In vivo methylation of mtDNA reveals the dynamics of protein–mtDNA interactions

Rebelo, Adriana P.; Williams, Siôn L.; Moraes, Carlos T.

doi:10.1093/nar/gkp727

Cited by 103 publications

(87 citation statements)

References 38 publications

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“…4B), (2) at inner sequence positions known to be affected by lower postmortem deamination rates (Supplemental Fig. S3.2), and (3) among Phusion mitochondrial reads in agreement with the absence or low levels of methylation present in this genome (Rebelo et al 2009). …”

Section: Cytosine Methylation Signalsupporting

confidence: 64%

Genome-wide nucleosome map and cytosine methylation levels of an ancient human genome

et al. 2013

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Epigenetic information is available from contemporary organisms, but is difficult to track back in evolutionary time. Here, we show that genome-wide epigenetic information can be gathered directly from next-generation sequence reads of DNA isolated from ancient remains. Using the genome sequence data generated from hair shafts of a 4000-yr-old Paleo-Eskimo belonging to the Saqqaq culture, we generate the first ancient nucleosome map coupled with a genome-wide survey of cytosine methylation levels. The validity of both nucleosome map and methylation levels were confirmed by the recovery of the expected signals at promoter regions, exon/intron boundaries, and CTCF sites. The top-scoring nucleosome calls revealed distinct DNA positioning biases, attesting to nucleotide-level accuracy. The ancient methylation levels exhibited high conservation over time, clustering closely with modern hair tissues. Using ancient methylation information, we estimated the age at death of the Saqqaq individual and illustrate how epigenetic information can be used to infer ancient gene expression. Similar epigenetic signatures were found in other fossil material, such as 110,000- to 130,000-yr-old bones, supporting the contention that ancient epigenomic information can be reconstructed from a deep past. Our findings lay the foundation for extracting epigenomic information from ancient samples, allowing shifts in epialleles to be tracked through evolutionary time, as well as providing an original window into modern epigenomics.

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Section: Cytosine Methylation Signalsupporting

confidence: 64%

Genome-wide nucleosome map and cytosine methylation levels of an ancient human genome

et al. 2013

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“…Several studies have already noted that epigenetic changes on the DNA control region could lead to the functional disorder of DNA replication and expression (14,15). Furthermore, the existence of DNA methyltransferases inside the mitochondria has been confirmed (16). All these data indicate that DNA methylation might be a method by which cells regulate their mtDNA expression.…”

Section: Discussionmentioning

confidence: 88%

Correlation between increased ND2 expression and demethylated displacement loop of mtDNA in colorectal cancer

Shi

Xiong

et al. 2012

Mol Med Report

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Abstract. Change in cellular glucose metabolism is considered to be a biochemical hallmark in cancer cells. The mitochondrion is the key organelle in which glucose metabolism occurs. However, whether DNA methylation at the displacement loop (D-loop) region of mitochondrial DNA (mtDNA) has an effect on the expression of the rate-limiting enzyme, and, therefore, on oxidative phosphorylation in colorectal cancer remains to be determined. Quantitative change in ND2 (a subunit of NADH) and the methylation status of the D-loop were observed during the initiation and progression of colorectal cancer. Furthermore, the possible correlations with clinicopathological stage were also investigated. Tumor and corresponding non-cancerous tissues were surgically resected from 44 colorectal cancer patients between 2008 and 2009. Cox IV expression was quantified in all of the specimens, and the ND2 expression was calculated. Quantitative changes in ND2 expression exhibited a significant increase. The average relative ratios of ND2 content were 1.67±0.44 in the tumor tissues and 0.89±0.44 in the corresponding non-cancerous tissues (p<0.01). In addition, the D-loop of most corresponding non-cancerous tissues was methylated and the percentage was 79.5%, while this percentage was much smaller in the tumor tissues (11.4%). Following correlation with clinicopathological data, changes in the ND2 expression in the colorectal cancer exhibited a significant association with clinicopathological stage. This increase was significant as early as in stage Ⅰ. Furthermore, the ratios of unmethylated D-loop cases were increased in both tumor and corresponding non-cancerous tissues, and the ND2 expression was also increased from stages Ⅰ to Ⅳ. Our results indicate that demethylation of the D-loop plays a key role in regulating ND2 expression during the initiation and/or progression of colorectal cancer.

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“…Consequently, nuclear DNA methylation patterns change with copy number of mtDNA (129), mtDNA variants with different oxidative phosphorylation efficiencies (130), and the content of intracellular ROS (131). In addition, recent studies show the presence of epigenetic modifications in the mtDNA (132)(133)(134)(135)(136). Limited information exists about a possible relationship between aging and mitochondrial epigenetic modifications.…”

Section: Metabolic Dysregulation As a Convergent Event In The Aging Cellmentioning

confidence: 99%

Mitochondria in the spotlight of aging and idiopathic pulmonary fibrosis

Mora¹,

Bueno²,

Rojas³

2017

Journal of Clinical Investigation

184

169

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One of the most remarkable medical accomplishments in the last century has been the increasing longevity of the human population. A decrease in birth rates, accompanied by a reduction in mortality among the elderly population, has collectively increased the percentage of the aged population, particularly in developed countries. Globally, it is estimated that the proportion of the population over the age of 60 will increase from 11% to 22% by 2050, and 28% by 2100. Currently, 18% of the US population is over 60 years of age (57 million), which is predicted to rise to 27% (107 million) in 2050 and up to 31% (149 million) by 2100 (1). The aging population has propelled an increase in the overall prevalence of chronic conditions. Several lung diseases, including acute lung injury and asthma, and some infectious diseases, such as pneumonia, increase in severity and mortality with age. Additionally, there has been a significant increase in incidence of chronic lung diseases -including chronic obstructive pulmonary disease, most forms of lung cancer, and idiopathic pulmonary fibrosis (IPF) -resulting in aging-related increases in prevalence.IPF is the most common form of idiopathic interstitial lung diseases. Its overall incidence in the US is 7 to 17 per 100,000 persons with a prevalence between 13.2 and 63 per 100,000 persons (2). A 1996 study initially demonstrated a higher incidence and prevalence of IPF in patients over 65 (3). These observations were confirmed more recently by Raghu et al. (4) and others, using both broad and narrow case-finding criteria for IPF diagnosis. These studies estimated that in the US, the prevalence of IPF increases with age, ranging from 4 per 100,000 for population aged between 18 and 34 years old to 227.2 per 100,000 among those 75 or older (4). This aging-related increase in cumulative incidence and prevalence of IPF has been corroborated by several studies that include populations in Europe and Asia (5-9). Accordingly, the median age at diagnosis of sporadic IPF ranges between 50 and 85 years old, and patients younger than 50 are more commonly associated with familial, rather than sporadic, forms of the disease (2). Mortality rates from IPF are steadily increasing worldwide, and a positive association has also been observed with advanced age (10). Examination of US government health insurance data for people aged 65 and older shows an increasing prevalence of IPF among older age groups (11). These studies confirm the growing concern that aging, and consequently age-related diseases, will drive up health care expenditures. As the elderly population in developed countries is expected to double in the next 25 years, there is an urgent need to understand the pathogenesis of IPF and develop interventions to attenuate or reverse lung fibrosis. The physiology of aging and the lungEvolutionary theories of aging include the concept of selection shadow that permits the accumulation of mutations with late deleterious effects, and the theory of antagonistic pleiotropy, which supports the sele...

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In vivo methylation of mtDNA reveals the dynamics of protein–mtDNA interactions

Cited by 103 publications

References 38 publications

Genome-wide nucleosome map and cytosine methylation levels of an ancient human genome

Genome-wide nucleosome map and cytosine methylation levels of an ancient human genome

Correlation between increased ND2 expression and demethylated displacement loop of mtDNA in colorectal cancer

Mitochondria in the spotlight of aging and idiopathic pulmonary fibrosis

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