A5061029876- RNA Research and Splicing
- RNA modifications and cancer
- RNA and protein synthesis mechanisms
- Histone Deacetylase Inhibitors Research
- Lung Cancer Treatments and Mutations
- Cancer-related gene regulation
- Proteoglycans and glycosaminoglycans research
- Peptidase Inhibition and Analysis
- Cell Adhesion Molecules Research
- RNA Interference and Gene Delivery
- Glycosylation and Glycoproteins Research
- Protein Degradation and Inhibitors
- Cancer-related molecular mechanisms research
- CRISPR and Genetic Engineering
- Substance Abuse Treatment and Outcomes
- RNA regulation and disease
- Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Genomics and Chromatin Dynamics
- Cannabis and Cannabinoid Research
- Pluripotent Stem Cells Research
- Trypanosoma species research and implications
- Neurogenetic and Muscular Disorders Research
- interferon and immune responses
- Chronic Myeloid Leukemia Treatments
- Malaria Research and Control
Nanyang Technological University
2016-2025
Hospital de Sant Pau
2022-2024
Cold Spring Harbor Laboratory
2003-2012
Universitat de Barcelona
1991-2010
Hospital Universitari Germans Trias i Pujol
1996-2009
Universitat Autònoma de Barcelona
1996-2009
Fundació Salut i Envelliment UAB
2007
Hospital de l'Esperança
1998
Johns Hopkins University
1998
University of Chicago
1998
We have collected over half a million splice sites from five species—Homo sapiens, Mus musculus, Drosophila melanogaster, Caenorhabditis elegans and Arabidopsis thaliana—and classified them into four subtypes: U2-type GT–AG GC–AG U12-type AT–AC. also found new examples of rare splice-site categories, such as introns without canonical borders, U2-dependent AT–AC introns. The sequences several tools to explore are available on public website (SpliceRack). For the introns, we find features...
Mice lacking desmin produce muscle fibers with Z disks and normal sarcomeric organization. However, the muscles are mechanically fragile degenerate upon repeated contractions. We report here a human patient severe generalized myopathy aberrant intrasarcoplasmic accumulation of intermediate filaments. Muscle tissue from this lacks wild-type allele has gene mutation encoding 7-aa deletion within coiled-coil segment protein. show that recombinant harboring cannot form proper filament networks...
Abstract N 6-methylation of 2′-O-methyladenosine (Am) in RNA occurs eukaryotic cells to generate N6,2′-O-dimethyladenosine (m6Am). Identification the methyltransferase responsible for m6Am catalysis has accelerated studies on function processing. While is generally found first transcribed nucleotide mRNAs, modification also internally within U2 snRNA. However, writer required catalyzing internal formation had remained elusive. By sequencing transcriptome-wide methylation at...
Abstract SRRM2 is a nuclear-speckle marker containing multiple disordered domains, whose dysfunction associated with several human diseases. Using mainly EGFP-SRRM2 knock-in HEK293T cells, we show that forms biomolecular condensates satisfying most hallmarks of liquid-liquid phase separation, including spherical shape, dynamic rearrangement, coalescence and concentration dependence supported by in vitro experiments. Live-cell imaging shows organizes nuclear speckles along the cell cycle. As...
Most mammalian genes generate messenger RNAs with variable untranslated regions (UTRs) that are important post-transcriptional regulators. In cancer, shortening at 3' UTR ends via alternative polyadenylation can activate oncogenes. However, internal splicing remains poorly understood as studies have traditionally focused on protein-coding alterations. Here we systematically map the pan-cancer landscape of and present this in SpUR ( http://www.cbrc.kaust.edu.sa/spur/home/ ). is widespread,...
Cryptic splice sites are used only when use of a natural site is disrupted by mutation. To determine the features that distinguish authentic from cryptic 5' (5'ss), we systematically analyzed set 76 5'ss derived 46 human genes. These have similar frequency distribution in exons and introns, usually located close to 5'ss. Statistical analysis strengths using Shapiro Senapathy matrix revealed significantly higher score values than 5'ss, which turn mutant ones. beta-Globin provides an...
We previously showed that the authentic 5′ splice site (5′ss) of first exon in human β-globin gene is intrinsically stronger than a cryptic 5′ss located 16 nucleotides upstream. Here we examined by mutational analysis contribution individual to discrimination between these two 5′ss. Based on vitro splicing efficiencies panel 26 wild-type and mutant substrates separate competition assays, established hierarchy grouped them into three functional subclasses: strong, intermediate, weak....
We describe 94 pathogenic NF1 gene alterations in a cohort of 97 Austrian neurofibromatosis type 1 patients meeting the NIH criteria. All mutations were fully characterized at genomic and mRNA levels. Over half carried novel mutations, only quarter recurrent minor-lesion 16 mutational warm spots. The remaining microdeletions (7%) rare recurring mutations. Thirty-six (38%) altered pre-mRNA splicing, fall into five groups: exon skipping resulting from authentic splice sites (type I), cryptic...
An established paradigm in pre-mRNA splicing is the recognition of 5′ splice site (5′ss) by canonical base-pairing to end U1 small nuclear RNA (snRNA). We recently reported that a subset 5′ss base-pair an alternate register shifted 1 nucleotide. Using genetic suppression experiments human cells, we now demonstrate many other are recognized via noncanonical registers involving bulged nucleotides on either or strand, which term “bulge registers.” By combining experimental evidence with...
Abstract Purpose: The BIM deletion polymorphism is associated with apoptosis resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI), such as gefitinib and erlotinib, in non–small cell lung cancer (NSCLC) harboring mutations. Here, we investigated whether the contributes against osimertinib, a third-generation EGFR-TKI. In addition, determined efficacy of histone deacetylase (HDAC) inhibitor, vorinostat, this form elucidated underlying mechanism. Experimental Design: We used EGFR-mutated...
We report the detailed transcriptomic profiles of human innate myeloid cells using RNA sequencing. Monocytes migrate from blood into infected or wounded tissue to differentiate macrophages, and control inflammation via phagocytosis cytokine secretion. differentiated culture primary monocytes with either GM- M-CSF obtain pro- anti-inflammatory respectively activated them LPS/IFNγ cytokines. also treated THP-1 monocytic cell line PMA similar cytokines mimic differentiation activation. detected...
Many human diseases, including Fanconi anemia, hemophilia B, neurofibromatosis, and phenylketonuria, can be caused by 5′-splice-site (5′ss) mutations that are not predicted to disrupt splicing, according position weight matrices. By using comparative genomics, we identify pairwise dependencies between 5′ss nucleotides as a conserved feature of the entire set 5′ss. These also in human–mouse pairs orthologous disease-associated these dependencies, some SNPs appear alter splicing. The...
The differentiation of human pluripotent stem cells into pancreatic involves cellular proliferation and apoptosis during cell fate transitions. However, their implications for establishing identity are unclear. Here, we profiled the expression BCL-2 family proteins specification observed an upregulation BCL-xL, downregulation BAK corresponding cleaved CASP3 representative apoptosis. Experimental inhibition BCL-xL reciprocally increased resulted in a decreased gene markers despite...
Accurate recognition of splice sites is essential for pre-messenger RNA splicing. Mammalian 5′ are mainly recognized by canonical base-pairing to the end U1 small nuclear RNA, yet we described multiple noncanonical registers shifting base-pair positions or allowing one-nucleotide bulges. By systematic mutational and suppressor analyses, prove three involving asymmetric loops show that two-nucleotide bulges but not longer can form in this context. Importantly, established a...
Alternative splicing contributes to complex traits, but whether this differs in trait-relevant cell types across diverse genetic ancestries is unclear. Here we describe cell-type-specific, sex-biased and ancestry-biased alternative ~1 M peripheral blood mononuclear cells from 474 healthy donors the Asian Immune Diversity Atlas. We identify widespread differential splicing, most of which cell-type-specific. 11,577 independent cis-splicing quantitative trait loci (sQTLs), 607 trans-sGenes 107...
Apolipoprotein B (APOB) is an integral part of the LDL, VLDL, IDL, Lp(a) and chylomicron lipoprotein particles. The APOB pre-mRNA consists 29 constitutively-spliced exons. exists as two natural isoforms: full-length APOB100 isoform, assembled into IDL secreted by liver in humans; C-terminally truncated APOB48, chylomicrons intestine humans. Down-regulation a potential therapy to lower circulating LDL cholesterol levels.We investigated ability 2'O-methyl RNA antisense oligonucleotides (ASOs)...
Aberrant changes in the expression of pro-apoptotic protein, BCL-2-like 11 (BIM), can result either impaired or excessive apoptosis, which contribute to tumorigenesis and degenerative disorders, respectively. Altering BIM pre-mRNA splicing is an attractive approach modulate apoptosis because activity partly determined by alternative exons 3 4, whereby exon 3-containing transcripts are not apoptotic. Here we identified several cis-acting elements factors involved splicing, as a step better...
Many tyrosine kinase-driven cancers, including chronic myeloid leukemia (CML), are characterized by high response rates to specific kinase inhibitors (TKIs) like imatinib. In East Asians, primary imatinib resistance is caused a deletion polymorphism in Intron 2 of the BIM gene, whose product required for TKI-induced apoptosis. The biases splicing from exon 4 3, generating splice isoforms lacking 4-encoded pro-apoptotic BH3 domain, which impairs ability TKIs induce We sought identify...
Alternative splicing of tau pre-mRNA is regulated by a 5' splice site (5'ss) hairpin present at the exon 10-intron 10 junction. Single mutations within sequence alter structural stability and/or binding factors, resulting in disease-causing aberrant 10. The structure contains about seven stably formed base pairs and thus may be suitable for targeting through antisense strands. Here, we used peptide nucleic acids (asPNAs) to probe target 5'ss strand invasion. We characterized electrophoretic...