by H&E staining, expression of DNMT1, DNMT3A, and DNMT3B was detected by immunohistochemistry and western blotting, microarray chip was used to screen distinguishable miRNAs and miRNAs targeting DNMTs whose validation assay was performed by quantitative real-time polymerase chain reaction (qRT-PCR). Our results revealed that normal crypt structure was shown in no. 1, while many aberrant crypt foci appeared in no. 3. Significant upregulation of DNMT1, DNMT3A, and DNMT3B expression was found in para-carcinoma tissues, compared with the histopathologically unchanged tissues (P<0.05), furthermore, distinguishable expression profiling was observed of target miRNAs in tissues with different distance. Our results provide additional insights for future research of colorectal carcinogenesis by introducing the tissue microenvironment.

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“…This includes methylation of cytosine bases at CpG sites of specific genomic regions during final cell division by DNA methyltransferases (DNMTases), which marks the genomic regions for transcription repression in a cell-type specific manner (e.g., genomic imprinting) [10]. This level also includes linear organization of gene clusters containing multiple functionally related genes that are co-regulated by a common enhancer, such as the locus control region LCR (e.g., the red/green opsin gene cluster [11][12][13]), or gene Fig.…”

Section: Level 1-dna Double Helixmentioning

confidence: 99%

Epigenetic regulation of retinal development and disease

Rao

Hennig

Malik

et al. 2011

j ocul biol dis inform

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Epigenetic regulation, including DNA methylation, histone modifications, and chromosomal organization, is emerging as a new layer of transcriptional regulation in retinal development and maintenance. Guided by intrinsic transcription factors and extrinsic signaling molecules, epigenetic regulation can activate and/or repress the expression of specific sets of genes, therefore playing an important role in retinal cell fate specification and terminal differentiation during development as well as maintaining cell function and survival in adults. Here, we review the major findings that have linked these mechanisms to the development and maintenance of retinal structure and function, with a focus on ganglion cells and photoreceptors. The mechanisms of epigenetic regulation are highly complex and vary among different cell types. Understanding the basic principles of these mechanisms and their regulatory pathways may provide new insight into the pathogenesis of retinal diseases associated with transcription dysregulation, and new therapeutic strategies for treatment.

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Maintenance of DNA methylation: Dnmt3b joins the dance

Cited by 53 publications

References 39 publications

Germline genes hypomethylation and expression define a molecular signature in peripheral blood of ICF patients: implications for diagnosis and etiology

Germline genes hypomethylation and expression define a molecular signature in peripheral blood of ICF patients: implications for diagnosis and etiology

Expression of DNA methyltransferases and target microRNAs in human tissue samples related to sporadic colorectal cancer

Epigenetic regulation of retinal development and disease

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