scholarly journals Association between sperm mitochondarial DNA copy number and nuclear DNA methylation

Epigenomics ◽  
2020 ◽  
Author(s):  
Oladele A Oluwayiose ◽  
Srinihaari Josyula ◽  
Emily Houle ◽  
Chelsea Marcho ◽  
Brian W Whitcomb ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Copy Number ◽  
Nuclear Dna ◽  
A Priori ◽  
Candidate Gene Approach ◽  
Treatment Results ◽  
Dna Copy Number ◽  
450K Array ◽  
Genome Wide ◽  
Mitochondria Dna

Aim: Accumulating evidence associates sperm mitochondria DNA copy number (mtDNAcn) with male infertility and reproductive success. However, the mechanism underlying mtDNAcn variation is largely unknown. Patients & methods: Sperm mtDNAcn and genome-wide DNA methylation were assessed using triplex probe-based quantitative PCR and Illumina’s 450K array, respectively. Multivariable models assessed the association between sperm mtDNAcn and DNA methylation profiles of 47 men seeking infertility treatment. Results:  A priori candidate-gene approach showed sperm mtDNAcn was associated with 16 CpGs located at/near POLG and TWNK genes. Unbiased genome-wide analysis revealed that sperm mtDNAcn was associated with 218 sperm differentially methylated regions (q <0.05), which displayed predominantly (94%) increases in methylation. Conclusion: Findings suggest that DNA methylation may play a role in regulating sperm mtDNAcn.

scholarly journals Mitochondrial DNA copy number can influence mortality and cardiovascular disease via methylation of nuclear DNA CpGs

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Christina A. Castellani ◽  
Ryan J. Longchamps ◽  
Jason A. Sumpter ◽  
Charles E. Newcomb ◽  
John A. Lane ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cardiovascular Disease ◽  
Mitochondrial Dna ◽  
Copy Number ◽  
Nuclear Dna ◽  
Dna Copy Number ◽  
Mitochondrial Dna Copy Number ◽  
Genome Wide ◽  
Genome Wide Significance ◽  
Experimental Modification

Abstract Background Mitochondrial DNA copy number (mtDNA-CN) has been associated with a variety of aging-related diseases, including all-cause mortality. However, the mechanism by which mtDNA-CN influences disease is not currently understood. One such mechanism may be through regulation of nuclear gene expression via the modification of nuclear DNA (nDNA) methylation. Methods To investigate this hypothesis, we assessed the relationship between mtDNA-CN and nDNA methylation in 2507 African American (AA) and European American (EA) participants from the Atherosclerosis Risk in Communities (ARIC) study. To validate our findings, we assayed an additional 2528 participants from the Cardiovascular Health Study (CHS) (N = 533) and Framingham Heart Study (FHS) (N = 1995). We further assessed the effect of experimental modification of mtDNA-CN through knockout of TFAM, a regulator of mtDNA replication, via CRISPR-Cas9. Results Thirty-four independent CpGs were associated with mtDNA-CN at genome-wide significance (P < 5 × 10− 8). Meta-analysis across all cohorts identified six mtDNA-CN-associated CpGs at genome-wide significance (P < 5 × 10− 8). Additionally, over half of these CpGs were associated with phenotypes known to be associated with mtDNA-CN, including coronary heart disease, cardiovascular disease, and mortality. Experimental modification of mtDNA-CN demonstrated that modulation of mtDNA-CN results in changes in nDNA methylation and gene expression of specific CpGs and nearby transcripts. Strikingly, the “neuroactive ligand receptor interaction” KEGG pathway was found to be highly overrepresented in the ARIC cohort (P = 5.24 × 10− 12), as well as the TFAM knockout methylation (P = 4.41 × 10− 4) and expression (P = 4.30 × 10− 4) studies. Conclusions These results demonstrate that changes in mtDNA-CN influence nDNA methylation at specific loci and result in differential expression of specific genes that may impact human health and disease via altered cell signaling.

scholarly journals Mitochondrial DNA Copy Number (mtDNA-CN) Can Influence Mortality and Cardiovascular Disease via Methylation of Nuclear DNA CpGs

2019 ◽  
Author(s):  
Christina A. Castellani ◽  
Ryan J. Longchamps ◽  
Jason A. Sumpter ◽  
Charles E. Newcomb ◽  
John A. Lane ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cardiovascular Disease ◽  
Mitochondrial Dna ◽  
Copy Number ◽  
Nuclear Dna ◽  
Dna Copy Number ◽  
Mitochondrial Dna Copy Number ◽  
Genome Wide ◽  
Genome Wide Significance ◽  
Experimental Modification

ABSTRACTBackgroundMitochondrial DNA copy number (mtDNA-CN) has been associated with a variety of aging-related diseases, including all-cause mortality. However, the mechanism by which mtDNA-CN influences disease is not currently understood. One such mechanism may be through regulation of nuclear gene expression via the modification of nuclear DNA (nDNA) methylation.MethodsTo investigate this hypothesis, we assessed the relationship between mtDNA-CN and nDNA methylation in 2,507 African American (AA) and European American (EA) participants from the Atherosclerosis Risk in Communities (ARIC) study. To validate our findings we assayed an additional 2,528 participants from the Cardiovascular Health Study (CHS) (N=533) and Framingham Heart Study (FHS) (N=1,995). We further assessed the effect of experimental modification of mtDNA-CN through knockout of TFAM, a regulator of mtDNA replication, via CRISPR-Cas9.ResultsThirty-four independent CpGs were associated with mtDNA-CN at genome-wide significance (P<5×10-8). Meta-analysis across all cohorts identified six mtDNA-CN associated CpGs at genome-wide significance (P<5×10-8). Additionally, over half of these CpGs were associated with phenotypes known to be associated with mtDNA-CN, including coronary heart disease, cardiovascular disease, and mortality. Experimental modification of mtDNA-CN demonstrated that modulation of mtDNA-CN directly drives changes in nDNA methylation and gene expression of specific CpGs and nearby transcripts. Strikingly, the ‘neuroactive ligand receptor interaction’ KEGG pathway was found to be highly overrepresented in the ARIC cohort (P= 5.24×10-12), as well as the TFAM knockout methylation (P=4.41×10-4) and expression (P=4.30×10-4) studies.ConclusionsThese results demonstrate that changes in mtDNA-CN influence nDNA methylation at specific loci and result in differential expression of specific genes that may impact human health and disease via altered cell signaling.

scholarly journals Evaluation of affinity-based genome-wide DNA methylation data: Effects of CpG density, amplification bias, and copy number variation

2010 ◽  
Vol 20 (12) ◽  
pp. 1719-1729 ◽  
Author(s):  
M. D. Robinson ◽  
C. Stirzaker ◽  
A. L. Statham ◽  
M. W. Coolen ◽  
J. Z. Song ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Copy Number Variation ◽  
Copy Number ◽  
Methylation Data ◽  
Amplification Bias ◽  
Genome Wide ◽  
Number Variation

Genome-Wide High-Resolution Screening in Dupuytren's Disease Reveals Common Regions of DNA Copy Number Alterations

2010 ◽  
Vol 35 (7) ◽  
pp. 1172-1183.e7 ◽  
Author(s):  
Barbara B. Shih ◽  
May Tassabehji ◽  
James S. Watson ◽  
Angus D. McGrouther ◽  
Ardeshir Bayat
Keyword(s):  
High Resolution ◽  
Copy Number ◽  
Dupuytren’S Disease ◽  
Copy Number Alterations ◽  
Dna Copy Number ◽  
Dupuytren's Disease ◽  
Genome Wide ◽  
Dna Copy Number Alterations

Dysregulation of schizophrenia-associated genes and genome-wide hypomethylation in neurons overexpressing DNMT1

Epigenomics ◽  
2021 ◽  
Author(s):  
Sonal Saxena ◽  
Sumana Choudhury ◽  
Pranay Amruth Maroju ◽  
Anuhya Anne ◽  
Lov Kumar ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Stem Cells ◽  
Copy Number ◽  
Embryonic Stem ◽  
Wild Type ◽  
Independent Manner ◽  
Transcript Levels ◽  
Genome Wide ◽  
Methylation Patterns ◽  
Increased Activity

Aim: To study the effects of DNMT1 overexpression on transcript levels of genes dysregulated in schizophrenia and on genome-wide methylation patterns. Materials & methods: Transcriptome and DNA methylome comparisons were made between R1 (wild-type) and Dnmt1tet/tet mouse embryonic stem cells and neurons overexpressing DNMT1. Genes dysregulated in both Dnmt1tet/tet cells and schizophrenia patients were studied further. Results & conclusions: About 50% of dysregulated genes in patients also showed altered transcript levels in Tet/Tet neurons in a DNA methylation-independent manner. These neurons unexpectedly showed genome-wide hypomethylation, increased transcript levels of Tet1 and Apobec 1-3 genes and increased activity and copy number of LINE-1 elements. The observed similarities between Tet/Tet neurons and schizophrenia brain samples reinforce DNMT1 overexpression as a risk factor.

scholarly journals Genome-wide DNA copy number predictors of lapatinib sensitivity in tumor-derived cell lines

2008 ◽  
Vol 7 (4) ◽  
pp. 935-943 ◽  
Author(s):  
Joel Greshock ◽  
Jie Cheng ◽  
David Rusnak ◽  
Anne Marie Martin ◽  
Richard Wooster ◽  
...  
Keyword(s):  
Cell Lines ◽  
Copy Number ◽  
Dna Copy Number ◽  
Genome Wide
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