Regulation of telomeric function by DNA methylation differs between humans and mice

2020 ◽  
Vol 29 (19) ◽  
pp. 3197-3210
Author(s):  
Shir Toubiana ◽  
Gal Larom ◽  
Riham Smoom ◽  
Robert J Duszynski ◽  
Lucy A Godley ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Cpg Islands ◽  
Open Chromatin ◽  
Chromatin Modifications ◽  
Embryonic Fibroblasts ◽  
Subtelomeric Heterochromatin ◽  
Non Coding Rna ◽  
Long Non Coding Rna

Abstract The most distal 2 kb region in the majority of human subtelomeres contains CpG-rich promoters for TERRA, a long non-coding RNA. When the function of the de novo DNA methyltransferase DNMT3B is disrupted, as in ICF1 syndrome, subtelomeres are abnormally hypomethylated, subtelomeric heterochromatin acquires open chromatin characteristics, TERRA is highly expressed, and telomeres shorten rapidly. In this study, we explored whether the regulation of subtelomeric epigenetic characteristics by DNMT3B is conserved between humans and mice. Studying the DNA sequence of the distal 30 kb of the majority of murine q-arm subtelomeres indicated that these regions are relatively CpG-poor and do not contain TERRA promoters similar to those present in humans. Despite the lack of human-like TERRA promoters, we clearly detected TERRA expression originating from at least seven q-arm subtelomeres, and at higher levels in mouse pluripotent stem cells in comparison with mouse embryonic fibroblasts (MEFs). However, these differences in TERRA expression could not be explained by differential methylation of CpG islands present in the TERRA-expressing murine subtelomeres. To determine whether Dnmt3b regulates the expression of TERRA in mice, we characterized subtelomeric methylation and associated telomeric functions in cells derived from ICF1 model mice. Littermate-derived WT and ICF1 MEFs demonstrated no significant differences in subtelomeric DNA methylation, chromatin modifications, TERRA expression levels, telomere sister chromatid exchange or telomere length. We conclude that the epigenetic characteristics of murine subtelomeres differ substantially from their human counterparts and that TERRA transcription in mice is regulated by factors others than Dnmt3b.

scholarly journals De novo DNA methyltransferase activity in colorectal cancer is directed towards H3K36me3 marked CpG islands

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Roza H. Ali Masalmeh ◽  
Francesca Taglini ◽  
Cristina Rubio-Ramon ◽  
Kamila I. Musialik ◽  
Jonathan Higham ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Methylation ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Cpg Islands ◽  
Dna Methyltransferases ◽  
Transcriptional Elongation ◽  
Methyltransferase Activity ◽  
Methylation Activity ◽  
Colorectal Tumours

AbstractThe aberrant gain of DNA methylation at CpG islands is frequently observed in colorectal tumours and may silence the expression of tumour suppressors such as MLH1. Current models propose that these CpG islands are targeted by de novo DNA methyltransferases in a sequence-specific manner, but this has not been tested. Using ectopically integrated CpG islands, here we find that aberrantly methylated CpG islands are subject to low levels of de novo DNA methylation activity in colorectal cancer cells. By delineating DNA methyltransferase targets, we find that instead de novo DNA methylation activity is targeted primarily to CpG islands marked by the histone modification H3K36me3, a mark associated with transcriptional elongation. These H3K36me3 marked CpG islands are heavily methylated in colorectal tumours and the normal colon suggesting that de novo DNA methyltransferase activity at CpG islands in colorectal cancer is focused on similar targets to normal tissues and not greatly remodelled by tumourigenesis.

scholarly journals Kaiso regulates DNA methylation homeostasis

2020 ◽  
Author(s):  
D Kaplun ◽  
G Filonova ◽  
Y. Lobanova ◽  
A Mazur ◽  
S Zhenilo
Keyword(s):  
Dna Methylation ◽  
Complex Formation ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Main Idea ◽  
Dna Methyltransferases ◽  
The Other ◽  
Dna Hypermethylation ◽  
Mouse Embryonic Fibroblasts ◽  
Embryonic Fibroblasts

ABSTRACTGain and loss of DNA methylation in cells is a dynamic process that tends to achieve an equilibrium. Many factors are involved in maintaining the balance between DNA methylation and demethylation. Previously, it was shown that methyl-DNA protein Kaiso may attract NcoR, SMRT repressive complexes affecting histone modifications. On the other hand, the deficiency of Kaiso resulted in slightly reduced methylation of ICR in H19/Igf2 locus and Oct4 promoter in mouse embryonic fibroblasts. However, nothing is known whether Kaiso may attract DNA methyltransferase to influence DNA methylation level. The main idea of this work is that Kaiso may lead to DNA hypermethylation attracting de novo DNA methyltransferases. We demonstrated that Kaiso regulates TRIM25 promoter methylation. It can form a complex with DNMT3b. BTB/POZ domain of Kaiso and ADD domain of DNA methyltransferase are essential for complex formation. Thus, Kaiso can affect DNA methylation.

scholarly journals Independence between pre-mRNA splicing and de novo DNA methylation in an isogenic minigene resource

2017 ◽  
Author(s):  
Kyster K. Nanan ◽  
Cody Ocheltree ◽  
David Sturgill ◽  
Mariana D. Mandler ◽  
Maria Prigge ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Expression Profiling ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Mrna Splicing ◽  
Direct Impact ◽  
Chromatin Modifications ◽  
Established Relationship ◽  
Splicing Efficiency ◽  
General Reduction

ABSTRACTActively transcribed genes adopt a unique chromatin environment with characteristic patterns of enrichment. Within gene bodies, H3K36me3 and cytosine DNA methylation are elevated at exons of spliced genes and have been implicated in the regulation of pre-mRNA splicing. H3K36me3 is further responsive to splicing, wherein splicing inhibition led to a redistribution and general reduction over gene bodies. In contrast, little is known of the mechanisms supporting elevated DNA methylation at actively spliced genic locations. Recent evidence associating the de novo DNA methyltransferase Dnmt3b with H3K36me3-rich chromatin raises the possibility that genic DNA methylation is influenced by splicing-associated H3K36me3. Here, we report the generation of an isogenic resource to test the direct impact of splicing on chromatin. A panel of minigenes of varying splicing potential were integrated into a single FRT site for inducible expression. Profiling of H3K36me3 confirmed the established relationship to splicing, wherein levels were directly correlated with splicing efficiency. In contrast, DNA methylation was equivalently detected across the minigene panel, irrespective of splicing and H3K36me3 status. In addition to revealing a degree of independence between genic H3K36me3 and DNA methylation, these findings highlight the generated minigene panel as a flexible platform for the query of splicing-dependent chromatin modifications.

scholarly journals A lncRNA/Lin28/Mirlet7 axis coupled to DNA methylation fine tunes the dynamics of a cell state transition

2017 ◽  
Author(s):  
Meng Amy Li ◽  
Paulo P. Amaral ◽  
Priscilla Cheung ◽  
Jan H. Bergmann ◽  
Masaki Kinoshita ◽  
...  
Keyword(s):  
Dna Methylation ◽  
State Transition ◽  
De Novo ◽  
Embryonic Stem ◽  
Lineage Specification ◽  
Cell State ◽  
Non Coding Rna ◽  
A Cell ◽  
Long Non Coding Rna ◽  
Stem Cell State

SummaryExecution of pluripotency requires progression from the naïve status represented by mouse embryonic stem cells (ESCs) to a condition poised for lineage specification. This process is controlled at transcriptional, post-transcriptional and epigenetic levels and non-coding RNAs are contributors to this regulation complexity. Here we identify a molecular cascade initiated by a long non-coding RNA (lncRNA), Ephemeron (Epn), that modulates the dynamics of exit from naïve pluripotency. Epn deletion delays the extinction of ESC identity, an effect mediated by perduring expression of the pivotal transcription factor Nanog. In the absence of Epn, Lin28a expression is reduced, resulting in an elevated level of Mirlet7g that suppresses de novo methyltransferases Dnmt3a/b. Dnmt3a/b deletion also retards exit from the ESC state, and is associated with delayed promoter methylation and slower down-regulation of Nanog. Altogether, our findings reveal a lncRNA/miRNA/DNA methylation axis that facilitates a timely stem cell state transition.

scholarly journals Targets and genomic constraints of ectopic Dnmt3b expression

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Yingying Zhang ◽  
Jocelyn Charlton ◽  
Rahul Karnik ◽  
Isabel Beerman ◽  
Zachary D Smith ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Cpg Island ◽  
Cpg Islands ◽  
Cell Types ◽  
Aberrant Methylation ◽  
Genome Wide Data ◽  
Mammalian Genomes ◽  
Different Cell Types

DNA methylation plays an essential role in mammalian genomes and expression of the responsible enzymes is tightly controlled. Deregulation of the de novo DNA methyltransferase DNMT3B is frequently observed across cancer types, yet little is known about its ectopic genomic targets. Here, we used an inducible transgenic mouse model to delineate rules for abnormal DNMT3B targeting, as well as the constraints of its activity across different cell types. Our results explain the preferential susceptibility of certain CpG islands to aberrant methylation and point to transcriptional state and the associated chromatin landscape as the strongest predictors. Although DNA methylation and H3K27me3 are usually non-overlapping at CpG islands, H3K27me3 can transiently co-occur with DNMT3B-induced DNA methylation. Our genome-wide data combined with ultra-deep locus-specific bisulfite sequencing suggest a distributive activity of ectopically expressed Dnmt3b that leads to discordant CpG island hypermethylation and provides new insights for interpreting the cancer methylome.

scholarly journals A lncRNA fine tunes the dynamics of a cell state transition involving Lin28, let-7 and de novo DNA methylation

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Meng Amy Li ◽  
Paulo P Amaral ◽  
Priscilla Cheung ◽  
Jan H Bergmann ◽  
Masaki Kinoshita ◽  
...  
Keyword(s):  
Dna Methylation ◽  
De Novo ◽  
Embryonic Stem ◽  
Rapid Progression ◽  
Lineage Specification ◽  
Nanog Expression ◽  
Non Coding Rna ◽  
A Cell ◽  
Species Specific ◽  
Long Non Coding Rna

Execution of pluripotency requires progression from the naïve status represented by mouse embryonic stem cells (ESCs) to a state capacitated for lineage specification. This transition is coordinated at multiple levels. Non-coding RNAs may contribute to this regulatory orchestra. We identified a rodent-specific long non-coding RNA (lncRNA) linc1281, hereafter Ephemeron (Eprn), that modulates the dynamics of exit from naïve pluripotency. Eprn deletion delays the extinction of ESC identity, an effect associated with perduring Nanog expression. In the absence of Eprn, Lin28a expression is reduced which results in persistence of let-7 microRNAs, and the up-regulation of de novo methyltransferases Dnmt3a/b is delayed. Dnmt3a/b deletion retards ES cell transition, correlating with delayed Nanog promoter methylation and phenocopying loss of Eprn or Lin28a. The connection from lncRNA to miRNA and DNA methylation facilitates the acute extinction of naïve pluripotency, a pre-requisite for rapid progression from preimplantation epiblast to gastrulation in rodents. Eprn illustrates how lncRNAs may introduce species-specific network modulations.

scholarly journals Two competing mechanisms of DNMT3A recruitment regulate the dynamics of de novo DNA methylation at PRC1-targeted CpG islands

2021 ◽  
Author(s):  
Daniel N. Weinberg ◽  
Phillip Rosenbaum ◽  
Xiao Chen ◽  
Douglas Barrows ◽  
Cynthia Horth ◽  
...  
Keyword(s):  
Dna Methylation ◽  
De Novo ◽  
Cpg Islands

scholarly journals UVR8 interacts with de novo DNA methyltransferase and suppresses DNA methylation in Arabidopsis

Nature Plants ◽  
2021 ◽  
Vol 7 (2) ◽  
pp. 184-197
Author(s):  
Jianjun Jiang ◽  
Jie Liu ◽  
Dean Sanders ◽  
Shuiming Qian ◽  
Wendan Ren ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
De Novo

scholarly journals DNMT1 reads heterochromatic H4K20me3 to reinforce LINE-1 DNA methylation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Wendan Ren ◽  
Huitao Fan ◽  
Sara A. Grimm ◽  
Jae Jin Kim ◽  
Linhui Li ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
Histone H3 ◽  
Genomic Stability ◽  
Mammalian Genome ◽  
Dna Methyltransferase 1 ◽  
Chromatin Modifications ◽  
Direct Link ◽  
Histone H4 ◽  
Radiation Induced

AbstractDNA methylation and trimethylated histone H4 Lysine 20 (H4K20me3) constitute two important heterochromatin-enriched marks that frequently cooperate in silencing repetitive elements of the mammalian genome. However, it remains elusive how these two chromatin modifications crosstalk. Here, we report that DNA methyltransferase 1 (DNMT1) specifically ‘recognizes’ H4K20me3 via its first bromo-adjacent-homology domain (DNMT1BAH1). Engagement of DNMT1BAH1-H4K20me3 ensures heterochromatin targeting of DNMT1 and DNA methylation at LINE-1 retrotransposons, and cooperates with the previously reported readout of histone H3 tail modifications (i.e., H3K9me3 and H3 ubiquitylation) by the RFTS domain to allosterically regulate DNMT1’s activity. Interplay between RFTS and BAH1 domains of DNMT1 profoundly impacts DNA methylation at both global and focal levels and genomic resistance to radiation-induced damage. Together, our study establishes a direct link between H4K20me3 and DNA methylation, providing a mechanism in which multivalent recognition of repressive histone modifications by DNMT1 ensures appropriate DNA methylation patterning and genomic stability.

Sign in / Sign up

Export Citation Format

Share Document