The Cumulative Formation of R-loop Interacts with Histone Modifications to Shape Cell Reprogramming

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.

Deciphering the decisive factors driving fate bifurcations in somatic cell reprogramming

“… 6 , 7 The discovery of induced pluripotency has further proved that transcription factors (TFs) are key determinants of cell fate, which can induce the expression of genes necessary for obtaining a pluripotent state. 8 , 9 , 10 , 11 , 12 Some researchers have tried to replace or improve the classical OSKM reprogramming system, including chemical cocktails 13 , 14 and the seven-factor system ( Jdp2 , Jhdm1b , Mkk6 , Glis1 , Nanog , Essrb , and Sall4 ). 8 The success of somatic cell reprogramming alternatives and optimization cocktails have proven that the identification and application of key factors can further overcome the reprogramming obstacles and improve reprogramming efficiency.…”

Non–B-form DNA tends to form in centromeric regions and has undergone changes in polyploid oat subgenomes

“…The DNA of eukaryotic cells is generally in a canonical right-handed B-form double helix (two DNA strands linked antiparallelly by forming base pairs in the B-form duplex). Interestingly, in addition to the canonical B-DNA structure, DNA can form noncanonical DNA structures such as G-quadruplexes, R-loops, hairpins/cruciforms, Z-DNA, triplexes, and slipped DNA ( 12 – 15 ). Noncanonical DNA structures, known as non–B-form DNA, have been implicated in gene expression ( 16 , 17 ), telomere maintenance ( 18 ), double-strand breaks ( 19 ), and the life cycle of transposable elements ( 20 ).…”