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HMGA2 links promoter-specific H2A.X deposition and active DNA demethylation [Mnase-Seq]

ABSTRACT: During transcriptional activation, chromatin undergoes structural changes with the help of various proteins such as chromatin remodeling factors and histone modifiers in order to make the DNA accessible for the transcription factors and RNA polymerase. We combined ChIP-, MNase- and RNA-sequencing analyzing the Hmga2 knock-out mice and found that HMGA2 is required for promoter specific deposition of the histone variant H2A.X. Consequently, the promoter specific H2A.X deposition resulted in an accumulation of active RNA Polymerase II at these promoters. Stimulation with TGFB1 resulted in increased accumulation of pH2A.X and expression of those “primed” target genes, whereas cells expressing no Hmga2 where not able to respond.

ORGANISM(S): Mus musculus

PROVIDER: GSE141265 | GEO | 2020/12/14

REPOSITORIES: GEO

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Project description: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). H2A.X Native ChIP coupling with SMRT sequencing (separate the short "S" and long "L" part to sequencing)

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HMGA2 links promoter-specific H2A.X deposition and active DNA demethylation [Mnase-Seq]

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