We highlight the following articles published in the last years by researchers at Fundación Ciencia & Vida:
Mario Rosemblatt (Cellular and Molecular Immunology Lab):
- Candia E, Reyes P, Covian C, Rodriguez F, Wainstein N, Morales J, Mosso C, Rosemblatt M, Fierro JA. Single and combined effect of retinoic acid and rapamycin modulate the generation, activity and homing potential of induced human regulatory T cells. PLoS One 12(7): e0182009. doi: 10.1371/journal.pone.0182009 (2017)
In this work, done in collaboration with Dr. Alberto Fierro from Clínica Las Condes, we propose new protocols for the production of more and better human regulatory T lymphocytes specific for an organ donor useful in transplant biology.
- Doñas C, Carrasco M, Fritz M, Prado C, Tejón G, Osorio-Barrios F, Manríquez V, Pacheco R, Reyes P, Bono MR, Loyola A, Rosemblatt M. GSK-J4 limits inflammation through the induction of a tolerogenic phenotype on DCs. J Autoimmun 75: 105-117. doi: 10.1016/j.jaut.2016.07.011 (2016)
In collaboration with Drs. Loyola and Pacheco (FCV) and Dr. Bono (Faculty of Sciences – University of Chile), we demonstrated that treatment of mice with the epigenetic drug GSK-J4 inhibited the development of a form of Multiple Sclerosis, opening the way for a new treatment for autoimmune diseases.
Alejandra Loyola (Epigenetics and Chromatin Lab):
- Saavedra F, Rivera C, Rivas E, Merino P, Garrido D, Hernández S, Forné I, Vassias I, Gurard-Levin ZA, Alfaro IE, Imhof A, Almouzni GA, Loyola A. PP32 and SET/TAF-Iβ proteins regulate the acetylation of newly synthesized histone H4. Nucleic Acids Res 45(20): 11700-11710. doi: 10.1093/nar/gkx775 (2017)
In this work, we demonstrate that post-translational modifications of recently synthesized histones are finely regulated by proteins that are associated with them.
- Alarcón V, Hernández S, Rubio L, Alvarez F, Flores Y, Varas-Godoy M, De Ferrari GV, Kann M, Villanueva RA, Loyola A. The enzymes LSD1 and Set1A cooperate with the viral protein HBx to establish an active hepatitis B viral chromatin state. Scientific Rep 6:25901. doi: 10.1038/srep25901 (2016)
In this article, we showed that the replication and transcription of the hepatitis B virus are regulated through post-translational modifications of the histones that are associated with the viral genome.
- Rivera C, Saavedra F, Alvarez F, Díaz-Celis C, Ugalde V, Li J, Forné I, Gurard-Levin ZA, Almouzni G, Imhof A, Loyola A. Methylation of histone H3 lysine 9 occurs during translation. Nucleic Acids Res 43(19): 9097-9106. doi: 10.1093/nar/gkv929 (2015)
In this work, we demonstrated that monomethylation of histone H3 lysine 9 (H3K9me1) takes place in the ribosome, while the histone is being synthesized.
Rodrigo Pacheco (Neuroimmunology Lab):
- Prado C, Gaiazzi M, González H, Ugalde V, Figueroa A, Osorio-Barrios FJ, López E, Lladser A, Rasini E, Marino F, Zaffaroni M, Cosentino M, Pacheco R. Dopaminergic stimulation of myeloid antigen-presenting cells attenuates signal transducer and activator of transcription 3-activation favouring the development of experimental autoimmune encephalomyelitis. Front Immunol 9:571. doi: 10.3389/fimmu.2018.00571 (2018)
In collaboration with Drs. Cosentino and Marino (University of Insubria, Varese, Italy) and Dr. Lladser (FCV), we demonstrated that dopamine receptor D5 signaling triggers an inhibition of STAT3 activation in myeloid antigen-presenting cells, thus promoting Th1 and Th17 responses and favoring the development of autoimmunity.
- Elgueta D, Aymerich MS, Contreras F, Montoya A, Celorrio M, Rojo-Bustamante E, Riquelme E, González H, Vásquez M, Franco R, Pacheco R. Pharmacologic antagonism of dopamine receptor D3 attenuates neurodegeneration and motor impairment in a mouse model of Parkinson’s disease. Neuropharmacology 113(Pt A): 110-123. doi: 10.1016/j.neuropharm.2016.09.028 (2017)
In collaboration with Drs. Franco (University of Barcelona, Barcelona, Spain) and Aymerich (University of Navarra, Pamplona, Spain), we demonstrated that the inhibition of dopamine receptor D3 signaling in astrocytes exerts a therapeutic effect in Parkinson’s disease attenuating the progression of the neurodegenerative process.
Raquel Quatrini (Microbial Ecophysiology Lab):
- Quatrini R, Johnson DB. Microbiomes in extremely acidic environments: functionalities and interactions that allow survival and growth of prokaryotes at low pH. Curr Opin Microbiol 43: 139-147. doi: 10.1016/j.mib.2018.01.011 (2018)
In this review, we explore knowledge emerging from several recent ‘meta-omic’ studies on the microbial communities that occur in man-made and natural extremely acidic environments of interest for mining biotechnologies.
- Nuñez H, Moya-Beltrán A, Covarrubias PC, Issotta F, Cardenas JP, Gonzalez M, Atavales J, Acuña LG, Johnson DB, Quatrini R. Molecular systematics of the genus Acidithiobacillus: insights into the phylogenetic structure and diversification of the taxon. Front Microbiol 8:30. doi: 10.3389/fmicb.2017.00030 (2017)
The hierarchical relationships among members of the genus Acidithiobacillus, all of which are part of a single order and a single family, have remained poorly understood in the past. Using molecular systematics approaches and an extensive set of strains and sequence clones from diverse global locations, we have revised the inherent diversity of the taxon and reconstructed a robust genus-level phylogeny. Results obtained in this study support, at a much wider scale, the recognition of the acidithiobacilli as a species complex.
Álvaro Lladser (Immunoncology Lab):
- Gálvez-Cancino F, López E, Menares E, Díaz X, Flores C, Cáceres P, Hidalgo S, Chovar O, Alcántara-Hernández M, Borgna V, Varas-Godoy M, Salazar-Onfray F, Idoyaga J, Lladser A. Vaccination-induced skin-resident memory CD8+ T cells mediate strong protection against cutaneous melanoma. Oncoimmunology 7: e1442163. doi: 10.1080/2162402X.2018.1442163 (2018)
In this article, we described that vaccination generates a new type of memory cells that permanently reside in vaccinated tissues and protect against tumors. These cells called “tissue-resident memory T cells” have a great potential for novel immunotherapies.
- Reading J, Gálvez-Cancino F, Swanton C, Lladser A, Peggs K, Quezada S. The function and dysfunction of memory CD8+ T cells in tumor immunity. Immunol Rev 283(1): 194-212. doi: 10.1111/imr.12657 (2018)
In this review, we summarize the role of memory T cells in antitumor immunity and discuss how tumors can suppress the activity of these memory T cells.
Luis Burzio (Non-coding RNAs & Cancer Lab):
- Varas-Godoy M, Lladser A, Farfan N, Villota C, Villegas J, Tapia JC, Burzio LO, Burzio VA, Valenzuela PDT. In vivo knockdown of antisense non-coding mitochondrial RNAs by a lentiviral-encoded shRNA inhibits melanoma tumor growth and lung colonization. Pigment Cell Melanoma Res 31(1): 64-72 (2018)
In this work, we induced knockdown of the mouse ASncmtRNAs using lentiviral vectors. As observed previously, with antisense oligonucleotides, the treatment reduced tumorigenesis and metastasis of B16F10 murine melanoma cells both in vitro and in vivo.
- Borgna V, Villegas J, Burzio VA, Belmar S, Araya M, Jeldes E, Lobos-González L, Silva V, Villota C, Oliveira-Cruz L, Lopez C, Socias T, Castillo O, Burzio LO. Mitochondrial ASncmtRNA-1 and ASncmtRNA-2 as potent targets to inhibit tumor growth and metastasis in the RenCa murine renal adenocarcinoma model. Oncotarget 8(27): 43692-43708 (2017)
The mouse renal adenocarcinoma cell line, RenCa, was used for in vitro and in vivo knockdown of ASncmtRNA. The treatment induced a reduction of tumorigenic and invasive potential in vitro and both subcutaneous and orthotopic syngeneic in vivo models. In the former, we observed a drastic reduction of large tumors (up to 800 mm3).
- Lobos-González L, Silva V, Araya M, Restovic F, Echenique J, Oliveira-Cruz L, Fitzpatrick C, Briones M, Villegas J, Villota C, Vidaurre S, Borgna V, Socias M, Valenzuela S, Lopez C, Socias T, Varas M, Díaz J, Burzio LO, Burzio VA. Targeting antisense mitochondrial ncRNAs inhibits murine melanoma tumor growth and metastasis through reduction in survival and invasion factors. Oncotarget 7(36): 58331-58350 (2016)
Using the mouse melanoma cell line B16F10, we performed syngeneic pre-clinical assays by targeting ASncmtRNA with antisense oligonucleotides, where we observed a reduction in tumorigenic and invasive properties, in vitro and in vivo.
Soledad Matus (Biology of Neurodegeneration Lab):
- Bargsted L, Medinas DB, Martínez F, Rozas P, Muñoz N, Nassif M, Jerez C, Catenaccio A, Court F, Hetz C, Matus S. TDP-43 aggregation and loss of motoneurons in central nervous system of TDP-43 A315T ALS/FTD mouse model. Sci Rep 7:14266 (2017)
In this study, we characterized the course of the disease of a mouse carrying a mutation in an amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) associated gene. We showed that mutant TDP-43 transgenic mice develop key features resembling essential aspects of ALS, highlighting its relevance to study disease pathogenesis.
- Woehlbier U, Colombo A, Saaranen MJ, Pérez V, Ojeda J, Bustos FJ, Andreu CI, Torres M, Valenzuela V, Medinas DB, Rozas P, Vidal RL, Lopez-Gonzalez R, Salameh J, Fernandez-Collemann S, Muñoz N, Matus S, Armisen R, Sagredo A, Palma K, Irrazabal T, Almeida S, Gonzalez-Perez P, Campero M, Gao FB, Henny P, van Zundert B, Ruddock LW, Concha ML, Henriquez JP, Brown RH, Hetz C. ALS-linked protein disulfide isomerase variants cause motor dysfunction. EMBO J 35(8): 845-865 (2016)
Here, we functionally characterized four ALS-linked mutations in two major protein disulfide isomerases (PDIs) and endoplasmic reticulum (ER) foldases, recently described in ALS. Our in vivo, cellular and biochemical studies identified distinct molecular defects underlying the pathogenicity of these PDI mutants, reflecting ER proteostasis imbalance as a risk factor for ALS, driving initial stages of the disease.
- Matus S, Lopez E, Valenzuela V, Nassif M, Hetz C. Functional role of the transcription factor ATF4 in the pathogenesis of amyotrophic lateral sclerosis. PLoS One 8(7):e66672 (2013)
In this study, we investigated the contribution of a key integrated stress response (ISR) transcription factor, ATF4. ATF4 deficiency in an ALS mouse model led to delayed disease onset, prolonged life span and completely attenuated the induction of pro-apoptotic genes. Our results support a functional role of ATF4 in ALS, offering a novel target for disease intervention.
David Holmes (Bioinformatics and Genome Biology):
- Cardenas JP, Quatrini R, Holmes DS. The genomics of acidophiles. Chapter 11, pp 179-197 in Acidophiles, Eds Quatrini R and D. B. Johnson DB, Caister Academic Press, UK (2016)
This is an extensive and the most complete review of information derived from analyses of over 60 genomes of extreme acidophiles (organisms that grow at very low pH; pH<3). It presents key information that can be used as a springboard for future investigations in extreme acidophiles.
- Jorquera R, Ortiz R, Ossandon F, Cárdenas JP, Sepúlveda R, Holmes DS. SinEx DB: A database for single exon coding sequences in mammalian genomes. DataBase, baw095 doi:10.1093/database/baw095 (2016)
A surprising percentage of genes in mammalian genomes consist of single exon genes (SEGs) (i.e. genes without exons). This paper describes a publicly accessible database that can be mined for information about SEGs opening new avenues of research regarding their origin, evolution and predicted function.
- Valdés J, Pedroso I, Dodson RJ, Quatrini R, Tettelin H, Blake R, Eisen JA, Holmes DS. Acidithiobacillus ferrooxidans metabolism: from genome sequence to industrial applications. BMC Genomics 9:597 (2008)
This is a highly cited paper that illustrates how the genome of an extreme acidophile can be mined for information regarding its metabolism, genetics and evolution, and how these features can be linked to biotechnological applications.