Abstract
Schistosoma mansoni is a flatworm that causes schistosomiasis, a neglected tropical disease that affects more than 200 million people worldwide. There is only one drug indicated for treatment, praziquantel, which may lead to parasite resistance emergence. The ribonucleoside analogue 5-azacytidine (5-AzaC) is an epigenetic drug that inhibits S. mansoni oviposition and ovarian development through interference with parasite transcription, translation and stem cell activities. Therefore, studying the downstream pathways affected by 5-AzaC in S. mansoni may contribute to the discovery of new drug targets. Long non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides with low or no protein coding potential that have been involved in reproduction, stem cell maintenance and drug resistance. We have recently published a catalog of lncRNAs expressed in S. mansoni life-cycle stages, tissues and single cells. However, it remains largely unknown if lncRNAs are responsive to epigenetic drugs in parasites. Here, we show by RNA-Seq re-analyses that hundreds of lncRNAs are differentially expressed after in vitro 5-AzaC treatment of S. mansoni females, including intergenic, antisense and sense lncRNAs. Many of these lncRNAs belong to co-expression network modules related to male metabolism and are also differentially expressed in unpaired compared with paired females and ovaries. Half of these lncRNAs possess histone marks at their genomic loci, indicating regulation by histone modification. Among a selected set of 8 lncRNAs, half of them were validated by RT-qPCR as differentially expressed in females, and some of them also in males. Interestingly, these lncRNAs are also expressed in other life-cycle stages. This study demonstrates that many lncRNAs potentially involved with S. mansoni reproductive biology are modulated by 5-AzaC and sheds light on the relevance of exploring lncRNAs in response to drug treatments in parasites.
Highlights
Schistosoma mansoni is a flatworm that causes schistosomiasis, a neglected tropical disease that affects more than 200 million people worldwide
As Long non-coding RNAs (lncRNAs) levels have been shown to be modulated by nucleoside analogs in other e ukaryotes[32,33], we hypothesized that lncRNA levels would be modulated by 5-AzaC in S. mansoni
We cross compared the lncRNAs differentially expressed after 5-AzaC exposure in females with lncRNAs that we found to be differentially expressed in a re-analysis of the Lu et al d ata[35] for lncRNAs differentially expressed between bisex females and single-sex females, between bisex ovaries and single-sex ovaries and between bisex ovaries(bO) and bisex females
Summary
Schistosoma mansoni is a flatworm that causes schistosomiasis, a neglected tropical disease that affects more than 200 million people worldwide. The ribonucleoside analogue 5-azacytidine (5-AzaC) is an epigenetic drug that inhibits S. mansoni oviposition and ovarian development through interference with parasite transcription, translation and stem cell activities. We have recently published a catalog of lncRNAs expressed in S. mansoni life-cycle stages, tissues and single cells It remains largely unknown if lncRNAs are responsive to epigenetic drugs in parasites. Among a selected set of 8 lncRNAs, half of them were validated by RT-qPCR as differentially expressed in females, and some of them in males These lncRNAs are expressed in other life-cycle stages. PZQ is a safe, cheap and tolerable d rug[6], cure rates of less than 50% have been r ecorded[7] and drug tolerance has already been r eported[8,9] This scenario reinforces the need of new and more efficient approaches in reducing morbidity or disease eradication, such as the development of a v accine[10] or alternative drugs[11]. Control of gene expression and its physiological consequences in schistosomes and, in the future, to the possible development of new chemotherapeutic strategies against schistosomiasis
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