The main objective of our group is to understand and elucidate the molecular mechanisms involved in regulating gene expression at the pre-mRNA processing level, in particular in polyadenylation and alternative splicing, with a specific interest in inflammatory and cancer cells. We mainly use molecular biology methodologies and take advantage of different model systems, in particular Drosophila melanogaster and human cells.
Many genes go through alternative pre-mRNA processing – splicing and polyadenylation - in different physiological conditions, with important implications in health and disease. Some of the fundamental question that remain unanswered and that we address in our group is how the cell chooses one polyA signal or a splicing signal instead of another in biologically relevant genes, how is this selection regulated and integrated with RNAPII transcription.
Polo/Plk1 is a key cell cycle kinase conserved in humans and Drosophila, overexpressed in a wide spectrum of cancers and a promising target in oncology. We are exploring new functions for Polo, specifically in transcriptional events.
The development of some human diseases (eg autoimmune diseases and cancer) is controlled by epigenetic mechanisms. We are identifying APA and AS "signatures" as new biomarkers in human diseases and we will apply our knowledge into the development of new diagnostic/therapeutic tools, in collaboration with more clinically oriented researchers.
We demonstrated that the physiological consequences of proper polyadenylation site selection in the 3’ untranslated region are remarkable, as deletion of the distal polyadenylation signal of the polo gene in Drosophila is lethal, in a collaboration work with CE Sunkel and NJ Proudfoot. We have also established the molecular mechanisms underneath this observation: the longer mRNA isoform produced by distal polyadenylation signal choice is more efficiently translated into Polo protein than the shorter isoform, and this increase in Polo levels is necessary for rapid cell division. We further demonstrated that alternative polyadenylation is regulated by Polo and the RNA polymerase II elongation rate in vivo, and proposed a new model integrating transcription kinetics and alternative polyadenylation (Pinto et al, EMBO J 2011).
In human T lymphocytes we focused on CD6, which has been associated with multiple sclerosis. We have identified a new CD6 alternatively spliced isoform with a distinct function in the immunological synapse, in collaboration with A Carmo (Castro et al, JI 2007). More recently, we have dissected the molecular mechanisms behind the generation of the CD6 alternative isoform that is induced upon T cell activation. We showed that a complex combination of chromatin acetylation marks, increases in RNA polymerase II occupancy and CD6 transcription, and a decrease in the levels of the splicing factor SRSF1, all contribute to up-regulate this CD6 isoform following T cell activation (Da Glória et al, JI 2014).
Transcription elongation rate has a tissue-specific impact on alternative cleavage and polyadenylation in Drosophila melanogaster. RNA23(12):1807-1816, 2017. [Journal: Article] [CI: 23] [IF: 4,5]
DOI: 10.1261/rna.062661.117 SCOPUS: 85034084061. .
Braz S.O., Cruz A., Lobo A., Bravo J., Moreira-Ribeiro J., Pereira-Castro I., Freitas J., Relvas J.B., Summavielle T., Moreira A.,
Expression of Rac1 alternative 3' UTRs is a cell specific mechanism with a function in dendrite outgrowth in cortical neurons. Biochimica et Biophysica Acta - Gene Regulatory Mechanisms1860(6):685-694, 2017. [Journal: Article] [CI: 2] [IF: 5,2]
DOI: 10.1016/j.bbagrm.2017.03.002 SCOPUS: 85018940086. .
Rodrigues P.M., Ribeiro A.R., Perrod C., Landry J.J.M., Araújo L., Pereira-Castro I., Benes V., Moreira A., Xavier-Ferreira H., Meireles C., Alves N.L.,
Thymic epithelial cells require p53 to support their long-term function in thymopoiesis in mice. Blood130(4):478-488, 2017. [Journal: Article] [CI: 9] [IF: 15,1]
DOI: 10.1182/blood-2016-12-758961 SCOPUS: 85026293874. .
Domingues R.G., Lago-Baldaia I., Pereira-Castro I., Fachini J.M., Oliveira L., Drpic D., Lopes N., Henriques T., Neilson J.R., Carmo A.M., Moreira A.,
CD5 expression is regulated during human T-cell activation by alternative polyadenylation, PTBP1, and miR-204. European Journal of Immunology46(6):1490-1503, 2016. [Journal: Article] [CI: 11] [IF: 4,2]
DOI: 10.1002/eji.201545663 SCOPUS: 84973661630. .
Duarte-Pereira S., Pereira-Castro I., Silva S.S., Correia M.G., Neto C., da Costa L.T., Amorim A., Silva R.M.,
Extensive regulation of nicotinate phosphoribosyltransferase (NAPRT) expression in human tissues and tumors. Oncotarget7(2):1973-1983, 2016. [Journal: Article] [CI: 28] [IF: 5,2]
DOI: 10.18632/oncotarget.6538 SCOPUS: 84957627325. .
Nogueira E., Mangialavori I.C., Loureiro A., Azoia N.G., Sárria M.P., Nogueira P., Freitas J., Härmark J., Shimanovich U., Rollett A., Lacroix G., Bernardes G.J.L., Guebitz G., Hebert H., Moreira A., Carmo A.M., Rossi J.P.F.C., Gomes A.C., Preto A., Cavaco-Paulo A.,
Peptide Anchor for Folate-Targeted Liposomal Delivery. Biomacromolecules16(9):2904-2910, 2015. [Journal: Article] [CI: 29] [IF: 5,6]
DOI: 10.1021/acs.biomac.5b00823 SCOPUS: 84941584525. .
Da Glória V.G., De Araújo M.M., Santos A.M., Leal R., De Almeida S.F., Carmo A.M., Moreira A.,
T cell activation regulates CD6 alternative splicing by transcription dynamics and SRSF1. Journal of Immunology193(1):391-399, 2014. [Journal: Article] [CI: 19] [IF: 4,9]
DOI: 10.4049/jimmunol.1400038 SCOPUS: 84903626125. .
Nogueira E., Loureiro A., Nogueira P., Freitas J., Almeida C.R., Härmark J., Hebert H., Moreira A., Carmo A.M., Preto A., Gomes A.C., Cavaco-Paulo A.,
Liposome and protein based stealth nanoparticles. Faraday Discussions166:417-429, 2013. [Journal: Review] [CI: 25] [IF: 4,2]
DOI: 10.1039/c3fd00057e SCOPUS: 84887481690. .
Pinto P.A.B., Henriques T., Freitas M.O., Martins T., Domingues R.G., Wyrzykowska P.S., Coelho P.A., Carmo A.M., Sunkel C.E., Proudfoot N.J., Moreira A.,
RNA polymerase II kinetics in polo polyadenylation signal selection. EMBO Journal30(12):2431-2444, 2011. [Journal: Article] [CI: 81] [IF: 9,2]
DOI: 10.1038/emboj.2011.156 SCOPUS: 79958859723. .