José Carlos Montañés

Hospital Del Mar

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María-Dolors Piulachs

Pompeu Fabra University

M. Mar Albà

Hospital Del Mar

Guillem Ylla

Jagiellonian University

Juan C. Laguna

Universitat de Barcelona

Miguel Baena

Universitat de Barcelona

Gemma Sangüesa

Consorci Institut D'Investigacions Biomediques August Pi I Sunyer

José L. Maestro

Pompeu Fabra University

Núria Roglans

Universitat de Barcelona

Xavier Bellés

Institut de Biologia Evolutiva

Marta Alegret

Institute for Research in Biomedicine

Cooperative Institutions

Pompeu Fabra University

Hospital del Mar Research Institute

Hospital Del Mar

Universitat de Barcelona

Centre for Genomic Regulation

European Bioinformatics Institute

Municipal Institute for Medical Research

Centro de Investigación Biomédica en Red de Cáncer

Instituto de Salud Carlos III

Yale University

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Native RNA sequencing in fission yeast reveals frequent alternative splicing isoforms

Genome Research (2022)

José Carlos Montañés Marta Huertas Simone G. Moro William R. Blevins Mercè Carmona

The unicellular yeast Schizosaccharomyces pombe (fission yeast) retains many of the splicing features observed in humans and is thus an excellent model to study the basic mechanisms of splicing. Nearly half the genes contain introns, but the impact of alternative splicing in gene regulation and proteome diversification remains largely unexplored. Here we leverage Oxford Nanopore Technologies native RNA sequencing (dRNA), as well as ribosome profiling data, to uncover the full range of polyadenylated transcripts and translated open reading frames. We identify 332 alternative isoforms affecting the coding sequences of 262 different genes, 97 of which occur at frequencies >20%, indicating that functional alternative splicing in S. pombe is more prevalent than previously suspected. Intron retention events make ∼80% of the cases; these events may be involved in the regulation of gene expression and, in some cases, generate novel protein isoforms, as supported by ribosome profiling data in 18 of the intron retention isoforms. One example is the rpl22 gene, in which intron retention is associated with the translation of a protein of only 13 amino acids. We also find that lowly expressed transcripts tend to have longer poly(A) tails than highly expressed transcripts, highlighting an interdependence between poly(A) tail length and transcript expression level. Finally, we discover 214 novel transcripts that are not annotated, including 158 antisense transcripts, some of which also show translation evidence. The methodologies described in this work open new opportunities to study the regulation of splicing in a simple eukaryotic model.

Schizosaccharomyces

Proteome

Ribosome profiling

10.1101/gr.276516.121

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Citations (10)

GENCODE: massively expanding the lncRNA catalog through capture long-read RNA sequencing

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Gazaldeep Kaur Tamara Perteghella Sílvia Carbonell Sala José M. González Toby Hunt

Abstract Accurate and complete gene annotations are indispensable for understanding how genome sequences encode biological functions. For twenty years, the GENCODE consortium has developed reference annotations for the human and mouse genomes, becoming a foundation for biomedical and genomics communities worldwide. Nevertheless, collections of important yet poorly-understood gene classes like long non-coding RNAs (lncRNAs) remain incomplete and scattered across multiple, uncoordinated catalogs, slowing down progress in the field. To address these issues, GENCODE has undertaken the most comprehensive lncRNAs annotation effort to date. This is founded on the manual annotation of full-length targeted long-read sequencing, on matched embryonic and adult tissues, of orthologous regions in human and mouse. Altogether 17,931 novel human genes (140,268 novel transcripts) and 22,784 novel mouse genes (136,169 novel transcripts) have been added to the GENCODE catalog representing a 2-fold and 6-fold increase in transcripts, respectively - the greatest increase since the sequencing of the human genome. Novel gene annotations display evolutionary constraints, have well-formed promoter regions, and link to phenotype-associated genetic variants. They greatly enhance the functional interpretability of the human genome, as they help explain millions of previously-mapped “orphan” omics measurements corresponding to transcription start sites, chromatin modifications and transcription factor binding sites. Crucially, our targeted design assigned human-mouse orthologs at a rate beyond previous studies, tripling the number of human disease-associated lncRNAs with mouse orthologs. The expanded and enhanced GENCODE lncRNA annotations mark a critical step towards deciphering the human and mouse genomes.

Massive parallel sequencing

10.1101/2024.10.29.620654

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Blattella germanica piRNAs in materno-zygotic transition

José Carlos Montañés Natalia Llonga Xavier Bellés Josep Bau María-Dolors Piulachs

Poster presented at the Eight International Symposium on Molecular Insect Science, held 7-10th July 2019 in Barcelona (Spain).

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Evolutionary Trajectories of New Duplicated and Putative De Novo Genes

Molecular Biology and Evolution (2023)

José Carlos Montañés Marta Huertas Xavier Messeguer M. Mar Albà

Abstract The formation of new genes during evolution is an important motor of functional innovation, but the rate at which new genes originate and the likelihood that they persist over longer evolutionary periods are still poorly understood questions. Two important mechanisms by which new genes arise are gene duplication and de novo formation from a previously noncoding sequence. Does the mechanism of formation influence the evolutionary trajectories of the genes? Proteins arisen by gene duplication retain the sequence and structural properties of the parental protein, and thus they may be relatively stable. Instead, de novo originated proteins are often species specific and thought to be more evolutionary labile. Despite these differences, here we show that both types of genes share a number of similarities, including low sequence constraints in their initial evolutionary phases, high turnover rates at the species level, and comparable persistence rates in deeper branchers, in both yeast and flies. In addition, we show that putative de novo proteins have an excess of substitutions between charged amino acids compared with the neutral expectation, which is reflected in the rapid loss of their initial highly basic character. The study supports high evolutionary dynamics of different kinds of new genes at the species level, in sharp contrast with the stability observed at later stages.

Rate of evolution

Sequence (biology)

Molecular evolution

10.1093/molbev/msad098

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Citations (14)

siRNA enrichment in Argonaute 2-depleted Blattella germanica

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms (2021)

José Carlos Montañés Carlos Rojano-Alfonso Guillem Ylla María-Dolors Piulachs José L. Maestro

RNA interference (RNAi) is a cellular mechanism used to fight various threats, including transposons, aberrant RNAs, and some types of viruses. This mechanism relies on the detection of dsRNA molecules, which through a pathway involving Dicer-2 (Dcr-2) and Argonaute 2 (AGO2), produces small interfering RNAs (siRNAs) that bind to the complementary RNAs triggering their degradation.Using the cockroach Blattella germanica as a model, we examined AGO2 activity by depleting its mRNA using RNAi and analyzing the phenotypes produced.Depleting AGO2 expression had no remarkable effect on nymphal development or reproduction. dsRNA treatment triggered an immediate and transitory increase in AGO2 expression, independently of Dcr-2 action. In addition, we analyzed the siRNAs generated after injecting a heterologous dsRNA in control and AGO2-depleted animals. The results revealed that obtained siRNAs mapped non-uniformly along the dsRNA sequence. In AGO2-depleted animals, the proportion of 22 nucleotide reads was higher and accumulations of reads appeared in areas less well-represented in the controls. We also detected a preference for cytosine as the first nucleotide in controls that was significantly attenuated in AGO2-depleted individuals.The siRNAs produced from a dsRNA mapped heterogeneously along the length of the dsRNA and this arrangement depends on the dsRNA sequence. AGO2 exerts its role as nuclease on the siRNA duplexes independently of its action on the corresponding mRNA. This study sheds light on an extremely useful process for reverse genetics in laboratories, in addition to the design of more effective, specific, and eco-friendly pest-control strategies.

Argonaute

Dicer

RNA Silencing

Trans-acting siRNA

Ribonuclease III

10.1016/j.bbagrm.2021.194704

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Chronic Liquid Fructose, but not Glucose, Supplementation Selectively Induces Visceral Adipose Tissue Leptin Resistance and Hypertrophy in Female Sprague‐Dawley Rats

Molecular Nutrition & Food Research (2018)

Gemma Sangüesa Núria Roglans José Carlos Montañés Miguel Baena Ana Magdalena Velázquez

The effect of chronic supplementation with simple-sugar solutions on leptin signaling in liver, hypothalamus, and visceral white adipose tissue (vWAT) is studied, which is designed to mimic the temporal pattern of consumption by humans.Solutions of fructose or glucose are isocalorically supplemented (7 months) in female Sprague-Dawley rats consuming ad libitum rodent chow. After sacrifice, plasma and tissue samples (liver, hypothalamus, and vWAT) are collected. Zoometric parameters, plasma analytes, and the tissue expression and activity of markers of leptin signaling are determined by biochemical and molecular biological methods. The two sugars cause different types of adiposopathy. Both sugars induce increases in plasma nonesterified fatty acids, and leptin resistance in the liver and the hypothalamus. Only fructose-supplemented rats show hyperleptinemia, and increased body weight due to a hypertrophy of vWAT, with no signs of leptin-mediated lipolysis. Glucose-supplemented rats show no significant changes in these parameters but present elevated plasma adiponectin concentrations, lipolysis, and inflammatory markers in vWAT, indicating a shift to a nonexpandable adipose tissue phenotype.Chronic consumption of fructose places a greater burden on metabolic homeostasis than equivalent consumption of glucose, inducing hyperleptinemia, generalized leptin resistance, and increased body weight due to expanded, hypertrophic vWAT.

10.1002/mnfr.201800777

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Citations (20)

High polymorphism levels of de novo ORFs in a Yoruba human population

Genome Biology and Evolution (2024)

Covadonga Vara José Carlos Montañés M. Mar Albà

During evolution, new open reading frames (ORFs) with the potential to give rise to novel proteins continuously emerge. A recent compilation of noncanonical ORFs with translation signatures in humans has identified thousands of cases with a putative de novo origin. However, it is not known which is their distribution in the population. Are they universally translated? Here, we use ribosome profiling data from 65 lymphoblastoid cell lines from individuals of Yoruba origin to investigate this question. We identify 2,587 de novo ORFs translated in at least one of the cell lines. In line with their de novo origin, the encoded proteins tend to be smaller than 100 amino acids and encode positively charged proteins. We observe that the de novo ORFs are more polymorphic in the population than the set of canonical proteins, with a substantial fraction of them being translated in only some of the cell lines. Remarkably, this difference remains significant after controlling for differences in the translation levels. These results suggest that variations in the level translation of de novo ORFs could be a relevant source of intraspecies phenotypic diversity in humans.

ORFS

Ribosome profiling

10.1093/gbe/evae126

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siRNA enrichment in Argonaute 2-depleted Blattella germanica

bioRxiv (Cold Spring Harbor Laboratory) (2021)

José Carlos Montañés Carlos Rojano-Alfonso Guillem Ylla María-Dolors Piulachs José L. Maestro

ABSTRACT Background RNA interference (RNAi) is a cellular mechanism used to fight various threats, including transposons, aberrant RNA, and some types of viruses. It relies on dsRNA detection and, through a mechanism involving Dicer-2 (Dcr-2) and Argonaute 2 (AGO2), together with a small RNA fragment (siRNA) as a complementary guide, binds to an RNA and cleaves it. Methods Using the cockroach Blattella germanica as a model, we examined AGO2 activity by depleting its mRNA levels using RNAi and analyzing the phenotypes produced. Results Silencing AGO2 expression had no remarkable effect on nymphal development or reproduction. dsRNA treatment triggered an immediate and transitory increase in AGO2 expression, independently of Dcr-2 action. In addition, we analyzed the siRNAs generated after injecting a heterologous dsRNA in control and AGO2 -depleted animals. The results revealed that siRNAs were distributed non-uniformly along the dsRNA sequence. In AGO2 -depleted animals, the proportion of 22 nucleotide reads was higher and accumulations of reads appeared in areas less well-represented in the controls. We also detected a slight preference for cytosine as the first nucleotide in controls to be lost in AGO2 -depleted individuals. Conclusions/General significance The siRNAs produced from a dsRNA are heterogeneously distributed along the length of the dsRNA and this arrangement depends on the sequence. AGO2 exerts its role as nuclease on the siRNA duplexes independently of its action on the homologous mRNA. This study sheds light on an extremely useful process for reverse genetics in laboratories, in addition to the design of more effective, specific, and eco-friendly pest-control strategies. Highlights - RNA interference is used to fight cellular threats including transposons and viruses - Silencing AGO2 in Blattella germanica does not affect development or reproduction - siRNA distribution along the dsRNA sequence is non-uniform and sequence dependent - AGO2 depletion increased the proportion of 22 nt reads in certain areas

Argonaute

RNA Silencing

Dicer

Trans-acting siRNA

10.1101/2021.02.11.430758

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DNA methylation in cockroaches is essential in early embryo development and reduces gene expression noise

bioRxiv (Cold Spring Harbor Laboratory) (2020)

Alba Ventós-Alfonso Guillem Ylla José Carlos Montañés Xavier Bellés

Abstract The influence of DNA methylation on gene behavior, and its consequent phenotypic effects appear to be very important, but the details are not well understood. Insects offer a diversity of DNA methylation modes, making them an excellent lineage for comparative analyses. However, functional studies have tended to focus on quite specialized holometabolan species, such as wasps, bees, beetles, and flies. Here we have studied DNA methylation in a hemimetabolan insect, the cockroach Blattella germanica , a model of early-branching insects. In this cockroach, one of the main genes responsible for DNA methylation, DNA methyltransferase 1 ( DNMT1 ), is expressed in early embryogenesis. In our experiments, DNMT1 interference by RNAi reduces DNA methylation and impairs blastoderm formation. Using Reduced Representation Bisulfite Sequencing (RRBS) and transcriptomic analyses, we observed that hypermethylated genes are associated with metabolism and are highly expressed, whereas hypomethylated genes are related to signaling and have low expression levels. Moreover, the expression change in hypermethylated genes is greter than that in hypomethylated genes, whereas hypermethylated genes have less expression variability than hypomethylated genes. The latter observation has also been reported for humans and in Arabidopsis plants. A reduction in expression noise may therefore be one of the few universal effects of DNA methylation.

RNA-Directed DNA Methylation

Bisulfite sequencing

DNMT1

DNA methyltransferase

10.1101/2020.08.26.267906

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Citations (2)

LCOR mediates interferon-independent tumor immunogenicity and responsiveness to immune-checkpoint blockade in triple-negative breast cancer

Nature Cancer (2022)

Iván Pérez-Núñez Catalina Rozalén José Ángel Palomeque Irene Sangrador Mariona Dalmau Montalà

Triple-negative breast cancer

Immune checkpoint

Corepressor

10.1038/s43018-022-00339-4

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Citations (39)