Abstract
R-loop, a three-stranded RNA/DNA structure, plays important roles in modulating genome stability and gene expression, but the molecular mechanism of R-loops in cell reprogramming remains elusive. Here, we comprehensively profiled the genome-wide landscape of R-loops during cell reprogramming. The results showed that the R-loop formation on most different types of repetitive elements is stage-specific in cell reprogramming. We unveiled that the cumulative deposition of an R-loop subset is positively correlated with gene expression during reprogramming. More importantly, the dynamic turnover of this R-loop subset is accompanied by the activation of the pluripotent transcriptional regulatory network (TRN). Moreover, the large accumulation of the active histone marker H3K4me3 and the reduction in H3K27me3 were also observed in these R-loop regions. Finally, we characterized the dynamic network of R-loops that facilitates cell fate transitions in reprogramming. Together, our study provides a new clue for deciphering the interplay mechanism between R-loops and HMs to control cell reprogramming.
Highlights
Academic Editor: Jiří FajkusR-loop is a special three-stranded nucleic acid structure composed of a DNA:RNA hybrid double helix and a single-stranded DNA molecule, which is ubiquitous in the whole organism
Based on the single-stranded DNA:RNA immunoprecipitation sequencing data, we aimed to elucidate the characteristics of global R-loop formation in the process of mouse embryonic fibroblast (MEF, D0) reprogramming to induced pluripotent stem cells (iPSCs), and found that R-loops showed a significant dynamic pattern during the reprogramming process
The results revealed that the dynamic change pattern of R-loops within the genes was intense throughout the whole reprogramming process, whereas the prominent change wave of gene expression pattern only emerged between the iPSC and D7 (Figure 2C,D)
Summary
R-loop is a special three-stranded nucleic acid structure composed of a DNA:RNA hybrid double helix and a single-stranded DNA (ssDNA) molecule, which is ubiquitous in the whole organism. The predominant R-loop formation shows a strong sequence preference, which usually occurs at multiple loci with high guanine–cytosine (GC) content, including the unmethylated CpG island [4] and strong G/C skew [calculated as (G − C)/(G + C)]. The formation events of R-loops occur in conserved regions that are associated with specific epigenetic modification marks [6,7]. Several studies have revealed that R-loops play a part in many biological processes, such as DNA replication [8], chromatin modification [9], DNA damage response [10], and genomic stability [11,12,13,14].
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