R-loops are three-stranded RNA:DNA loops when the nascent mRNA, or lncRNA anneals with the template DNA strand and displaces the non-template DNA as unpaired single strand. R- loop misregulation is associated with DNA damage, hyper-recombination, and genomic instability. Mounting evidences now support R-loops regulate gene expression in ways including epigenetic regulation, transcriptional initiation and elongation.

Transcription Regulation by mRNA Organized R-loops

• DNA methylation regulation

Normally in healthy cells, the R-loop at gene promoter repels DNMT binding, prevents DNA methylation, and facilitates transcription. However in amyotrophic lateral sclerosis (ALS4), senataxin mutation reduces R-loop formation, leading to increased negative TGFb regulator BAMBI gene promoter methylation, transcription repression, TGFb signal transduction upregulation, and ALS progression (Fig.1)[1].

• mRNA organized R-loop as promoter

The R-loops, formed by nascent mRNA invading the DNA duplex behind the progressing PolII, can functionally act as a promoter for divergent antisense LncRNA (AS transcript). There, the ssDNA in the R-loop becomes the template for the antisense RNA[2].

Fig 1.DNA methylation regulation by mRNA organized R-loops[1]

Arraystar DRIPc-seq(DNA–RNA immunoprecipitation followed by cDNA conversion coupled to high-throughput sequencing) profiles LncRNA/mRNA organized R-loop distribution in the genome. The DRIPc-seq, along withLncRNA Array,MeDIP-sequencing, orChIP-seq, is able to provide valuable functional insights in epigenetic and transcriptional regulation by R-loops.

References
1. Grunseich C. et al (2018) Mol Cell 69(3):426-437.e7 [PMID:29395064]
2. Arab K. et al (2019) Nat Genet 51(2):217-223 [PMID:30617255]

Circular RNA
• Yuan Q, et al. (2023)
   Signal Transduction &Targeted Therapy
   [PMID: 36882410]
• Zhong GL, et al. (2023)
   Molecular Cancer
   [PMID: 37004067]

RNA Modification
• Yan W, et al. (2023)
   International Journal of Oral Science
   [PMID: 36631441]

DRIPc-Seq provides valuable functional insights in transcriptional regulation by LncRNA/mRNA organized R-loops.

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