scholarly journals Multi-species and multi-tissue methylation clocks for age estimation in toothed whales and dolphins

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Todd R. Robeck ◽  
Zhe Fei ◽  
Ake T. Lu ◽  
Amin Haghani ◽  
Eve Jourdain ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Age Estimation ◽  
Species Conservation ◽  
Genome Wide ◽  
Epigenetic Aging ◽  
Highly Correlated ◽  
Methylation Patterns ◽  
Cg Dinucleotides ◽  
Free Ranging ◽  
Unique Species

AbstractThe development of a precise blood or skin tissue DNA Epigenetic Aging Clock for Odontocete (OEAC) would solve current age estimation inaccuracies for wild odontocetes. Therefore, we determined genome-wide DNA methylation profiles using a custom array (HorvathMammalMethyl40) across skin and blood samples (n = 446) from known age animals representing nine odontocete species within 4 phylogenetic families to identify age associated CG dinucleotides (CpGs). The top CpGs were used to create a cross-validated OEAC clock which was highly correlated for individuals (r = 0.94) and for unique species (median r = 0.93). Finally, we applied the OEAC for estimating the age and sex of 22 wild Norwegian killer whales. DNA methylation patterns of age associated CpGs are highly conserved across odontocetes. These similarities allowed us to develop an odontocete epigenetic aging clock (OEAC) which can be used for species conservation efforts by provide a mechanism for estimating the age of free ranging odontocetes from either blood or skin samples.

scholarly journals Genome-wide genetic variations are highly correlated with proximal DNA methylation patterns

2012 ◽  
Vol 22 (8) ◽  
pp. 1419-1425 ◽  
Author(s):  
W. Qu ◽  
S.-i. Hashimoto ◽  
A. Shimada ◽  
Y. Nakatani ◽  
K. Ichikawa ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Genetic Variations ◽  
Genome Wide ◽  
Highly Correlated ◽  
Methylation Patterns

scholarly journals Comparative analysis of genome-wide DNA methylation identifies patterns that associate with conserved transcriptional programs in osteosarcoma

2020 ◽  
Author(s):  
Lauren J. Mills ◽  
Milcah C. Scott ◽  
Pankti Shah ◽  
Anne R. Cunanan ◽  
Archana Deshpande ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Large Scale ◽  
Immune Cell ◽  
Cell Types ◽  
Structural Variations ◽  
Canine Osteosarcoma ◽  
Genome Wide ◽  
Highly Correlated ◽  
Murine Osteosarcoma ◽  
Methylation Patterns

AbstractOsteosarcoma is an aggressive tumor of the bone that primarily affects young adults and adolescents. Osteosarcoma is characterized by genomic chaos and heterogeneity. While inactivation of tumor suppressor p53 TP53 is nearly universal other high frequency mutations or structural variations have not been identified. Despite this genomic heterogeneity, key conserved transcriptional programs associated with survival have been identified across human, canine and induced murine osteosarcoma. The epigenomic landscape, including DNA methylation, plays a key role in establishing transcriptional programs in all cell types. The role of epigenetic dysregulation has been studied in a variety of cancers but has yet to be explored at scale in osteosarcoma. Here we examined genome-wide DNA methylation patterns in 24 human and 44 canine osteosarcoma samples identifying groups of highly correlated DNA methylation marks in human and canine osteosarcoma samples. We also link specific DNA methylation patterns to key transcriptional programs in both human and canine osteosarcoma. Building on previous work, we built a DNA methylation-based measure for the presence and abundance of various immune cell types in osteosarcoma. Finally, we determined that the underlying state of the tumor, and not changes in cell composition, were the main driver of differences in DNA methylation across the human and canine samples.SignificanceThis is the first large scale study of DNA methylation in osteosarcoma and lays the ground work for the exploration of DNA methylation programs that help establish conserved transcriptional programs in the context of different genomic landscapes.

scholarly journals Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging

2018 ◽  
Author(s):  
Aaron R Jeffries ◽  
Reza Maroofian ◽  
Claire G. Salter ◽  
Barry A. Chioza ◽  
Harold E. Cross ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Biological Aging ◽  
Growth Disorders ◽  
Sotos Syndrome ◽  
Dna Hypomethylation ◽  
Genome Wide ◽  
Epigenetic Aging ◽  
Methylation Patterns

AbstractGermline mutations in fundamental epigenetic regulatory molecules including DNA methyltransferase 3A (DNMT3A) are commonly associated with growth disorders, whereas somatic mutations are often associated with malignancy. We profiled genome-wide DNA methylation patterns in DNMT3A c.2312G>A; p.(Arg771Gln) carriers in a large Amish sibship with Tatton-Brown-Rahman syndrome (TBRS), their mosaic father and 15 TBRS patients with distinct pathogenic de novo DNMT3A variants. This defined widespread DNA hypomethylation at specific genomic sites enriched at locations annotated to genes involved in morphogenesis, development, differentiation, and malignancy predisposition pathways. TBRS patients also displayed highly accelerated DNA methylation aging. Notably, these findings were most striking in a carrier of the AML associated driver mutation p.Arg882Cys. Our studies additionally defined phenotype related accelerated and decelerated epigenetic aging in two histone methyltransferase disorders; NSD1 Sotos syndrome overgrowth disorder and KMT2D Kabuki syndrome growth impairment. Together, our findings provide fundamentally new insights into aberrant epigenetic mechanisms, the role of epigenetic machinery maintenance and determinants of biological aging in these growth disorders.

scholarly journals Divergent neuronal DNA methylation patterns across human cortical development: Critical periods and a unique role of CpH methylation

2018 ◽  
Author(s):  
AJ Price ◽  
L Collado-Torres ◽  
NA Ivanov ◽  
W Xia ◽  
EE Burke ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Developmental Trajectories ◽  
Postnatal Life ◽  
Critical Periods ◽  
Neocortical Development ◽  
Genome Wide ◽  
Genome Bisulfite Sequencing ◽  
Highly Correlated ◽  
Methylation Patterns

AbstractWe have characterized the landscape of DNA methylation (DNAm) across the first two decades of human neocortical development in NeuN+ neurons using whole-genome bisulfite sequencing and compared them to non-neurons (primarily glia) and prenatal homogenate cortex. We show that DNAm changes more dramatically during the first five years of postnatal life than during the entire remaining period. We further refined global patterns of increasingly divergent neuronal CpG and CpH methylation (mCpG and mCpH) into six developmental trajectories and found that in contrast to genome-wide patterns, neighboring mCpG and mCpH levels within these regions were highly correlated. We then integrated paired RNA-seq data and identified direct regulation of hundreds of transcripts and their splicing events exclusively by mCpH levels, independently from mCpG levels, across this period. We finally explored the relationship between DNAm patterns and development of brain-related phenotypes and found enriched heritability for many phenotypes within DNAm features we identify.

scholarly journals Aging-associated distinctive DNA methylation changes of LINE-1 retrotransposons in pure cell-free DNA from human blood

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Wardah Mahmood ◽  
Lars Erichsen ◽  
Pauline Ott ◽  
Wolfgang A. Schulz ◽  
Johannes C. Fischer ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cell Free Dna ◽  
The Past ◽  
Free Dna ◽  
Genome Wide ◽  
Cancerous Cell ◽  
Pure Cell ◽  
Epigenetic Biomarker ◽  
Methylation Patterns ◽  
Cancerous Cells

AbstractLINE-1 hypomethylation of cell-free DNA has been described as an epigenetic biomarker of human aging. However, in the past, insufficient differentiation between cellular and cell-free DNA may have confounded analyses of genome-wide methylation levels in aging cells. Here we present a new methodological strategy to properly and unambiguously extract DNA methylation patterns of repetitive, as well as single genetic loci from pure cell-free DNA from peripheral blood. Since this nucleic acid fraction originates mainly in apoptotic, senescent and cancerous cells, this approach allows efficient analysis of aged and cancerous cell-specific DNA methylation patterns for diagnostic and prognostic purposes. Using this methodology, we observe a significant age-associated erosion of LINE-1 methylation in cfDNA suggesting that the threshold of hypomethylation sufficient for relevant LINE-1 activation and consequential harmful retrotransposition might be reached at higher age. We speculate that this process might contribute to making aging the main risk factor for many cancers.

Genome-Wide DNA Methylation Patterns Analysis of Noncoding RNAs in Temporal Lobe Epilepsy Patients

2017 ◽  
Vol 55 (1) ◽  
pp. 793-803 ◽  
Author(s):  
Wenbiao Xiao ◽  
Yuze Cao ◽  
Hongyu Long ◽  
Zhaohui Luo ◽  
Shuyu Li ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Temporal Lobe Epilepsy ◽  
Temporal Lobe ◽  
Noncoding Rnas ◽  
Genome Wide ◽  
Methylation Patterns

scholarly journals Investigation of measurable residual disease in acute myeloid leukemia by DNA methylation patterns

Leukemia ◽  
2021 ◽  
Author(s):  
Tanja Božić ◽  
Chao-Chung Kuo ◽  
Jan Hapala ◽  
Julia Franzen ◽  
Monika Eipel ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Amplicon Sequencing ◽  
Multiparametric Flow Cytometry ◽  
Methylation Patterns ◽  
Cg Dinucleotides ◽  
Measurable Residual Disease ◽  
Acute Myeloid

AbstractAssessment of measurable residual disease (MRD) upon treatment of acute myeloid leukemia (AML) remains challenging. It is usually addressed by highly sensitive PCR- or sequencing-based screening of specific mutations, or by multiparametric flow cytometry. However, not all patients have suitable mutations and heterogeneity of surface markers hampers standardization in clinical routine. In this study, we propose an alternative approach to estimate MRD based on AML-associated DNA methylation (DNAm) patterns. We identified four CG dinucleotides (CpGs) that commonly reveal aberrant DNAm in AML and their combination could reliably discern healthy and AML samples. Interestingly, bisulfite amplicon sequencing demonstrated that aberrant DNAm patterns were symmetric on both alleles, indicating that there is epigenetic crosstalk between homologous chromosomes. We trained shallow-learning and deep-learning algorithms to identify anomalous DNAm patterns. The method was then tested on follow-up samples with and without MRD. Notably, even samples that were classified as MRD negative often revealed higher anomaly ratios than healthy controls, which may reflect clonal hematopoiesis. Our results demonstrate that targeted DNAm analysis facilitates reliable discrimination of malignant and healthy samples. However, since healthy samples also comprise few abnormal-classified DNAm reads the approach does not yet reliably discriminate MRD positive and negative samples.

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.

Genome-wide DNA methylation patterns in coronary heart disease

Herz ◽  
2017 ◽  
Vol 43 (7) ◽  
pp. 656-662 ◽  
Author(s):  
X. Wang ◽  
A.-H. Liu ◽  
Z.-W. Jia ◽  
K. Pu ◽  
K.-Y. Chen ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Coronary Heart Disease ◽  
Heart Disease ◽  
Genome Wide ◽  
Methylation Patterns

scholarly journals Intergenerational epigenetic inheritance in reef-building corals

2018 ◽  
Author(s):  
Yi Jin Liew ◽  
Emily J. Howells ◽  
Xin Wang ◽  
Craig T. Michell ◽  
John A. Burt ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Intergenerational Transmission ◽  
Epigenetic Inheritance ◽  
Cpg Methylation ◽  
Epigenetic Mechanisms ◽  
Transgenerational Inheritance ◽  
Genome Wide ◽  
Methylation Patterns ◽  
Hypermethylated Genes

MainThe notion that intergenerational or transgenerational inheritance operates solely through genetic means is slowly being eroded: epigenetic mechanisms have been shown to induce heritable changes in gene activity in plants1,2and metazoans1,3. Inheritance of DNA methylation provides a potential pathway for environmentally induced phenotypes to contribute to evolution of species and populations1–4. However, in basal metazoans, it is unknown whether inheritance of CpG methylation patterns occurs across the genome (as in plants) or as rare exceptions (as in mammals)4. Here, we demonstrate genome-wide intergenerational transmission of CpG methylation patterns from parents to sperm and larvae in a reef-building coral. We also show variation in hypermethylated genes in corals from distinct environments, indicative of responses to variations in temperature and salinity. These findings support a role of DNA methylation in the transgenerational inheritance of traits in corals, which may extend to enhancing their capacity to adapt to climate change.

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