Passive and active DNA methylation and the interplay with genetic variation in gene regulation

Gutiérrez‐Arcelus, María; Lappalainen, Tuuli; Montgomery, Stephen B.; Buil, Alfonso; Ongen, Halit; Yurovsky, Alisa; Bryois, Julien; Giger, Thomas; Romano, Luciana; Planchon, Alexandra; Falconnet, Emilie; Bielser, Deborah; Gagnebin, Maryline; Padioleau, Ismaël; Borel, Christelle; Letourneau, Audrey; Makrythanasis, Periklis; Guipponi, Michel; Gehrig, Corinne; Antonarakis, Stylianos E.; Dermitzakis, Emmanouil T.

doi:10.7554/elife.00523

Cited by 395 publications

(480 citation statements)

References 57 publications

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“…To date, the potential relationships between DNA methylation and gene expression have only been systematically analyzed in a small subset of studies (Gevaert, Tibshirani & Plevritis, 2015; Gutierrez‐Arcelus et al., 2013, 2015), and the potential effects of these relationships on aging and cancer are yet to be elucidated. To this end, we explored the establishment of potential correlations between these two processes using the TCGA‐KIRC dataset.…”

Section: Discussionmentioning

confidence: 99%

Distinct chromatin signatures of DNA hypomethylation in aging and cancer

et al. 2018

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SummaryCancer is an aging‐associated disease, but the underlying molecular links between these processes are still largely unknown. Gene promoters that become hypermethylated in aging and cancer share a common chromatin signature in ES cells. In addition, there is also global DNA hypomethylation in both processes. However, the similarity of the regions where this loss of DNA methylation occurs is currently not well characterized, and it is unknown if such regions also share a common chromatin signature in aging and cancer. To address this issue, we analyzed TCGA DNA methylation data from a total of 2,311 samples, including control and cancer cases from patients with breast, kidney, thyroid, skin, brain, and lung tumors and healthy blood, and integrated the results with histone, chromatin state, and transcription factor binding site data from the NIH Roadmap Epigenomics and ENCODE projects. We identified 98,857 CpG sites differentially methylated in aging and 286,746 in cancer. Hyper‐ and hypomethylated changes in both processes each had a similar genomic distribution across tissues and displayed tissue‐independent alterations. The identified hypermethylated regions in aging and cancer shared a similar bivalent chromatin signature. In contrast, hypomethylated DNA sequences occurred in very different chromatin contexts. DNA hypomethylated sequences were enriched at genomic regions marked with the activating histone posttranslational modification H3K4me1 in aging, while in cancer, loss of DNA methylation was primarily associated with the repressive H3K9me3 mark. Our results suggest that the role of DNA methylation as a molecular link between aging and cancer is more complex than previously thought.

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Section: Discussionmentioning

confidence: 99%

Distinct chromatin signatures of DNA hypomethylation in aging and cancer

et al. 2018

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“…Genetic variation has been shown to contribute to longevity, evidenced by the fact that longevity runs in families (Schoenmaker et al ., 2006). Clear relationships also exist between DNA methylation and genetic variability, and recent studies have identified genetic loci whose variation is strongly associated with DNA methylation at nearby sites (Fraser et al ., 2012; Gamazon et al ., 2013; Gutierrez Arcelus et al ., 2013; Moen et al ., 2013). Thus, it is possible that genetic variants associated with longevity may also be correlated with DNA methylation changes.…”

Section: Considerations For Studies Of Epigenetics and Agingmentioning

confidence: 99%

“…Approximately 60–70% of genes have a CpG island associated with their promoters, and promoters can be classified according to their CpG density (Saxonov et al ., 2006; Weber et al ., 2007). Levels of DNA methylation at a promoter‐associated CpG island are generally negatively associated with gene expression, although some specific genes show the opposite effect (Weber et al ., 2007; Lam et al ., 2012; Gutierrez Arcelus et al ., 2013). Interestingly, this negative correlation is not upheld when comparing expression and DNA methylation for a specific gene across individuals (van Eijk et al ., 2012; Lam et al ., 2012; Gutierrez Arcelus et al ., 2013; Wagner et al ., 2014).…”

Section: Introductionmentioning

confidence: 99%

“…Levels of DNA methylation at a promoter‐associated CpG island are generally negatively associated with gene expression, although some specific genes show the opposite effect (Weber et al ., 2007; Lam et al ., 2012; Gutierrez Arcelus et al ., 2013). Interestingly, this negative correlation is not upheld when comparing expression and DNA methylation for a specific gene across individuals (van Eijk et al ., 2012; Lam et al ., 2012; Gutierrez Arcelus et al ., 2013; Wagner et al ., 2014). Conversely, DNA methylation in the gene body is often positively associated with levels of gene expression (Lister et al ., 2009; Gutierrez Arcelus et al ., 2013).…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, this negative correlation is not upheld when comparing expression and DNA methylation for a specific gene across individuals (van Eijk et al ., 2012; Lam et al ., 2012; Gutierrez Arcelus et al ., 2013; Wagner et al ., 2014). Conversely, DNA methylation in the gene body is often positively associated with levels of gene expression (Lister et al ., 2009; Gutierrez Arcelus et al ., 2013). DNA methylation also functions to repress repetitive elements, such as Alu and LINE‐1, which are generally highly methylated in the human genome.…”

Section: Introductionmentioning

confidence: 99%

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DNA methylation and healthy human aging

2015

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SummaryThe process of aging results in a host of changes at the cellular and molecular levels, which include senescence, telomere shortening, and changes in gene expression. Epigenetic patterns also change over the lifespan, suggesting that epigenetic changes may constitute an important component of the aging process. The epigenetic mark that has been most highly studied is DNA methylation, the presence of methyl groups at CpG dinucleotides. These dinucleotides are often located near gene promoters and associate with gene expression levels. Early studies indicated that global levels of DNA methylation increase over the first few years of life and then decrease beginning in late adulthood. Recently, with the advent of microarray and next‐generation sequencing technologies, increases in variability of DNA methylation with age have been observed, and a number of site‐specific patterns have been identified. It has also been shown that certain CpG sites are highly associated with age, to the extent that prediction models using a small number of these sites can accurately predict the chronological age of the donor. Together, these observations point to the existence of two phenomena that both contribute to age‐related DNA methylation changes: epigenetic drift and the epigenetic clock. In this review, we focus on healthy human aging throughout the lifetime and discuss the dynamics of DNA methylation as well as how interactions between the genome, environment, and the epigenome influence aging rates. We also discuss the impact of determining ‘epigenetic age’ for human health and outline some important caveats to existing and future studies.

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Characterization of DNA methylomic signatures in induced pluripotent stem cells during neuronal differentiation

Imm

2020

Alzheimer's & Dementia

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Background In development, inducing pluripotency and differentiation into different cell types results in global epigenetic changes, although the extent this occurs in induced pluripotent stem cell (iPSC)‐based neuronal models has not been extensively characterized. Method Human fibroblast cells were reprogrammed using lentiviral transfection. The resulting iPSC colonies were expanded, differentiated and collected at three different time points: day0 (iPSCs), day16 (neuronal progenitor cells), day37 and day58 (mature neurons). DNA methylation was assessed using the Illumina EPIC array. Using WGCNA, trajectory inference modelling and pathway analysis we identified loci undergoing dynamic changes during differentiation and the pathways these loci are associated with. Result This study has identified methylomic variation associated with neuronal differentiation and maturation. We identified 5,866 Bonferroni‐significant loci during differentiation using lineage modelling and noted that these loci are involved in pathways associated with head development, transcriptional regulation and cellular signalling. A gene‐gene interaction network analysis identified 50 densely connected genes that are influential in the differentiation of neurons, with STAT3 being the gene with the highest connectivity. Finally, we demonstrated that despite being functionally mature these iPSC‐derived neurons have a fetal epigenome. Conclusion We have shown that there are large epigenetic changes occurring throughout neuronal differentiation. These changes are within pathways that are key to neuronal development. Alongside this we have also identified an epigenetic trajectory signature associated with maturation and shown that neurons derived from iPSCs have a fetal epigenome.

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Passive and active DNA methylation and the interplay with genetic variation in gene regulation

Cited by 395 publications

References 57 publications

Distinct chromatin signatures of DNA hypomethylation in aging and cancer

Distinct chromatin signatures of DNA hypomethylation in aging and cancer

DNA methylation and healthy human aging

Characterization of DNA methylomic signatures in induced pluripotent stem cells during neuronal differentiation

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