Ricky Joshi | Universitat de Barcelona (original) (raw)

Papers by Ricky Joshi

(A) After selecting one CpG per VMR with the highest variance, we app... more (A) After selecting one CpG per VMR with the highest variance, we applied WGCNA to identify networks of significantly co-regulated VMRs. The Circos plot shows a representation of one of the largest co-regulated VMR modules identified in fibroblasts, which comprises 34 independent VMRs located on four different chromosomes, comprising all four clusters of HOX genes (outer circle). CpGs within VMRs in the co-regulated module are represented by blue tick marks (inner grey circle), with black lines joining VMRs that have methylation levels with pair wise absolute correlation values R≥0.7 (highlighted in yellow). Green bars show locations of genes at each locus. Blue bars show the location of transcription factor binding sites for SUZ12, EZH2 and CTBP2, all of which are significantly enriched within this co-regulated module. (B) Analysis of transcription factor binding sites defined using ChIP-seq [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1007707#pgen.1007707.ref064" target="_blank">64</a>] showed that VMRs within the co-regulated HOX gene module shown in (A) are significantly enriched for SUZ12, EZH2 and CTBP2 binding compared to all VMRs defined in fibroblasts (Bonferroni corrected p = 5.3x10-11, p = 1.5x10-9 and p = 5x10-5, respectively). Thus, binding of these TFs represents a potential mechanism by which epigenetic variation could be coordinated at multiple independent loci in trans. (C) Results of Gene Ontology (GO) analysis of genes associated with VMRs in the most significant co-regulated module identified in fibroblasts. We identified highly significant enrichments for multiple biological processes, including body patterning, growth and morphogenesis (<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1007707#pgen.1007707.s011" target="_blank">S5 Table</a>).</p

The top three Gene Ontology terms associated with co-regulated VMR modules found in each... more The top three Gene Ontology terms associated with co-regulated VMR modules found in each cell type.</p

Top 5 transcription factor binding sites overlapping with VMRs in various WGCNA modules ... more Top 5 transcription factor binding sites overlapping with VMRs in various WGCNA modules in 5 cell types.</p

Cell Reports

Highlights d Facial recognition algorithms identify ''look-alike'' humans for multiomics studies ... more Highlights d Facial recognition algorithms identify ''look-alike'' humans for multiomics studies d Intrapair look-alikes share common genetic sequences such as face trait variants d DNA methylation and microbiome profiles only contribute modestly to human likeness d The identified SNPs impact physical and behavioral phenotypes beyond facial features

(A) To directly assess the effect of varying environmental conditions... more (A) To directly assess the effect of varying environmental conditions on epigenetic state, we grew genetically-identical fibroblasts under conditions of varying cell density and culture media replenishment. Cells from a single human fibroblast line were seeded in parallel at low density in ten culture flasks, and allowed to grow continuously for up to 10 days, either with or without regular change of media. Every 48 hours one flask was harvested and genome-wide DNA methylation patterns profiled. (B) Applying a sliding window approach identified 135 VMRs where methylation levels showed robust changes with varying culture conditions, including loci at HOX genes and multiple imprinted loci. Gene ontology analysis of VMRs induced by cell culture showed enrichments for fundamental control of growth, including similar GO categories to the co-methylated network identified in fibroblasts from the Gencord cohort (<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1007707#pgen.1007707.s015" target="_blank">S9 Table</a>). (C) Environmentally-responsive VMRs induced by cell culture showed a 35-fold enrichment for probes within the differentially methylated regions associated with seven different imprinted genes (p = 5.6x10-79). The left plot shows methylation profiles at the imprinted region of GNAS, which was also identified as a VMR in cultured fibroblasts. Each line shows the methylation profile at a different time point, with lighter shades of grey with increasing time. The right plot shows the change in methylation level with time at a single CpG (cg09885502) within the GNAS VMR.</p

CpGs on both axes are ordered by genomic position, revealing the presence of multiple VM... more CpGs on both axes are ordered by genomic position, revealing the presence of multiple VMRs located on different chromosomes that show highly correlated methylation levels in trans. Black bars (right and top) show the location of the HOXA (chr7), HOXB (chr17), HOXC (chr12) and HOXD (chr2) gene clusters, which correspond to some of the strongest regions of correlated methylation in both cis and trans. This observation suggests coordinated epigenetic regulation among loci distributed genome-wide.</p

(A) While some VMRs are common to multiple different cell types, in c... more (A) While some VMRs are common to multiple different cell types, in contrast, other VMRs identified in one cell type show minimal epigenetic variation in other tissues. (B) Venn diagram showing the degree of overlap for VMRs found in B-cells, T-cells, Fibroblasts, Neurons and Glia.</p

Positional dependence of transcriptional inhibition by DNA torsional stress in yeast chromosomes ... more Positional dependence of transcriptional inhibition by DNA torsional stress in yeast chromosomes This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits distribution, and reproduction in any medium, provided the original author and source are credited. This license does not permit commercial exploitation without specific permission.

Protein Phosphatase Enzymes (PPE) and protein kinases simultaneously control phosphorylation mech... more Protein Phosphatase Enzymes (PPE) and protein kinases simultaneously control phosphorylation mechanisms that tightly regulate intracellular signaling pathways and stimulate cellular responses. In human malignancies, PPE and protein kinases are frequently mutated resulting in uncontrolled kinase activity and PPE suppression, leading to cell proliferation, migration and resistance to anti-cancer therapies. Cancer associated DNA hypermethylation at PPE promoters gives rise to transcriptional silencing (epimutations) and is a hallmark of cancer. Despite recent advances in sequencing technologies, data availability and computational capabilities, only a fraction of PPE have been reported as transcriptionally inactive as a consequence of epimutations. Using the Infinium HumanMethylation450 BeadChip, we compared DNA methylation profiles from 705 cancer patients across 5 major tissues and 3 cancer cell models against a cohort of healthy controls. Here, we report epimutations in PPE (and the...

Hereditary hemochromatosis type 3, iron overload, missense, nonsense, p.Gly792Arg, splicing mutat... more Hereditary hemochromatosis type 3, iron overload, missense, nonsense, p.Gly792Arg, splicing mutation, TFR2 gene

American journal of human genetics, Sep 24, 2016

Genomic imprinting is a mechanism in which gene expression varies depending on parental origin. I... more Genomic imprinting is a mechanism in which gene expression varies depending on parental origin. Imprinting occurs through differential epigenetic marks on the two parental alleles, with most imprinted loci marked by the presence of differentially methylated regions (DMRs). To identify sites of parental epigenetic bias, here we have profiled DNA methylation patterns in a cohort of 57 individuals with uniparental disomy (UPD) for 19 different chromosomes, defining imprinted DMRs as sites where the maternal and paternal methylation levels diverge significantly from the biparental mean. Using this approach we identified 77 DMRs, including nearly all those described in previous studies, in addition to 34 DMRs not previously reported. These include a DMR at TUBGCP5 within the recurrent 15q11.2 microdeletion region, suggesting potential parent-of-origin effects associated with this genomic disorder. We also observed a modest parental bias in DNA methylation levels at every CpG analyzed acr...

Nucleic Acids Research, 2016

Despite representing an important source of genetic variation, tandem repeats (TRs) remain poorly... more Despite representing an important source of genetic variation, tandem repeats (TRs) remain poorly studied due to technical difficulties. We hypothesized that TRs can operate as expression (eQTLs) and methylation (mQTLs) quantitative trait loci. To test this we analyzed the effect of variation at 4849 promoterassociated TRs, genotyped in 120 individuals, on neighboring gene expression and DNA methylation. Polymorphic promoter TRs were associated with increased variance in local gene expression and DNA methylation, suggesting functional consequences related to TR variation. We identified >100 TRs associated with expression/methylation levels of adjacent genes. These potential eQTL/mQTL TRs were enriched for overlaps with transcription factor binding and DNaseI hypersensitivity sites, providing a rationale for their effects. Moreover, we showed that most TR variants are poorly tagged by nearby single nucleotide polymorphisms (SNPs) markers, indicating that many functional TR variants are not effectively assayed by SNP-based approaches. Our study assigns biological significance to TR variations in the human genome, and suggests that a significant fraction of TR variations exert functional effects via alterations of local gene expression or epigenetics. We conclude that targeted studies that focus on geno-typing TR variants are required to fully ascertain functional variation in the genome.

Molecular Genetics & Genomic Medicine, 2015

Anti-Cancer Drugs, 2005

In the present study, we describe the cytotoxicity of the new drug prodigiosin (PG) in two small ... more In the present study, we describe the cytotoxicity of the new drug prodigiosin (PG) in two small cell lung carcinoma (SCLC) cell lines, GLC4 and its derived doxorubicin-resistant GLC4/ADR cell line, which overexpresses multidrug-related protein 1 (MRP-1). We observed through Western blot that PG mediated cytochrome c release, caspase cascade activation and PARP cleavage, thereby leading to apoptosis in a dose-response manner. MRP-1 expression increased after PG treatment, although that does not lead to protein accumulation. The MTT assay showed no difference in sensitivity to PG between the two cell lines. Our results support PG as a potential drug for the treatment of lung cancer as it overcomes the multidrug resistance phenotype produced by MRP-1 overexpression.

Nucleic Acids Research, 2012

Trabajo presentado en el EMBO Workshop: DNA topoisomerases and DNA topology, celebrado en Les Dia... more Trabajo presentado en el EMBO Workshop: DNA topoisomerases and DNA topology, celebrado en Les Diablerets (Suiza), del 17 al 21 de septiembre de 2017

Durante la transcripcion del ADN, se acumula tension helicoidal positiva (+) en el frente de avan... more Durante la transcripcion del ADN, se acumula tension helicoidal positiva (+) en el frente de avance de la maquinaria transcripcional y tension helicoidal negativa (-) detras. En la replicacion, hay tambien una produccion de tension helicoidal positiva en el frente de avance de la horquilla de replicacion. Las topoisomerasas de ADN son enzimas que producen cortes transitorios en una o en las dos cadenas del ADN duplex, para resolver encademientos y para modular la tension helicoidal del ADN. Topo I y Topo II relajan la tension helicoidal positiva (+) y negativa (-). En esta tesis, me propongo estudiar el efecto de las dosis alteradas de estas dos enzimas en el transcriptoma de Saccharomyces cerevisiae a traves de la tecnologia de microarrays de ADN. En el transcurso del trabajo, se observo que las topoisomerases no fueron capaces de compensar la una la deficiencia de la otra al nivel de ARNm, en celulas con un desequilibrio de la dosis normal de topoisomerasas. Tambien se vio que top...

European Journal of Human Genetics

In the original publication of the article, consortium author lists were missing in the article. ... more In the original publication of the article, consortium author lists were missing in the article. The details are as below.

European Journal of Human Genetics

Reanalysis of inconclusive exome/genome sequencing data increases the diagnosis yield of patients... more Reanalysis of inconclusive exome/genome sequencing data increases the diagnosis yield of patients with rare diseases. However, the cost and efforts required for reanalysis prevent its routine implementation in research and clinical environments. The Solve-RD project aims to reveal the molecular causes underlying undiagnosed rare diseases. One of the goals is to implement innovative approaches to reanalyse the exomes and genomes from thousands of well-studied undiagnosed cases. The raw genomic data is submitted to Solve-RD through the RD-Connect Genome-Phenome Analysis Platform (GPAP) together with standardised phenotypic and pedigree data. We have developed a programmatic workflow to reanalyse genome-phenome data. It uses the RD-Connect GPAP’s Application Programming Interface (API) and relies on the big-data technologies upon which the system is built. We have applied the workflow to prioritise rare known pathogenic variants from 4411 undiagnosed cases. The queries returned an aver...

Cell Reports

American journal of human genetics, Sep 24, 2016

Nucleic Acids Research, 2016

Molecular Genetics & Genomic Medicine, 2015

Anti-Cancer Drugs, 2005

Nucleic Acids Research, 2012

European Journal of Human Genetics