R-loops are unique structures in the cell, composed of RNA–DNA hybrids and a displaced single-stranded DNA, that are commonly found in around transcribed genes. However, R-loops are also dynamic and widespread entities that play unclear regulatory and epigenetic roles in the genome. A recent study by Chinese scientists at the Guangzhou Institutes of Biomedicine and Health (GIBH) of the Chinese Academy of Sciences has shed light on the activity of R-loops in the reprogramming of somatic cells to induced pluripotent stem cells (iPSCs). Their work reveals that R-loops influence the reprogramming of somatic cells into iPSCs, and disrupting this activity leads to defects in the reprogramming of somatic cells to iPSCs.
R-loops may act as epigenetic markers by altering transcription factor binding, chromatin modifications, and DNA methylation. Researchers mapped the landscape of R-loops during OSKM (Oct4, Sox2, Klf4, and c-Myc, four transcription factors in the reprogramming cocktail) mediated somatic cell reprogramming and showed a dynamic association between R-loop formation and dissolution and the process of somatic cell reprogramming.
“Our data indicates that R-loops cause sharp changes at both the early and late stages of reprogramming, but they have transient and subtle changes at the intermediate stage, which shows a similar pattern with chromatin opening, DNA methylation, and gene expression during reprogramming,” said YAO Hongjie, author of the study from GIBH.
Yao and his colleagues found that some R-loops formed in advance of gene expression, suggesting R-loops are poising genes ready for transcription. Their research revealed that the transcription factor Sox2 (but not any other Yamanaka factor in the reprogramming cocktail) was intimately involved in forming a complex with R-loops. “It is not only a transcription factor that induces transcription but also an essential regulator that maintains the balance of R-loops, and further promotes reprogramming together with R-loop–resolving factors,” said YAO.
The results of this study were published online in the latest issue of Science Advances on June 10, entitled “R-loops Coordinate with SOX2 in Regulating Reprogramming to Pluripotency”.
YAO Hongjie,Ph.D Principle Investigator
CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences.