| Autor: |
Trinh, Bon Q., Ummarino, Simone, Zhang, Yanzhou, Ebralidze, Alexander K., Bassal, Mahmoud A., Nguyen, Tuan M., Heller, Gerwin, Coffey, Rory, Tenen, Danielle E., van der Kouwe, Emiel, Fabiani, Emiliano, Gurnari, Carmelo, Wu, Chan-Shuo, Angarica, Vladimir Espinosa, Yang, Henry, Chen, Sisi, Zhang, Hong, Thurm, Abby R., Marchi, Francisco, Levantini, Elena, Staber, Philipp B., Zhang, Pu, Voso, Maria Teresa, Pandolfi, Pier Paolo, Kobayashi, Susumu S., Chai, Li, Di Ruscio, Annalisa, Tenen, Daniel G. |
| Zdroj: |
Blood; October 2021, Vol. 138 Issue: 15 p1331-1344, 14p |
| Abstrakt: |
The mechanism underlying cell type-specific gene induction conferred by ubiquitous transcription factors as well as disruptions caused by their chimeric derivatives in leukemia is not well understood. Here, we investigate whether RNAs coordinate with transcription factors to drive myeloid gene transcription. In an integrated genome-wide approach surveying for gene loci exhibiting concurrent RNA and DNA interactions with the broadly expressed Runt-related transcription factor 1 (RUNX1), we identified the long noncoding RNA (lncRNA) originating from the upstream regulatory element of PU.1(LOUP). This myeloid-specific and polyadenylated lncRNA induces myeloid differentiation and inhibits cell growth, acting as a transcriptional inducer of the myeloid master regulator PU.1. Mechanistically, LOUPrecruits RUNX1 to both the PU.1enhancer and the promoter, leading to the formation of an active chromatin loop. In t(8;21) acute myeloid leukemia (AML), wherein RUNX1 is fused to ETO, the resulting oncogenic fusion protein, RUNX1-ETO, limits chromatin accessibility at the LOUPlocus, causing inhibition of LOUPand PU.1expression. These findings highlight the important role of the interplay between cell-type–specific RNAs and transcription factors, as well as their oncogenic derivatives in modulating lineage-gene activation and raise the possibility that RNA regulators of transcription factors represent alternative targets for therapeutic development. |
| Databáze: |
Supplemental Index |
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