scholarly journals Nucleosomes and DNA methylation shape meiotic DSB frequency in Arabidopsis transposons and gene regulatory regions

2017 ◽  
Author(s):  
Kyuha Choi ◽  
Xiaohui Zhao ◽  
Christophe Lambing ◽  
Charles J. Underwood ◽  
Thomas J. Hardcastle ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
Genome Instability ◽  
Nucleosome Occupancy ◽  
Plant Genome ◽  
Gene Promoters ◽  
Regulatory Regions ◽  
Plant Genomes ◽  
Meiotic Dsbs ◽  
Gene Regulatory

AbstractMeiotic recombination initiates via DNA double strand breaks (DSBs) generated by SPO11 topoisomerase-like complexes. Recombination frequency varies extensively along eukaryotic chromosomes, with hotspots controlled by chromatin and DNA sequence. To map meiotic DSBs throughout a plant genome, we purified and sequenced Arabidopsis SPO11-1-oligonucleotides. DSB hotspots occurred in gene promoters, terminators and introns, driven by AT-sequence richness, which excludes nucleosomes and allows SPO11-1 access. A strong positive relationship was observed between SPO11-1 DSBs and final crossover levels. Euchromatic marks promote recombination in fungi and mammals, and consistently we observe H3K4me3 enrichment in proximity to DSB hotspots at gene 5’-ends. Repetitive transposons are thought to be recombination-silenced during meiosis, in order to prevent non-allelic interactions and genome instability. Unexpectedly, we found strong DSB hotspots in nucleosome-depleted Helitron/Pogo/Tc1/Mariner DNA transposons, whereas retrotransposons were coldspots. Hotspot transposons are enriched within gene regulatory regions and in proximity to immunity genes, suggesting a role as recombination-enhancers. As transposon mobility in plant genomes is restricted by DNA methylation, we used the met1 DNA methyltransferase mutant to investigate the role of heterochromatin on the DSB landscape. Epigenetic activation of transposon meiotic DSBs occurred in met1 mutants, coincident with reduced nucleosome occupancy, gain of transcription and H3K4me3. Increased met1 SPO11-1 DSBs occurred most strongly within centromeres and Gypsy and CACTA/EnSpm coldspot transposons. Together, our work reveals complex interactions between chromatin and meiotic DSBs within genes and transposons, with significance for the diversity and evolution of plant genomes.

Abstract 40: Disturbed Flow Alters Genomewide DNA Methylation Patterns, Regulating Endothelial Gene Expression and Atherosclerosis

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Jessilyn Dunn ◽  
Haiwei Qiu ◽  
Soyeon Kim ◽  
Daudi Jjingo ◽  
Ryan Hoffman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Dna Methyltransferase ◽  
Methylation Status ◽  
Western Diet ◽  
Dependent Manner ◽  
Gene Promoters ◽  
Genome Wide ◽  
Methylation Patterns ◽  
Endothelial Gene Expression

Atherosclerosis preferentially occurs in arterial regions of disturbed blood flow (d-flow), which alters gene expression, endothelial function, and atherosclerosis. Here, we show that d-flow regulates genome-wide DNA methylation patterns in a DNA methyltransferase (DNMT)-dependent manner. We found that d-flow induced expression of DNMT1, but not DNMT3a or DNMT3b, in mouse arterial endothelium in vivo and in cultured endothelial cells by oscillatory shear (OS) compared to unidirectional laminar shear in vitro. The DNMT inhibitor 5-Aza-2’deoxycytidine (5Aza) or DNMT1 siRNA significantly reduced OS-induced endothelial inflammation. Moreover, 5Aza reduced lesion formation in two atherosclerosis models using ApoE-/- mice (western diet for 3 months and the partial carotid ligation model with western diet for 3 weeks). To identify the 5Aza mechanisms, we conducted two genome-wide studies: reduced representation bisulfite sequencing (RRBS) and transcript microarray using endothelial-enriched gDNA and RNA, respectively, obtained from the partially-ligated left common carotid artery (LCA exposed to d-flow) and the right contralateral control (RCA exposed to s-flow) of mice treated with 5Aza or vehicle. D-flow induced DNA hypermethylation in 421 gene promoters, which was significantly prevented by 5Aza in 335 genes. Systems biological analyses using the RRBS and the transcriptome data revealed 11 mechanosensitive genes whose promoters were hypermethylated by d-flow but rescued by 5Aza treatment. Of those, five genes contain hypermethylated cAMP-response-elements in their promoters, including the transcription factors HoxA5 and Klf3. Their methylation status could serve as a mechanosensitive master switch in endothelial gene expression. Our results demonstrate that d-flow controls epigenomic DNA methylation patterns in a DNMT-dependent manner, which in turn alters endothelial gene expression and induces atherosclerosis.

Sensitivity of Diffuse Large B-Cell Lymphomas to DNA Methyltransferase Inhibitors Is Associated with a Specific Epigenetic Signature.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 831-831
Author(s):  
Megan Ryan ◽  
Leandro Cerchietti ◽  
Maria E. Figueroa ◽  
John Greally ◽  
Ari Melnick
Keyword(s):  
Dna Methylation ◽  
B Cell ◽  
Cell Lines ◽  
Dna Methyltransferase ◽  
Serum Starvation ◽  
Gene Promoters ◽  
B Cell Lymphomas ◽  
Response Curves ◽  
Differentially Methylated Genes ◽  
Large B Cell

Abstract DNA methyltransferase inhibitor drugs (MTIs) such as decitabine can overcome gene silencing due to aberrant hypermethylation of gene promoters. Presumably, this effect is responsible for the therapeutic activity of MTIs as clinically demonstrated in myelodysplasias (MDS) and leukemias. Other tumors such as diffuse large B-cell lymphomas (DLBCLs) can also present with aberrant promoter hypermethylation. However, it is currently difficult to prospectively identify patients likely to respond to MTIs, since specific methylation markers or signatures have not yet been identified. We predicted that decitabine would have anti-lymphoma activity in a subset of DLBCLs, and that these cases would exhibit specific methylation signatures predictive of response to these drugs. To determine whether this is the case we first exposed a panel of 7 DLBCL cell lines (Ly1, Ly7, Ly10, SU-DHL6, Farage, Pfeiffer and Toledo) to increasing concentrations of decitabine (0.5, 1, 2.5, 5, 10, 50 and 100 μM) administered after synchronization by 12 hr serum starvation. Viability was assessed after 48 hr of culture by MTS-based assay and Trypan blue exclusion. The IC25 and IC50 were calculated for all cell lines by constructing dose-response curves. The IC25 was used to discriminate sensitive (6.3 ± 1.2 μM) vs. resistant (49.4 ± 5 μM, p < 0.01) cell lines. Interestingly, there was no correlation between MTI sensitivity and DLBCL subtype as defined by recent gene expression profiling classification efforts (i.e. GCB vs. ABC, or BCR vs. OxPhos). To identify the methylation signatures of these DLBCL cells we used a method that we developed for genome-wide DNA methylation quantification called HELP (HpaII tiny fragment Enrichment by LM-PCR). HELP is based on comparative Msp1 and HpaII digestion of genomic DNA, followed by size specific amplification and co-hybridization to custom high-density oligonucleotide arrays designed to provide uniform data collection over 25,000 promoters. HELP compares favorably to other high throughput methods in that it is highly reproducible (R > 0.98) and has an extremely robust signal-to-noise ratio. DNA was collected from the DLBCL cells for HELP prior to drug treatment. Most significantly we found that unsupervised (i.e. unbiased) clustering of DNA methylation profiles could readily segregate decitabine resistant vs. sensitive DLBCL cell lines. Correspondence analysis clearly identified a methylation signature consisting of 133 differentially methylated genes that distinguishes between decitabine sensitive and resistant cells. Most of these appeared to be functionally relevant including such genes as Caspase-9, RARB, JUNB, and ELK1. Biological assays to determine the contribution of these genes to the phenotype are underway. Taken together, our data suggest that MTIs might be effective in a cohort of DLBCL cases that exhibit the specific methylation signature that we have identified. Prospective evaluation of the predictive value of this signature may allow optimal selection of patients for clinical trials with these agents.

scholarly journals The DNA Methylation Maintenance Protein UHRF1 Regulates Fetal Globin Expression Independent of HBG Promoter DNA Methylation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 410-410
Author(s):  
Ruopeng Feng ◽  
Phillip A Doerfler ◽  
Yu Yao ◽  
Xing Tang ◽  
Yong-Dong Wang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
Clinical Symptoms ◽  
Conflicts Of Interest ◽  
Globin Gene ◽  
Gene Promoters ◽  
Methylated Dna ◽  
Cpg Sites ◽  
Cd34 Cells ◽  
Gene Switching

Abstract Pharmacological or genetic induction of fetal hemoglobin (HbF, α2γ2) in adult red blood cells is a proven strategy to ameliorate the clinical symptoms of sickle cell disease (SCD) and β-thalassemia. Therefore, efforts are underway to better understand mechanisms that mediate the perinatal switch from HbF to adult hemoglobin (HbA, α2β2). We performed a CRISPR-Cas9/guide (g) RNA screen to identify novel proteins that regulate HbF production in HUDEP-2 cells, a human erythroid line that normally expresses HbA. We identified UHRF1 (ubiquitin-like with PHD and RING finger domains 1) as a repressor of HbF production. UHRF1 binds hemi-methylated DNA and recruit DNA methyltransferase 1 (DNMT1) to ensure faithful maintenance of DNA methylation during DNA replication. Numerous UHRF1-interacting proteins, including DNMT1, EHMT1/2 and HDAC2 are associated with γ-globin repression. We used CRISPR/Cas9 and RNA interference to validate UHRF1 as a HbF regulator. Compared to non-targeting gRNA UHRF1 disruption using Cas9 + 2 separate gRNAs increased the γ-globin/γ+β-globin RNA ratio from 1.9 to 25.8/27.1% (P<0.01), increased the fraction of HbF immunostaining cells ("F-cells") from 7.5 to 25.1/35.4% and increased HbF protein from 2.10 to 16.3/15.0% (P<0.01) in HUDEP-2 cells. Compared to a control luciferase shRNA, 2 different UHRF1 shRNAs increased theγ-globin/γ+β-globin RNA ratio from 9.68% to 21.59/28.93% (P<0.01), increased the F-cell fraction from 37.9 to 49.8/55.6% and increased HbF protein from 9.1 to 16.18/18.5% (P<0.05) in erythroid cells derived from normal adult peripheral blood CD34+ cells. UHRF1 deficiency did not alter erythroid maturation or expression of key transcription factor genes that regulate HbF expression in HUDEP-2 or CD34+ cells (BCL11A, ZBTB7A, MYB and KLF1). UHRF1 mutant proteins defective in recognizing H3K9me2 (FW237/238AA), binding to hemi-methylated DNA (R491A) or ubiquitination of H3K23 to enhance DNMT1 recruitment (C741A), were unable to repress HBG1/HBG2. These mutations have the most profound effects on maintaining DNA methylation, indicating that UHRF1 represses HBG1/HBG2 in HUDEP-2 cells through this mechanism. UHRF1 knockout induced genome-wide demethylation including 6 CpG sites located at positions -162, -53, -50, +6, +17, +50 positions relative to the γ-globin (HBG1 and HBG2) transcription start site. Demethylation of these sites is thought to be required for γ-globin de-repression. However, forced demethylation of these cytosines in HUDEP-2 cells using specific gRNAs + dead (d) Cas9-TET1 was not sufficient to activate γ-globin expression when UHRF1 was present. Additionally, dCas9-DNMT3a-mediated methylation of the HBG promoter CpG residues in UHRF1 knockdown HUDEP-2 cells did not inhibit γ-globin expression in UHRF1 knockout HUDEP-2 cells. Based on these studies, we conclude that: 1) UHRF1 regulates γ-globin transcription; 2) demethylation of CpG sites at the HBG gene promoters is neither necessary or sufficient for γ-globin induction; 3) UHRF1 regulates γ-to-β globin gene switching either by methylating DNA regions other than those present around the HBG promoter or through non-canonical activities. Distinguishing these mechanisms will elucidate further our understanding of globin gene switching and could identify new pathways for pharmacological induction of HbF. Disclosures No relevant conflicts of interest to declare.

Genetic vs. Epigenetic Disruption of the CEBPA Locus Yields Epigenomically and Biologically Distinct Leukemia Phenotypes.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2117-2117 ◽  
Author(s):  
Maria E. Figueroa ◽  
Bas J. Wouters ◽  
Yushan Li ◽  
Peter Valk ◽  
Bob Lowenberg ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
Gene Promoters ◽  
Loss Of Function ◽  
Biological Difference ◽  
Significance Level ◽  
Dna Methyltransferase Inhibitors ◽  
Genome Wide ◽  
P38mapk Signaling ◽  
Cebpa Mutations

Abstract Acute Myeloid Leukemia (AML) is a heterogeneous disease from the molecular and biological standpoints. In order to resolve some of this complexity, a recent microarray-based expression profiling study segregated cohorts of patients with common gene signatures. One of these signatures was associated with alterations of the CCAAT/enhancer-binding protein alpha (CEBPA) gene. Among these patients, a subset harbored CEBPA mutations, while the remainder failed to express CEBPA, which in a number of cases correlated with hypermethylation of its promoter. This latter subgroup of leukemias with silenced CEBPA presented with significant biological differences compared to CEBPA mutant patients, including expression of T-cell markers and activating mutations of NOTCH1 (Wouters BJ et. al., PMID:17671232). Since our preliminary data show that DNA methylation profiling is extremely accurate in identifying distinct biological phenotypes in AML and other tumors, we wondered whether genome-wide epigenetic analysis would identify the biological difference between these patients. In order to determine the DNA methylation profiles of these patients we performed HELP (HpaII tiny fragment Enrichment by Ligation-mediated PCR), a quantitative genome-wide DNA methylation method, using a 400,000 feature cutom-desinged microarray, representing 24,000 gene promoters with 50-mer oligonucleotides. We studied the complete previously identified cluster of AML cases presenting with a CEBPA expression signature, and compared and contrasted the DNA methylation profiles of cases carrying the CEBPA mutation and those presenting with CEBPA silencing. Remarkably, unsupervised (unbiased) clustering of DNA methylation profiles revealed that samples were readily segregated into two groups that overlapped perfectly with the presence or absence of the CEBPA mutation, indicating the presence of underlying genome-wide DNA methylation differences between these two groups. We next performed supervised analysis of the samples to compare the DNA methylation profiles of CEBPA mutated vs. CEBPA non-mutated samples. The analysis was performed using a moderated T test, and 291 genes promoters were identified as differentially methylated between the two groups at a significance level of p &lt;0.001. Within this differentially methylated signature, we detected a clear predominance (90%) of hypermethylated genes in the CEBPA silenced group. The critical importance of CEBPA loss of function in mediating the phenotype of these tumors was underlined by the fact that multiple other members of the CEBPA network were likewise hypermethylated. Other than the CEBPA network, the two other most hypermethylated biological pathways involved p38MAPK signaling and PDGF/LCK signaling. Thus, we conclude i) that hypermethylation of the CEBPA promoter is not an isolated event, but rather part of a more widespread epigenetic regulation, and ii) that the original CEBPA signature group is composed of two distinct subgroups originating through two distinct mechanisms, a genetic one and an epigenetic one. The significance of these findings may be supported by the fact that the hypermethylated cohort of patients tended to show a worse prognosis than CEBPA mutant patients. These patients might be good candidates for DNA methyltransferase inhibitors in prospective clinical trials.

scholarly journals Lsh Is Essential for Maintaining Global DNA Methylation Levels in Amphibia and Fish and Interacts Directly with Dnmt1

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Donncha S. Dunican ◽  
Sari Pennings ◽  
Richard R. Meehan
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
Repetitive Sequences ◽  
Global Dna Methylation ◽  
Dependent Manner ◽  
Gene Promoters ◽  
Cpg Dinucleotides ◽  
Mouse Cells ◽  
Eukaryotic Genomes

Eukaryotic genomes are methylated at cytosine bases in the context of CpG dinucleotides, a pattern which is maintained through cell division by the DNA methyltransferase Dnmt1. Dramatic methylation losses are observed in plant and mouse cells lacking Lsh (lymphoid specific helicase), predominantly at repetitive sequences and gene promoters. However, the mechanism by which Lsh contributes to the maintenance of DNA methylation is unknown. Here we show that DNA methylation is lost in Lsh depleted frog and fish embryos, both of which exhibit developmental delay. Additionally, we show that both Lsh and Dnmt1 are associated with chromatin and that Lsh knockdown leads to a decreased Dnmt1-chromatin association. Coimmunoprecipitation experiments reveal that Lsh and Dnmt1 are found in the same protein complex, and pulldowns show this interaction is direct. Our data indicate that Lsh is usually diffuse in the nucleus but can be recruited to heterochromatin in a HP1α-dependent manner. These data together (a) show that the role of Lsh in DNA methylation is conserved in plants, amphibian, fish, and mice and (b) support a model in which Lsh contributes to Dnmt1 binding to chromatin, explaining how its loss can potentially lead to perturbations in DNA methylation maintenance.

scholarly journals Contrasting epigenetic control of transgenes and endogenous genes promotes post-transcriptional transgene silencing in Arabidopsis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Nicolas Butel ◽  
Agnès Yu ◽  
Ivan Le Masson ◽  
Filipe Borges ◽  
Taline Elmayan ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Host Plant ◽  
Transgene Silencing ◽  
Plant Genome ◽  
Plant Genomes ◽  
Epigenetic Control ◽  
Specific Attenuation ◽  
Endogenous Genes ◽  
Chromatin Modifying Complex

AbstractTransgenes that are stably expressed in plant genomes over many generations could be assumed to behave epigenetically the same as endogenous genes. Here, we report that whereas the histone H3K9me2 demethylase IBM1, but not the histone H3K4me3 demethylase JMJ14, counteracts DNA methylation of Arabidopsis endogenous genes, JMJ14, but not IBM1, counteracts DNA methylation of expressed transgenes. Additionally, JMJ14-mediated specific attenuation of transgene DNA methylation enhances the production of aberrant RNAs that readily induce systemic post-transcriptional transgene silencing (PTGS). Thus, the JMJ14 chromatin modifying complex maintains expressed transgenes in a probationary state of susceptibility to PTGS, suggesting that the host plant genome does not immediately accept expressed transgenes as being epigenetically the same as endogenous genes.

scholarly journals In plants distal regulatory sequences overlap with unmethylated rather than low-methylated regions, in contrast to mammals

2020 ◽  
Author(s):  
Rurika Oka ◽  
Mattijs Bliek ◽  
Huub C.J. Hoefsloot ◽  
Maike Stam
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Arabidopsis Thaliana ◽  
Transcriptional Repression ◽  
Genome Stability ◽  
Regulation Of Gene Expression ◽  
Regulatory Sequences ◽  
Regulatory Regions ◽  
Plant Genomes ◽  
Underlying Mechanisms

AbstractBackgroundDNA methylation is an important factor in the regulation of gene expression and genome stability. High DNA methylation levels are associated with transcriptional repression. In mammalian systems, unmethylated, low methylated and fully methylated regions (UMRs, LMRs, and FMRs, respectively) can be distinguished. UMRs are associated with proximal regulatory regions, while LMRs are associated with distal regulatory regions. Although DNA methylation is mainly limited to the CG context in mammals, while it occurs in CG, CHG and CHH contexts in plants, UMRs and LMRs were expected to occupy similar genomic sequences in both mammals and plants.ResultsThis study investigated major model and crop plants such as Arabidopsis thaliana, tomato (Solanum lycopersicum), rice (Oryza sativa) and maize (Zea mays), and shows that plant genomes can also be subdivided in UMRs, LMRs and FMRs, but that LMRs are mainly present in the CHG context rather than the CG context. Strikingly, the identified CHG LMRs were enriched in transposable elements rather than regulatory regions. Maize candidate regulatory regions overlapped with UMRs. LMRs were enriched for heterochromatic histone modifications and depleted for DNase accessibility and H3K9 acetylation. CHG LMRs form a distinct, abundant cluster of loci, indicating they have a different role than FMRs.ConclusionsBoth mammalian and plant genomes can be segmented in three distinct classes of loci, UMRs, LMRs and FMRs, indicating similar underlying mechanisms. Unlike in mammals, distal regulatory sequences in plants appear to overlap with UMRs instead of LMRs. Our data indicate that LMRs in plants have a different function than those in mammals.

scholarly journals DNA Methylation of Enhancer Elements in Myeloid Neoplasms: Think Outside the Promoters?

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1424 ◽  
Author(s):  
Ordoñez ◽  
Martínez-Calle ◽  
Agirre ◽  
Prosper
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Epigenetic Modification ◽  
Myeloproliferative Neoplasms ◽  
Regulation Of Gene Expression ◽  
Fine Tuning ◽  
Specific Gene ◽  
Gene Promoters ◽  
Regulatory Regions ◽  
Genome Wide

Gene regulation through DNA methylation is a well described phenomenon that has a prominent role in physiological and pathological cell-states. This epigenetic modification is usually grouped in regions denominated CpG islands, which frequently co-localize with gene promoters, silencing the transcription of those genes. Recent genome-wide DNA methylation studies have challenged this paradigm, demonstrating that DNA methylation of regulatory regions outside promoters is able to influence cell-type specific gene expression programs under physiologic or pathologic conditions. Coupling genome-wide DNA methylation assays with histone mark annotation has allowed for the identification of specific epigenomic changes that affect enhancer regulatory regions, revealing an additional layer of complexity to the epigenetic regulation of gene expression. In this review, we summarize the novel evidence for the molecular and biological regulation of DNA methylation in enhancer regions and the dynamism of these changes contributing to the fine-tuning of gene expression. We also analyze the contribution of enhancer DNA methylation on the expression of relevant genes in acute myeloid leukemia and chronic myeloproliferative neoplasms. The characterization of the aberrant enhancer DNA methylation provides not only a novel pathogenic mechanism for different tumors but also highlights novel potential therapeutic targets for myeloid derived neoplasms.

scholarly journals Simplified MethylRAD Sequencing to Detect Changes in DNA Methylation at Enhancer Elements in Differentiating Embryonic Stem Cells

Epigenomes ◽  
2020 ◽  
Vol 4 (4) ◽  
pp. 24
Author(s):  
Debapriya Saha ◽  
Allison B. Norvil ◽  
Nadia A. Lanman ◽  
Humaira Gowher
Keyword(s):  
Dna Methylation ◽  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Embryonic Stem ◽  
Bioinformatic Analysis ◽  
Analysis Tool ◽  
Regulatory Regions ◽  
Genome Wide ◽  
Gene Regulatory ◽  
Pluripotency Genes

Differential DNA methylation is characteristic of gene regulatory regions, such as enhancers, which mostly constitute low or intermediate CpG content in their DNA sequence. Consequently, quantification of changes in DNA methylation at these sites is challenging. Given that DNA methylation across most of the mammalian genome is maintained, the use of genome-wide bisulfite sequencing to measure fractional changes in DNA methylation at specific sites is an overexertion which is both expensive and cumbersome. Here, we developed a MethylRAD technique with an improved experimental plan and bioinformatic analysis tool to examine regional DNA methylation changes in embryonic stem cells (ESCs) during differentiation. The transcriptional silencing of pluripotency genes (PpGs) during ESC differentiation is accompanied by PpG enhancer (PpGe) silencing mediated by the demethylation of H3K4me1 by LSD1. Our MethylRAD data show that in the presence of LSD1 inhibitor, a significant fraction of LSD1-bound PpGe fails to gain DNA methylation. We further show that this effect is mostly observed in PpGes with low/intermediate CpG content. Underscoring the sensitivity and accuracy of MethylRAD sequencing, our study demonstrates that this method can detect small changes in DNA methylation in regulatory regions, including those with low/intermediate CpG content, thus asserting its use as a method of choice for diagnostic purposes.

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