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Starshin, A.

Publications and source records attributed to Starshin, A..

2 recordsLinked to original sources

Epigenetic variations are landmarks of freshwater adaptation in threespine sticklebacks

For evolutionary biology, the phenotypic consequences of epigenetic variations and their potential contribution to adaptation and diversification are pressing issues. Marine and freshwater sticklebacks represent an ideal model for studying both genetic and epigenetic components of phenotypic plasticity that allow fish to inhabit water with different salinity. Here, we applied single-cell genomics (scRNA-seq and scATAC-seq) and whole-genome bisulfite sequencing to characterize intercellular variability in transcription, the abundance of open chromatin regions, and CpG methylation level in gills of marine and freshwater stickleback morphs. We found little difference in overall transcriptional variance between the morphs but observed significant changes in chromatin openness variance. In addition, genomic divergence islands (DIs) coincided with regions of increased methylation entropy in freshwater fish. Moreover, analysis of transcription factor binding sites within DIs revealed that [C]TCF motifs around marker SNPs were significantly enriched within the region. Altogether, our data show that increased epigenetic variance accompanies the adaptation of marine sticklebacks to freshwater.

evolutionary biology↗

An IDH-independent mechanism of DNA hypermethylation upon VHL inactivation in cancer

Hypermethylation of tumor suppressors and other aberrations of DNA methylation in tumors play a significant role in cancer progression. DNA methylation can be affected by various environmental conditions including hypoxia. The response to hypoxia is mainly achieved through activation of the transcription program associated with HIF1a transcription factor. VHL inactivation by genetic or epigenetic events, which also induces aberrant activation of HIF1a, is the most common driver event for renal cancer. With whole-genome bisulfite sequencing and LC-MS, we demonstrated that VHL inactivation induced global genome hypermethylation in human kidney cancer cells under normoxic conditions. This effect was reverted by exogenous expression of wild-type VHL. We show that global genome hypermethylation in VHL mutants can be explained by transcriptional changes in MDH and L2HGDH genes that cause the accumulation of 2-hydroxyglutarate--a metabolite that inhibits DNA demethylation by Tet enzymes. Unlike the known cases of DNA hypermethylation in cancer, 2-hydroxyglutarate was accumulated in IDH wild type cells. Key pointsO_LIInactivation of VHL gene leads to genome hypermethylation in kidney cancer cells. The DNA methylation phenotype can be rescued by endogenous expression of wild-type VHL. C_LIO_LIDNA hypermethylation can be attributed to the accumulation of a Tet inhibitor 2-hydroxyglutarate C_LIO_LIThe accumulation of 2-hydroxyglutarate in IDH wild-type cells is explained by gene expression changes in key metabolic enzymes (malate dehydrogenase MDH and 2-hydroxyglutrarate dehydrogenase L2HGDH). C_LI

cancer biology↗