Abstract
The parasite Trypanosoma brucei causes African sleeping sickness that is fatal to patients if untreated. Parasite differentiation from a replicative slender form into a quiescent stumpy form promotes host survival and parasite transmission. Long noncoding RNAs (lncRNAs) are known to regulate cell differentiation in other eukaryotes. To determine whether lncRNAs are also involved in parasite differentiation, we used RNA sequencing to survey the T. brucei genome, identifying 1428 previously uncharacterized lncRNA genes. We find that grumpy lncRNA is a key regulator that promotes parasite differentiation into the quiescent stumpy form. This function is promoted by a small nucleolar RNA encoded within the grumpy lncRNA. snoGRUMPY binds to messenger RNAs of at least two stumpy regulatory genes, promoting their expression. grumpy overexpression reduces parasitemia in infected mice. Our analyses suggest that T. brucei lncRNAs modulate parasite-host interactions and provide a mechanism by which grumpy regulates cell differentiation in trypanosomes.
| Original language | English |
|---|---|
| Article number | eabn2706 |
| Journal | Science advances |
| Volume | 8 |
| Issue number | 24 |
| DOIs | |
| State | Published - 17 Jun 2022 |
Bibliographical note
Publisher Copyright:Copyright © 2022 The Authors, some rights reserved
Funding
We would like to thank M. Machado for valuable help with the in vivo mouse T. brucei infection experiments. We also thank H. Manso, A. R. Grosso, and N. Barbosa Morais for valuable help with computational analysis; L. Pinho for managing the orders, the production of culture medium, and the laboratory environment; and all members of the laboratory for stimulating discussion during this project. This work was supported in part by Fundação para a Ciência e Tecnologia (FCT) grant, awarded to F.G. and entitled “Long noncoding RNAs as new diagnostic biomarkers for African Sleeping sickness” (PTDC/DTPEPI/7099/2014, start date: 1 January 2016, end date: 31 December 2018); also by Howard Hughes Medical Institute International Early Career Scientist Program (project title: “How parasites use epigenetics to evade host defenses,” project no. 55007419, start date: 1 February 2012, end date: 31 January 2017); and by the European Research Council (project title: “Exploring the hidden life of African trypanosomes: parasite fat tropism and implications for the disease,” project no. 771714, start date: 1 August 2018, end date: 31 January 2024), both awarded to L.M.F. The project leading to these results have received funding from “la Caixa” Foundation under the agreement LCF/PR/HR20/52400019 [project title: “Mechanism and function of epitranscriptomic poly(A) tail modifications in African trypanosomes,” project no. HR20-00361, start date: 1 March 2021, end date: 29 February 2024]. L.M.F. is supported by FCT (IF/01050/2014, project title: “Molecular basis for the efficient biology of trypanossome parasitism,” start date: 1 January 2015, end date: 31 December 2019) and by CEEC institutional program (CEECINST/00110/2018, start date: 1 January 2020, end date: 14 December 2020). C.N. acknowledges the support of the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) to the EMBL partnership, the Centro de Excelencia Severo Ochoa and the CERCA Programme/Generalitat de Catalunya. S. Michaeli acknowledges the support of the Israel Science Foundation (ref. 1959/20) from October 2020 to October 2025, entitled “Functional analysis of rRNA processing and the role of rRNA modification for specialized translation in the two life stages of trypanosomes” and U.S. Binational Science Foundation (ref. 2015/219) from October 2015 to October 2019, entitled “The role and mechanism of RNA pseudo-uridylation and sugar methylation (Nm) during the developmental cycle of trypanosomes.” The work done in A.D.'s laboratory was supported by National Science Center SONATA BIS grant, entitled “Non-canonical RNA tailing and other post-transcriptional regulatory mechanisms in T cell-mediated adaptive immunity” (proposal ID: 492777, agreement no: UMO-2020/38/E/NZ2/00372, start date: 22 March 2021, end date: 21 March 2026); National Science Center OPUS grant, entitled “Analysis of the role of cytoplasmic polyadenylation in the regulation of the innate immune response” (proposal ID: 443521, agreement no.: UMO-2019/33/B/NZ2/01773, start date: 2 March 2020, end date: 1 March 2023); and European Union's Horizon 2020 (H2020-WIDESPREAD-03-2017)-ERAChair, entitled “MOlecular Signaling in Health and Disease - Interdisciplinary Centre of Excellence” (acronym: MOSaIC, agreement no.: 810425, implementation period: start date: 1 November 2018, end date: 31 October 2023).
| Funders | Funder number |
|---|---|
| Centro de Excelencia Severo Ochoa | |
| de Catalunya | |
| Howard Hughes Medical Institute | 55007419 |
| Horizon 2020 Framework Programme | 771714 |
| European Molecular Biology Laboratory | |
| European Commission | H2020-WIDESPREAD-03-2017, 810425 |
| European Commission | LCF/PR/HR20/52400019, HR20-00361, CEECINST/00110/2018, IF/01050/2014 |
| United States-Israel Binational Science Foundation | 2015/219 |
| Fundação para a Ciência e a Tecnologia | PTDC/DTPEPI/7099/2014 |
| Ministerio de Economía y Competitividad | |
| Israel Science Foundation | 1959/20 |
| Narodowe Centrum Nauki | 443521, UMO-2019/33/B/NZ2/01773, UMO-2020/38/E/NZ2/00372, 492777 |
| Ministerio de Asuntos Económicos y Transformación Digital, Gobierno de España |
