Qiangfeng Cliff Zhang’s group collaborated with Howard Chang’s lab from Stanford University and revealed RNA structure maps across mammalian cellular compartments
A joint research led by Qiangfeng Cliff Zhang’s group from Tsinghua University and Howard Chang’s lab from Stanford University recently resolved comprehensive RNA structure maps for both human and mouse cell lines in subcellular compartments. Published in Nature Structural & Molecular Biology on March. 18, 2019., the study substantially expanded RNA structures including those of many lncRNAs, and revealed the dynamic nature of RNA structures and its functional significance in gene regulation.
RNA undergoes a complex life cycle in eukaryotic cells, mirrored by its movement into distinct cytotopic locales. RNA structure is thought to form co-transcriptionally on the chromatin template, reshaped by RNA chemical modification and processing in the nucleus, and undergo further changes in the cytoplasm during translation and RNA decay. Yet to date, studies of RNA structure in living cells have averaged the RNA structure signal in the entire cell, which potentially obscures these critical dynamic features.
Fig 1. Combining subcellular RNA fractioning and icSHAPE to obtain cytotopic RNA structure maps
The researchers pioneer the first compartment-specific view of RNA structure transcriptome wide in human and mouse cells. They used icSHAPE, a recently developed RNA structure mapping method from the Chang lab (Spitale et al., Nature, 2015) that provides structural information on all four bases for RNAs, to map the RNA structurome in chromatin, nucleus, and cytosol. The research had led to cytotopic RNA structure maps that substantially expanded the scope and comprehensiveness of RNA structures, particularly for introns and nuclear-enriched lncRNAs that are the focus of many investigations. It also revealed a large number of dynamic RNA structural motifs, which undergo changes as RNAs experience distinct steps in their life cycles. Finally, the researchers developed a framework to identify the RNA binding proteins and chemical modifications that may underlie the dynamic RNA structure changes.
This approach proved to be especially insightful for understanding RNA chemical modification. The researchers found that while the canonical reader YTHDF1 directly reads m6A modification, the newly identified readers HNRNPC and IGF2BP proteins can read the structural changes induced by the so-called m6A-switch. They further discovered and validated the novel role of the pluripotency regulator LIN28A as an anti-reader for m6A modification. This discovery unifies the functional and molecular mechanisms of LIN28A in pluripotency, microRNA biogenesis, and post-transcriptional gene regulation.
Prof. Qiangfeng Cliff Zhang from School of Life Sciences of Tsinghua University, and Prof. Howard Chang from Stanford University School of Medicine are the co-corresponding authors of this work. PhD student Lei Sun from School of Life Sciences at Tsinghua, postdoc fellow Dr. Furqan Fazal from Stanford University School of Medicine, and PhD student Pan Li from School of Life Sciences at Tsinghua are the co-first authors of this work. The study was supported by National Institutes (NIH) grants, Howard Hughes Medical Institute, the National Natural Science Foundation of China, the National Thousand Young Talents Program of China, the funding from the THU-PKU Center for Life Sciences, and the Arnold O. Beckman Postdoctoral Fellowship.
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