scholarly journals Role of transcription complexes in the formation of the basal methylation pattern in early development

2018 ◽  
Vol 115 (41) ◽  
pp. 10387-10391 ◽  
Author(s):  
Razi Greenfield ◽  
Amalia Tabib ◽  
Ilana Keshet ◽  
Joshua Moss ◽  
Ofra Sabag ◽  
...  
Keyword(s):  
De Novo ◽  
Cpg Islands ◽  
Embryonic Stem ◽  
Methylation Pattern ◽  
Entire Genome ◽  
Genome Wide ◽  
Topological Pattern ◽  
Histone H3k4 ◽  
Transcription Complexes ◽  
De Novo Methylation

Following erasure in the blastocyst, the entire genome undergoes de novo methylation at the time of implantation, with CpG islands being protected from this process. This bimodal pattern is then preserved throughout development and the lifetime of the organism. Using mouse embryonic stem cells as a model system, we demonstrate that the binding of an RNA polymerase complex on DNA before de novo methylation is predictive of it being protected from this modification, and tethering experiments demonstrate that the presence of this complex is, in fact, sufficient to prevent methylation at these sites. This protection is most likely mediated by the recruitment of enzyme complexes that methylate histone H3K4 over a local region and, in this way, prevent access to the de novo methylation complex. The topological pattern of H3K4me3 that is formed while the DNA is as yet unmethylated provides a strikingly accurate template for modeling the genome-wide basal methylation pattern of the organism. These results have far-reaching consequences for understanding the relationship between RNA transcription and DNA methylation.

QSER1 protects DNA methylation valleys from de novo methylation

Science ◽  
2021 ◽  
Vol 372 (6538) ◽  
pp. eabd0875 ◽  
Author(s):  
Gary Dixon ◽  
Heng Pan ◽  
Dapeng Yang ◽  
Bess P. Rosen ◽  
Therande Jashari ◽  
...  
Keyword(s):  
Dna Methylation ◽  
De Novo ◽  
Embryonic Stem ◽  
Central Question ◽  
Mammalian Development ◽  
Uncharacterized Gene ◽  
Pathological Conditions ◽  
Genome Wide ◽  
A Genome ◽  
De Novo Methylation

DNA methylation is essential to mammalian development, and dysregulation can cause serious pathological conditions. Key enzymes responsible for deposition and removal of DNA methylation are known, but how they cooperate to regulate the methylation landscape remains a central question. Using a knockin DNA methylation reporter, we performed a genome-wide CRISPR-Cas9 screen in human embryonic stem cells to discover DNA methylation regulators. The top screen hit was an uncharacterized gene, QSER1, which proved to be a key guardian of bivalent promoters and poised enhancers of developmental genes, especially those residing in DNA methylation valleys (or canyons). We further demonstrate genetic and biochemical interactions of QSER1 and TET1, supporting their cooperation to safeguard transcriptional and developmental programs from DNMT3-mediated de novo methylation.

Genome-Wide De Novo Methylation in Epithelial Ovarian Cancer

2011 ◽  
Vol 21 (2) ◽  
pp. 269-279 ◽  
Author(s):  
Rachel Michaelson-Cohen ◽  
Ilana Keshet ◽  
Ravid Straussman ◽  
Merav Hecht ◽  
Howard Cedar ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Differentiation ◽  
Gene Silencing ◽  
De Novo ◽  
Cpg Islands ◽  
Aberrant Methylation ◽  
Genome Wide ◽  
A Genome ◽  
Treatment Responsiveness ◽  
De Novo Methylation

Background:DNA methylation regulates gene expression during development. The methylation pattern is established at the time of implantation. CpG islands are genome regions usually protected from methylation; however, selected islands are methylated later. Many undergo methylation in cancer, causing epigenetic gene silencing. Aberrant methylation occurs early in tumorigenesis, in a specific pattern, inhibiting differentiation.Although methylation of specific genes in ovarian tumors has been demonstrated in numerous studies, they represent only a fraction of all methylated genes in tumorigenesis.Objectives:To explore the hypermethylation design in ovarian cancer compared with the methylation profile of normal ovaries, on a genome-wide scale, thus shedding light on the role of gene silencing in ovarian carcinogenesis.Identifying genes that undergo de novo methylation in ovarian cancer may assist in creating biomarkers for disease diagnosis, prognosis, and treatment responsiveness.Methods:DNA was collected from human epithelial ovarian cancers and normal ovaries. Methylation was detected by immunoprecipitation using 5-methyl-cytosine-antibodies. DNA was hybridized to a CpG island microarray containing 237,220 gene promoter probes. Results were analyzed by hybridization intensity, validated by bisulfite analysis.Results:A total of 367 CpG islands were specifically methylated in cancer cells. There was enrichment of methylated genes in functional categories related to cell differentiation and proliferation inhibition. It seems that their silencing enables tumor proliferation.Conclusions:This study provides new perspectives on methylation in ovarian carcinoma, genome-wide. It illustrates how methylation of CpG islands causes silencing of genes that have a role in cell differentiation and functioning. It creates potential biomarkers for diagnosis, prognosis, and treatment responsiveness.

scholarly journals Methylation-Associated Gene Silencing ofRARBin Areca Carcinogens Induced Mouse Oral Squamous Cell Carcinoma

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Zi-Lun Lai ◽  
Yung-An Tsou ◽  
Shin-Ru Fan ◽  
Ming-Hsui Tsai ◽  
Hsiao-Ling Chen ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Oral Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
De Novo ◽  
Retinoic Acid Receptor ◽  
Cpg Islands ◽  
Dna Methyltransferases ◽  
Methylation Pattern ◽  
Genome Wide

Regarding oral squamous cell carcinoma (OSCC) development, chewing areca is known to be a strong risk factor in many Asian cultures. Therefore, we established an OSCC induced mouse model by 4-nitroquinoline-1-oxide (4-NQO), or arecoline, or both treatments, respectively. These are the main two components of the areca nut that could increase the occurrence of OSCC. We examined the effects with the noncommercial MCGI (mouse CpG islands) microarray for genome-wide screening the DNA methylation aberrant in induced OSCC mice. The microarray results showed 34 hypermethylated genes in 4-NQO plus arecoline induced OSCC mice tongue tissues. The examinations also used methylation-specific polymerase chain reaction (MS-PCR) and bisulfite sequencing to realize the methylation pattern in collected mouse tongue tissues and human OSCC cell lines of different grades, respectively. These results showed that retinoic acid receptorβ(RARB) was indicated in hypermethylation at the promoter region and the loss of expression during cancer development. According to the results of real-time PCR, it was shown thatde novoDNA methyltransferases were involved in gene epigenetic alternations of OSCC. Collectively, our results showed thatRARBhypermethylation was involved in the areca-associated oral carcinogenesis.

scholarly journals TET proteins safeguard bivalent promoters from de novo methylation in human embryonic stem cells

2017 ◽  
Vol 50 (1) ◽  
pp. 83-95 ◽  
Author(s):  
Nipun Verma ◽  
Heng Pan ◽  
Louis C. Doré ◽  
Abhijit Shukla ◽  
Qing V. Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Human Embryonic Stem Cells ◽  
De Novo ◽  
Embryonic Stem ◽  
Tet Proteins ◽  
De Novo Methylation

Strain-specific transgene methylation occurs early in mouse development and can be recapitulated in embryonic stem cells

Development ◽  
1995 ◽  
Vol 121 (9) ◽  
pp. 2853-2859 ◽  
Author(s):  
A. Weng ◽  
T. Magnuson ◽  
U. Storb
Keyword(s):  
De Novo ◽  
Es Cells ◽  
Embryonic Stem ◽  
Dependent Manner ◽  
Mouse Development ◽  
Partial Methylation ◽  
Distal Chromosome ◽  
Before And After ◽  
Endogenous Genes ◽  
De Novo Methylation

A murine transgene, HRD, is methylated only when carried in certain inbred strain backgrounds. A locus on distal chromosome 4, Ssm1 (strain-specific modifier), controls this phenomenon. In order to characterize the activity of Ssm1, we have investigated developmental acquisition of methylation over the transgene. Analysis of postimplantation embryos revealed that strain-specific methylation is initiated prior to embryonic day (E) 6.5. Strain-specific transgene methylation is all-or-none in pattern and occurs exclusively in the primitive ectoderm lineage. A strain-independent pattern of partial methylation occurs in the primitive endoderm and trophectoderm lineages. To examine earlier stages, embryonic stem (ES) cells were derived from E3.5 blastocysts and examined for transgene methylation before and after differentiation. Though the transgene had already acquired some methylation in undifferentiated ES cells, differentiation induced further, de novo methylation in a strain-dependent manner. Analysis of methylation in ES cultures suggests that the transgene and endogenous genes (such as immunoglobulin genes) are synchronously methylated during early development. These results are interpreted in the context of a model in which Ssm1-like modifier genes produce alterations in chromatin structure during and/or shortly after implantation, thereby marking target loci for de novo methylation with the rest of the genome during gastrulation.

TRANSCRIPTIONAL REGULATION OF HYAL-2 HYALURONIDASE BY DE NOVO METHYLATION OF CpG ISLANDS IN BRAIN

Hyaluronan ◽  
2002 ◽  
pp. 187-194
Author(s):  
Günter Lepperdinger ◽  
Birgit Strobl ◽  
Johannes Müllcgger ◽  
Günther Kreil
Keyword(s):  
Transcriptional Regulation ◽  
De Novo ◽  
Cpg Islands ◽  
De Novo Methylation

scholarly journals Susceptibility of Nonpromoter CpG Islands to De Novo Methylation in Normal and Neoplastic Cells

2001 ◽  
Vol 93 (19) ◽  
pp. 1465-1472 ◽  
Author(s):  
C. Nguyen ◽  
G. Liang ◽  
T. T. Nguyen ◽  
D. Tsao-Wei ◽  
S. Groshen ◽  
...  
Keyword(s):  
De Novo ◽  
Cpg Islands ◽  
Neoplastic Cells ◽  
De Novo Methylation

scholarly journals Nucleosomes Correlate with In Vivo Progression Pattern of De Novo Methylation of p16 CpG Islands in Human Gastric Carcinogenesis

PLoS ONE ◽  
2012 ◽  
Vol 7 (4) ◽  
pp. e35928 ◽  
Author(s):  
Zhe-Ming Lu ◽  
Jing Zhou ◽  
Xiuhong Wang ◽  
Zhenpo Guan ◽  
Hua Bai ◽  
...  
Keyword(s):  
De Novo ◽  
Cpg Islands ◽  
Gastric Carcinogenesis ◽  
De Novo Methylation

scholarly journals De novo methylation of CpG island sequences in human fibroblasts overexpressing DNA (cytosine-5-)-methyltransferase.

1996 ◽  
Vol 16 (8) ◽  
pp. 4555-4565 ◽  
Author(s):  
P M Vertino ◽  
R W Yen ◽  
J Gao ◽  
S B Baylin
Keyword(s):  
Enzyme Activity ◽  
De Novo ◽  
Cpg Island ◽  
Human Fibroblasts ◽  
Methylation Status ◽  
Cpg Islands ◽  
Parental Cell Line ◽  
Direct Role ◽  
Cpg Island Methylation ◽  
De Novo Methylation

Recent studies showing a correlation between the levels of DNA (cytosine-5-)-methyltransferase (DNA MTase) enzyme activity and tumorigenicity have implicated this enzyme in the carcinogenic process. Moreover, hypermethylation of CpG island-containing promoters is associated with the inactivation of genes important to tumor initiation and progression. One proposed role for DNA MTase in tumorigenesis is therefore a direct role in the de novo methylation of these otherwise unmethylated CpG islands. In this study, we sought to determine whether increased levels of DNA MTase could directly affect CpG island methylation. A full-length cDNA for human DNA MTase driven by the cytomegalovirus promoter was constitutively expressed in human fibroblasts. Individual clones derived from cells transfected with DNA MTase (HMT) expressed 1- to 50-fold the level of DNA MTase protein and enzyme activity of the parental cell line or clones transfected with the control vector alone (Neo). To determine the effects of DNA MTase overexpression on CpG island methylation, we examined 12 endogenous CpG island loci in the HMT clones. HMT clones expressing > or = 9-fold the parental levels of DNA MTase activity were significantly hypermethylated relative to at least 11 Neo clones at five CpG island loci. In the HMT clones, methylation reached nearly 100% at susceptible CpG island loci with time in culture. In contrast, there was little change in the methylation status in the Neo clones over the same time frame. Taken together, the data indicate that overexpression of DNA MTase can drive the de novo methylation of susceptible CpG island loci, thus providing support for the idea that DNA MTase can contribute to tumor progression through CpG island methylation-mediated gene inactivation.

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