Wei Wen Teo # 1, Xinang Cao # 1 2, Chan-Shuo Wu 1, Hong Kee Tan 1 3, Qiling Zhou 1, Chong Gao 4, Kim Vanuytsel 5 6, Sara S Kumar 5 6, George J Murphy 5 6, Henry Yang 1, Li Chai 7, Daniel G Tenen 8 9 10
Affiliations
1Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
2Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
3National University of Singapore, Graduate School for Integrative Sciences and Engineering, Singapore, Singapore.
4Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA.
5Section of Hematology and Medical Oncology, School of Medicine, Boston University, Boston, MA, USA.
6Center for Regenerative Medicine, Boston University and Boston Medical Center, Boston, MA, USA.
7Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA. lchai@bwh.harvard.edu.
8Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore. daniel.tenen@nus.edu.sg.
9Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, USA. daniel.tenen@nus.edu.sg.
10Harvard Initiative for RNA Medicine, Harvard Medical School, Boston, MA, USA. daniel.tenen@nus.edu.sg.
#Contributed equally.
Abstract
Polycomb Repressive Complex 2 (PRC2) is an epigenetic regulator required for gene silencing during development. Although PRC2 is a well-established RNA-binding complex, the biological function of PRC2-RNA interaction has been controversial. Here, we study the gene-regulatory role of the inhibitory PRC2-RNA interactions. We report a nuclear long non-coding RNA, LEVER, which mapped 236 kb upstream of the ?-globin cluster as confirmed by Nanopore sequencing. LEVER RNA interacts with PRC2 in its nascent form, and this prevents the accumulation of the H3K27 repressive histone marks within LEVER locus. Interestingly, the accessible LEVER chromatin, in turn, suppresses the chromatin interactions between the ?-globin locus and ?-globin locus control region (LCR), resulting in a repressive effect on ?-globin gene expression. Our findings validate that the nascent RNA-PRC2 interaction inhibits local PRC2 function in situ. More importantly, we demonstrate that such a local process can in turn regulate the expression of neighboring genes.
© 2022. The Author(s).
