A long noncoding RNA promotes parasite differentiation in African trypanosomes

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.

Current Status of Regulatory Non-Coding RNAs Research in the Tritryp

“…However, evidence of a functional role in these organisms has only recently emerged. Studies estimate several hundred lncRNAs [ 57 , 144 ], mostly present in previously unannotated regions of the T. brucei genome. Only a few have been experimentally characterized with proposed roles in translation regulation [ 30 ] parasite development and present a variable expression in culture conditions compared to wild type cells [ 57 , 144 ].…”

“…Studies estimate several hundred lncRNAs [ 57 , 144 ], mostly present in previously unannotated regions of the T. brucei genome. Only a few have been experimentally characterized with proposed roles in translation regulation [ 30 ] parasite development and present a variable expression in culture conditions compared to wild type cells [ 57 , 144 ]. Interestingly, the work by Guegan et al shows that a lncRNA in T. brucei plays a key role in promoting differentiation to the stumpy form.…”

“…Interestingly, the work by Guegan et al shows that a lncRNA in T. brucei plays a key role in promoting differentiation to the stumpy form. This effect is mediated by the processing of the lncRNA into a snoRNA, snoGRUMPY, which regulates translation of its mRNA targets [ 57 ] ( Figure 3 ). This work points to the significance of this biotype in trypanosomatid biology, a subject that has been mostly unexplored in this group of parasites.…”

“…Figure 3. Regulatory non-canonical ncRNAs with experimentally demonstrated roles reported in trypanosomatids.The illustrations represent the structure, processing and proposed mechanisms of action of the four ncRNAs reported so far[28,30,37,57]. Created with BioRender.com(accessed on 13 May 2022).…”

Epitranscriptomics in parasitic protists: Role of RNA chemical modifications in posttranscriptional gene regulation

“…So far, very little is known regarding epitranscriptomic landscapes of lncRNAs and circRNAs in parasitic protists. However, a particular lncRNA in T. brucei, snoGRUMPY, was recently found to play a role in cell differentiation and is a C/D box snoRNA family [130]. The typical role of this family of snoRNA is guiding 2 0 -O-methylation (Nm) in rRNA, which was tested using RiboMeth-seq (ribose methylation sequencing) [130].…”