DSpace Angular :: Browsing by Author "Montecino, Martín"

Browsing by Author "Montecino, Martín"

Now showing 1 - 4 of 4

BET bromodomain inhibitors PFI-1 and JQ1 are identified in an epigenetic compound screen to enhance C9ORF72 gene expression and shown to ameliorate C9ORF72-associated pathological and behavioral abnormalities in a C9ALS/FTD model
(2021) Quezada, Esteban; Cappelli, Claudio; Díaz, Iván; Jury, Nur; Wightman, Nicholas; Brown Jr., Robert H.; Montecino, Martín; Zundert, Brigitte van
Abstract Background An intronic GGGGCC (G4C2) hexanucleotide repeat expansion (HRE) in the C9ORF72 gene is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), referred to as C9ALS/FTD. No cure or effective treatment exist for C9ALS/FTD. Three major molecular mechanisms have emerged to explain C9ALS/FTD disease mechanisms: (1) C9ORF72 loss-of-function through haploinsufficiency, (2) dipeptide repeat (DPR) proteins mediated toxicity by the translation of the repeat RNAs, and more controversial, (3) RNA-mediated toxicity by bidirectional transcription of the repeats that form intranuclear RNA foci. Recent studies indicate a double-hit pathogenic mechanism in C9ALS/FTD, where reduced C9ORF72 protein levels lead to impaired clearance of toxic DPRs. Here we explored whether pharmacological compounds can revert these pathological hallmarks in vitro and cognitive impairment in a C9ALS/FTD mouse model (C9BAC). We specifically focused our study on small molecule inhibitors targeting chromatin-regulating proteins (epidrugs) with the goal of increasing C9ORF72 gene expression and reduce toxic DPRs. Results We generated luciferase reporter cell lines containing 10 (control) or ≥ 90 (mutant) G4C2 HRE located between exon 1a and 1b of the human C9ORF72 gene. In a screen of 14 different epidrugs targeting bromodomains, chromodomains and histone-modifying enzymes, we found that several bromodomain and extra-terminal domain (BET) inhibitors (BETi), including PFI-1 and JQ1, increased luciferase reporter activity. Using primary cortical cultures from C9BAC mice, we further found that PFI-1 treatment increased the expression of V1-V3 transcripts of the human mutant C9ORF72 gene, reduced poly(GP)-DPR inclusions but enhanced intranuclear RNA foci. We also tested whether JQ1, an BETi previously shown to reach the mouse brain by intraperitoneal (i.p.) injection, can revert behavioral abnormalities in C9BAC mice. Interestingly, it was found that JQ1 administration (daily i.p. administration for 7 days) rescued hippocampal-dependent cognitive deficits in C9BAC mice. Conclusions Our findings place BET bromodomain inhibitors as a potential therapy for C9ALS/FTD by ameliorating C9ORF72-associated pathological and behavioral abnormalities. Our finding that PFI-1 increases accumulation of intranuclear RNA foci is in agreement with recent data in flies suggesting that nuclear RNA foci can be neuroprotective by sequestering repeat transcripts that result in toxic DPRs.
DNA sequencing in the classroom: complete genome sequence of two earwig (Dermaptera; Insecta) species
(2023) Kobayashi, Sanae; Maldonado, Jonathan E.; Gaete, Alexis; Araya, Ingrid; Aguado-Norese, Constanza; Cumplido, Nicolás; Díaz, Sebastián; Espinoza, Alonso; Fernández, Edelmira; Gajardo, Felipe; González-Ordenes, Felipe; Hauyon, Khantati; Maldonado, Piedad; Maldonado, Rodrigo; Pochet, Isabel; Riveros, Aníbal; Sandoval, Paula; Sepúlveda-González, Ailynne; Stuardo, Camila; Tapia-Reyes, Patricio; Thornton, Carolina; Undurraga, Soledad; Varas, Macarena; Valdivieso, Camilo; Gutiérrez Ilabaca, Rodrigo Antonio; Orellana, Ariel; Montecino, Martín; Maass, Alejandro; González, Mauricio; Allende, Miguel L.; Hodar, Christian; Irles, Paula
Background Despite representing the largest fraction of animal life, the number of insect species whose genome has been sequenced is barely in the hundreds. The order Dermaptera (the earwigs) suffers from a lack of genomic information despite its unique position as one of the basally derived insect groups and its importance in agroecosystems. As part of a national educational and outreach program in genomics, a plan was formulated to engage the participation of high school students in a genome sequencing project. Students from twelve schools across Chile were instructed to capture earwig specimens in their geographical area, to identify them and to provide material for genome sequencing to be carried out by themselves in their schools. Results The school students collected specimens from two cosmopolitan earwig species: Euborellia annulipes (Fam. Anisolabididae) and Forficula auricularia (Fam. Forficulidae). Genomic DNA was extracted and, with the help of scientific teams that traveled to the schools, was sequenced using nanopore sequencers. The sequence data obtained for both species was assembled and annotated. We obtained genome sizes of 1.18 Gb (F. auricularia) and 0.94 Gb (E. annulipes) with the number of predicted protein coding genes being 31,800 and 40,000, respectively. Our analysis showed that we were able to capture a high percentage (≥ 93%) of conserved proteins indicating genomes that are useful for comparative and functional analysis. We were also able to characterize structural elements such as repetitive sequences and non-coding RNA genes. Finally, functional categories of genes that are overrepresented in each species suggest important differences in the process underlying the formation of germ cells, and modes of reproduction between them, features that are one of the distinguishing biological properties that characterize these two distant families of Dermaptera. Conclusions This work represents an unprecedented instance where the scientific and lay community have come together to collaborate in a genome sequencing project. The versatility and accessibility of nanopore sequencers was key to the success of the initiative. We were able to obtain full genome sequences of two important and widely distributed species of insects which had not been analyzed at this level previously. The data made available by the project should illuminate future studies on the Dermaptera.
Mitotic Inheritance of mRNA Facilitates Translational Activation of the Osteogenic-Lineage Commitment Factor Runx2 in Progeny of Osteoblastic Cells
(2016) Varela Figueroa, Nelson; Aránguiz Quezada, Katherine Alejandra; Lizama, Carlos; Sepúlveda, Hugo; Antonelli Anativia, Juan; Thaler, Román; Moreno Mauro, Ricardo D.; Montecino, Martín; Stein, Gary S.; Van Wijnen, Andre; Galindo Díaz, Mario
Prenatal Stress Down-Regulates Reelin Expression by Methylation of Its Promoter and Induces Adult Behavioral Impairments in Rats
(2015) Palacios García, Ismael José; Lara Vásquez, Ariel Fernando; Montiel, Juan F.; Díaz Véliz, Gabriela F.; Sepúlveda, Hugo; Utreras, Elías; Montecino, Martín; González Billault, Christian; Aboitiz, Francisco

Browsing by Author "Montecino, Martín"

Results Per Page

Sort Options