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Your Environment. Your Health.

University of North Carolina-Chapel Hill: Dataset Details, ID=GSE71940

Superfund Research Program

Elucidating Risks: From Exposure and Mechanism to Outcome

Center Director: Rebecca C. Fry
Grant Number: P42ES005948
Funding Period: 1992-2018
View this project in the NIH Research Portfolio Online Reporting Tools (RePORT)

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Title: H2A.X SMRT-ChIP

Accession Number: GSE71940

Link to Dataset: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE71940

Repository: Gene Expression Omnibus (GEO)

Data Type(s): Gene Expression

Experiment Type(s): Genome binding/occupancy profiling by high throughput sequencing

Organism(s): Mus musculus

Summary: It has widely accepted that 5-methylcytosine is the only form of DNA methylation in mammalian genomes, whereas the other forms, such as N6-methyladenine, primarily exist in prokaryotes and only a few eukaryotes. Herein, we demonstrated the surprising presence of N6-methyladenine in mammalian genomes, especially, mouse embryonic stem cells. This modification is enriched at histone variant H2A.X-deposited genomic regions in wild type embryonic stem cells. Our work also showed that a previously unknown DNA demethylase, Alkbh1, is the major demethylase for N6-methyladenine in embryonic stem cells. Increase of N6-methyladenine levels in Alkbh1 deficient cells leads to silencing of genes that regulate embryonic development. Surprisingly, genes located on the X-chromosome, but not the Y-chromosome or autosomes are preferentially silenced by N6-methyladenine. Strikingly, N6-methyladenine in Alkbh1 deficient cells are specifically deposition at young, full-length subfamilies of LINE1 transposons that are strongly enriched on the X chromosome. Furthermore, N6-methyladenine deposition on LINE1s pattern is inversely correlated with their evolutionary age. The deposition of N6-methyladenine results in epigenetic silencing of such L1s, which are otherwise actively transcribed in wild type embryonic stem cells, and the neighboring enhancers and genes. Furthermore, N6-methyladenine induced-silencing resists gene activation signals during embryonic stem cell differentiation. Thus, N6-methyladenine adopts a new function in epigenetic silencing in evolution, distinct from its role in gene activation in other organisms. In summary, our results demonstrate that N6-methyladenine unexpectedly constitutes a crucial component of the epigenetic regulation repertoire in mammalian genomes. First, we used a native-ChIP approach to enrich for DNA molecules residing in H2A.X-deposition regions in mouse ESCs as previously described. Then, co-purified DNA molecules from WT or KO ESCs were subject to SMRT sequencing and data analysis for DNA modifications (Pacific Biosciences).

Publication(s) associated with this dataset:
  • Wu TP, Wang T, Seetin MG, Lai Y, Zhu S, Lin K, Liu Y, Byrum SD, Mackintosh SG, Zhong M, Tackett A, Wang G, Hon LS, Fang G, Swenberg JA, Xiao AZ. 2016. DNA methylation on N(6)-adenine in mammalian embryonic stem cells. Nature 532(7599):329-333. doi:10.1038/nature17640 PMID:27027282 PMCID:PMC4977844
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