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Mechanisms of action of long non-coding RNAs involved with gene activation programs in eukaryotes

Grant number: 18/23693-5
Support type:Research Projects - Thematic Grants
Duration: July 01, 2019 - June 30, 2024
Field of knowledge:Biological Sciences - Biochemistry
Principal Investigator:Sergio Verjovski Almeida
Grantee:Sergio Verjovski Almeida
Home Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
Assoc. researchers:Chao Yun Irene Yan ; Christoph Grunau ; Eliana Nakano ; Felipe Cesar Ferrarezi Beckedorff ; João Carlos Setubal ; Jorge Elias Kalil Filho ; Mayana Zatz ; Murilo Sena Amaral ; RONALDO DE CARVALHO AUGUSTO

Abstract

In recent years, with the intensive use of large-scale sequencing replacing microarrays for the detection of gene expression in several organisms, it has become clear that, in all eukaryotes studied so far, thousands of long (> 200 nucleotides) non-protein coding RNAs (lncRNAs) represent a very diverse and very tissue-specific class of RNAs in a cell. Despite this, only about four dozen lncRNAs in humans have had their molecular mechanisms of action identified and characterized in detail, which has revealed their role as regulators of gene transcription in eukaryotes. The current challenge is still to find the most relevant experimental models and cellular processes, looking for lncRNAs that are key targets in these processes, and to show the loss and gain of function in a particular cell type or organ when the transcription of one of these lncRNAs is repressed or it is over-expressed. The project proposed here focuses on relevant cellular processes in two species, the human and the parasite Schistosoma mansoni, which have been the study interest of our group in the last 15 years. In humans, we will study the involvement of lncRNAs in human embryonic stem cell differentiation programs into neural cortex cells and into placental trophoblasts, and the involvement of lncRNAs in androgen regulation of prostate cancer. In S. mansoni we will study the role of lncRNAs in the sexual maturation of parasites, the role of lncRNAs in the response of parasites to drugs, and the involvement of lncRNAs during in vitro parasite death induced by immunized sera of infected Rhesus monkeys that had self-cured from the disease. The project has the advantage of having already obtained preliminary results on new lncRNAs that are candidates to have regulatory roles on some of these biological processes. The application of new technologies to detect the interaction between lncRNAs, proteins and their possible binding sites in genomic DNA, and the parallel detection of the modifications of chromatin marks and the transcriptional activity of genes proposed here, will allow us to understand the regulatory role of lncRNAs, and knowledge of these mechanisms may open doors to the eventual use of these lncRNAs as therapeutic targets. (AU)

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