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Cristina M Kenney, Deepika Malik, Shari Atilano, Javier Caceres del Carpio, Marilyn Chwa, Anthony B Nesburn, David S Boyer, Baruch Kuppermann, Nitin Udar; Different Epigenetic Methylation Patterns in Cells with African versus European Inherited Mitochondrial DNA Haplogroups: Possible Mechanism for Disease Susceptibilities?. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2189.
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© ARVO (1962-2015); The Authors (2016-present)
Recent studies comparing cybrids (cytoplasmic hybrids) with H haplogroup (most common European) versus L haplogroup (African origin) showed that L cybrids had (a) lower expression levels of complement pathway and innate immunity genes and (b) increased levels of inflammation-related signaling genes, which are critical in human ocular diseases (Kenney et al. BBA, 2013). These findings support our hypothesis that mitochondrial (mt) DNA haplogroups, representing populations from different geographic origins, may play a role in differential susceptibilities to eye diseases. Epigenetic regulation is a global cellular mechanism by which gene expression is altered without changes in nucleotide sequence. The present study was conducted to determine if cybrids with mtDNA haplogroups H versus L show differences in expression levels of methylation genes, which are important for epigenetic modification of nuclear genes.
Cybrids were created by fusing Rho0 ARPE-19 cells (depleted of mitochondria) with platelets isolated from haplogroup H (n=3) or L (n=3) individuals. The haplogroup profiles were determined with PCR and restriction enzyme digestion. Global DNA methylation status was detected using the MethylFlash Methylated DNA Quantification Kit. Q-PCR for six methylation genes was performed.
L cybrids showed significantly higher global methylation (5-methyC%) compared to H cybrids (difference between mean = -0.0154 ± 0.0025, p=0.001). L cybrids had lower expression levels for HDAC1 (0.43-fold, p=0.008), HDAC6 (0.55-fold, p=0.0140, HDAC11 (0.4-fold, p=0.004), SIN3A (0.43-fold, p=0.006), MBD4 (0.68-fold, p=0.007) and higher levels for MAT2B (1.44-fold, p=0.006) compared to the H cybrids.
Transmitochondrial cybrids, which have identical nuclei but either H (European origin) or L (African origin) mtDNA haplogroups, have different total global methylation levels and different expression levels of key methylation genes. These findings support the hypothesis that mtDNA variants can induce epigenetic changes in the nucleus and act as a “modifier” for nuclear gene expression to contribute to the phenotypic variations between different ethnic/racial groups.
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