DNA Topoisomerase I differentially modulates R-loops across the human genome

DNA Replication 0301 basic medicine 570 Chromatin Immunoprecipitation Transcription, Genetic Bioinformatics QH301-705.5 1.1 Normal biological development and functioning Type I QH426-470 Small Interfering Resting Phase, Cell Cycle Histones 03 medical and health sciences Genetic Underpinning research Information and Computing Sciences Heterochromatin Genetics Humans Gene Silencing Biology (General) RNA, Small Interfering 0303 health sciences Genome Chromatin Immunoprecipitation; DNA; DNA Replication; DNA Topoisomerases, Type I; G1 Phase Cell Cycle Checkpoints; Gene Silencing; HEK293 Cells; Heterochromatin; Histones; Humans; Lamin Type B; Nucleic Acid Conformation; RNA Polymerase II; RNA, Small Interfering; Resting Phase, Cell Cycle; Genome, Human; Transcription, Genetic; Ecology, Evolution, Behavior and Systematics; Genetics; Cell Biology Lamin Type B Genome, Human Research Cell Cycle DNA Biological Sciences G1 Phase Cell Cycle Checkpoints Chromatin Immunoprecipitation; DNA; DNA Replication; DNA Topoisomerases, Type I; G1 Phase Cell Cycle Checkpoints; Gene Silencing; HEK293 Cells; Heterochromatin; Histones; Humans; Lamin Type B; Nucleic Acid Conformation; RNA Polymerase II; RNA, Small Interfering; Resting Phase, Cell Cycle; Genome, Human; Transcription, Genetic HEK293 Cells DNA Topoisomerases, Type I RNA Resting Phase Nucleic Acid Conformation Generic health relevance RNA Polymerase II Transcription DNA Topoisomerases Environmental Sciences Human
DOI: 10.1186/s13059-018-1478-1 Publication Date: 2018-07-30T11:17:28Z
ABSTRACT
Co-transcriptional R-loops are abundant non-B DNA structures in mammalian genomes. DNA Topoisomerase I (Top1) is often thought to regulate R-loop formation owing to its ability to resolve both positive and negative supercoils. How Top1 regulates R-loop structures at a global level is unknown.Here, we perform high-resolution strand-specific R-loop mapping in human cells depleted for Top1 and find that Top1 depletion results in both R-loop gains and losses at thousands of transcribed loci, delineating two distinct gene classes. R-loop gains are characteristic for long, highly transcribed, genes located in gene-poor regions anchored to Lamin B1 domains and in proximity to H3K9me3-marked heterochromatic patches. R-loop losses, by contrast, occur in gene-rich regions overlapping H3K27me3-marked active replication initiation regions. Interestingly, Top1 depletion coincides with a block of the cell cycle in G0/G1 phase and a trend towards replication delay.Our findings reveal new properties of Top1 in regulating R-loop homeostasis in a context-dependent manner and suggest a potential role for Top1 in modulating the replication process via R-loop formation.
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