title: R-loop formation is a distinctive characteristic of unmethylated human CpG island promoters.
abstract: CpG islands (CGIs) function as promoters for approximately 60% of human genes. Most of these elements remain protected from CpG methylation, a prevalent epigenetic modification associated with transcriptional silencing. Here, we report that methylation-resistant CGI promoters are characterized by significant strand asymmetry in the distribution of guanines and cytosines (GC skew) immediately downstream from their transcription start sites. Using innovative genomics methodologies, we show that transcription through regions of GC skew leads to the formation of long R loop structures. Furthermore, we show that GC skew and R loop formation potential is correlated with and predictive of the unmethylated state of CGIs. Finally, we provide evidence that R loop formation protects from DNMT3B1, the primary de novo DNA methyltransferase in early development. Altogether, these results suggest that protection from DNA methylation is a built-in characteristic of the DNA sequence of CGI promoters that is revealed by the cotranscriptional formation of R loop structures.
authors.affiliation: Department of Molecular and Cellular Biology, University of California, Davis, Davis, CA 95616, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Ginno
authors.forename: Paul L
authors.initials: PL
authors.lastname: Lott
authors.forename: Holly C
authors.initials: HC
authors.lastname: Christensen
authors.forename: Ian
authors.initials: I
authors.lastname: Korf
authors.forename: Frédéric
authors.initials: F
authors.lastname: Chédin
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D018899:CpG Islands; D003596:Cytosine; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015894:Genome, Human; D006147:Guanine; D006801:Humans; D051379:Mice; D009690:Nucleic Acid Conformation; D010957:Plasmids / Q000235:genetics; D011401:Promoter Regions, Genetic; D024363:Transcription Initiation Site; D055517:snRNP Core Proteins / Q000235:genetics
chemical_list: D001057:Apolipoproteins E; D055517:snRNP Core Proteins; D006147:Guanine; D003596:Cytosine