Independence between pre-mRNA splicing and DNA methylation in an isogenic minigene resource

Actively transcribed genes adopt a unique chromatin environment with characteristic patterns of enrichment. Within gene bodies, H3K36me3 and cytosine DNA methylation are elevated at exons of spliced genes and have been implicated in the regulation of pre-mRNA splicing. H3K36me3 is further responsive...

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Bibliographic Details
Published in:Nucleic acids research 2017-12, Vol.45 (22), p.12780-12797
Main Authors: Nanan, Kyster K, Ocheltree, Cody, Sturgill, David, Mandler, Mariana D, Prigge, Maria, Varma, Garima, Oberdoerffer, Shalini
Format: Article
Language:English
Subjects:
Animals
Chromatin - genetics
Chromatin - metabolism
DNA (Cytosine-5-)-Methyltransferases - metabolism
DNA Methylation
DNA Methyltransferase 3B
Exons - genetics
Gene Expression Regulation
Gene regulation, Chromatin and Epigenetics
HEK293 Cells
Histones - metabolism
Humans
Lysine - metabolism
Methylation
Mice
Models, Genetic
RNA Precursors - genetics
RNA Splicing
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Summary:Actively transcribed genes adopt a unique chromatin environment with characteristic patterns of enrichment. Within gene bodies, H3K36me3 and cytosine DNA methylation are elevated at exons of spliced genes and have been implicated in the regulation of pre-mRNA splicing. H3K36me3 is further responsive to splicing, wherein splicing inhibition led to a redistribution and general reduction over gene bodies. In contrast, little is known of the mechanisms supporting elevated DNA methylation at actively spliced genic locations. Recent evidence associating the de novo DNA methyltransferase Dnmt3b with H3K36me3-rich chromatin raises the possibility that genic DNA methylation is influenced by splicing-associated H3K36me3. Here, we report the generation of an isogenic resource to test the direct impact of splicing on chromatin. A panel of minigenes of varying splicing potential were integrated into a single FRT site for inducible expression. Profiling of H3K36me3 confirmed the established relationship to splicing, wherein levels were directly correlated with splicing efficiency. In contrast, DNA methylation was equivalently detected across the minigene panel, irrespective of splicing and H3K36me3 status. In addition to revealing a degree of independence between genic H3K36me3 and DNA methylation, these findings highlight the generated minigene panel as a flexible platform for the query of splicing-dependent chromatin modifications.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gkx900