PT  - JOURNAL ARTICLE
AU  - Maggie M. Balas
AU  - Erik W. Hartwick
AU  - Chloe Barrington
AU  - Justin T. Roberts
AU  - Stephen K. Wu
AU  - Ryan Bettcher
AU  - April M. Griffin
AU  - Jeffrey S. Kieft
AU  - Aaron M. Johnson
TI  - RNA matchmaking remodels lncRNA structure and promotes PRC2 activity
AID  - 10.1101/2020.04.13.040071
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.04.13.040071
4099  - http://biorxiv.org/content/early/2020/04/14/2020.04.13.040071.short
4100  - http://biorxiv.org/content/early/2020/04/14/2020.04.13.040071.full
AB  - Polycomb Repressive Complex 2 (PRC2) contributes to initiation of heterochromatin through catalysis of histone H3 lysine 27 (H3K27) methylation. Human PRC2 can work productively with specific long noncoding RNAs (lncRNAs) at certain target loci, yet the underlying mechanism is unclear. In apparent contradiction to lncRNA-mediated PRC2 activity, PRC2 binds to RNA in a low-specificity, high-affinity manner, effectively competing with chromatin and making RNA a potent catalytic inhibitor of H3K27 methylation activity. We address this contradiction by testing the model that intermolecular RNA-RNA interactions between the lncRNA HOTAIR and its target genes can generate a context that is favorable for PRC2 activity. This RNA matchmaking activity is promoted by the heterogenous nuclear ribonucleoprotein (hnRNP) B1, which uses multiple protein domains to bind to specific regions of HOTAIR via multi-valent protein-RNA interactions. Using chemical probing, we find that RNA-RNA interaction and B1 binding facilitate RNA structural changes in HOTAIR. Finally, we demonstrate that RNA-RNA matches of HOTAIR with target gene RNAs can relieve the inhibitory effect of a single lncRNA for PRC2 activity. By dissecting molecular details of RNA matchmaking within the HOTAIR mechanism, we highlight a switch that can occur as PRC2 samples RNA interactions broadly in the nucleus, being activated on chromatin by specific RNA matches. This concept may generalize to many contexts where RNA plays a role in potentiating PRC2 activity.Competing Interest StatementThe authors have declared no competing interest.