Biology subjects

Pancaldi, V.

Publications and source records attributed to Pancaldi, V..

32 records · Page 2Linked to original sources

bioRxiv2020

Tysserand - Fast reconstruction of spatial networks from bioimages

SummaryNetworks provide a powerful framework to analyze spatial omics experiments. However, we lack tools that integrate several methods to easily reconstruct networks for further analyses with dedicated libraries. In addition, choosing the appropriate method and parameters can be challenging. We propose tysserand, a Python library to reconstruct spatial networks from spatially resolved omics experiments. It is intended as a common tool to which the bioinformatics community can add new methods to reconstruct networks, choose appropriate parameters, clean resulting networks and pipe data to other libraries. Availability and implementationtysserand software and tutorials with a Jupyter notebook to reproduce the results are available at https://github.com/VeraPancaldiLab/tysserand Supplementary informationSupplementary data are available at Bioarxiv online.

bioinformatics↗

bioRxiv2020

A Boolean Model of the Formation of Tumour Associated Macrophages in an in-vitro Model of Chronic Lymphocytic Leukaemia

The tumour microenvironment is the collection of cells in and surrounding cancer cells in a tumour including a variety of immune cells, especially neutrophils and monocyte-derived macrophages. In a tumour setting, macrophages encompass a spectrum between a tumour-suppressive (M1) or tumour-promoting (M2) state. The biology of macrophages found in tumours (Tumour Associated Macrophages) remains unclear, but understanding their impact on tumour progression is highly important. In this paper, we perform a comprehensive analysis of a macrophage polarization network, following two lines of enquiry: (i) we reconstruct the macrophage polarization network based on literature, extending it to include important stimuli in a tumour setting, and (ii) we build a dynamical model able to reproduce macrophage polarization in the presence of different stimuli, including the contact with cancer cells. Our simulations recapitulate the documented macrophage phenotypes and their dependencies on specific receptors and transcription factors, while also elucidating the formation of a special type of tumour associated macrophages in an in-vitro model of chronic lymphocytic leukaemia. This model constitutes the first step towards elucidating the cross-talk between immune and cancer cells inside tumours, with the ultimate goal of identifying new therapeutic targets that could control the formation of tumour associated macrophages in patients.

systems biology↗

bioRxiv2020

Low replication stress leads to specific replication timing advances associated to chromatin remodelling in cancer cells

DNA replication is well orchestrated in mammalian cells through a tight regulation of the temporal order of replication origin activation, named the replication timing, a robust and conserved process in each cell type. Upon low replication stress, the slowing of replication forks induces delayed replication of fragile regions leading to genetic instability. The impact of low replication stress on the replication timing in different cellular backgrounds has not been explored yet. Here we analysed the whole genome replication timing in a panel of 6 human cell lines under low replication stress. We first demonstrated that cancer cells were more impacted than non-tumour cells. Strikingly, we unveiled an enrichment of specific replication domains undergoing a switch from late to early replication in some cancer cells. We found that advances in replication timing correlate with heterochromatin regions poorly sensitive to DNA damage signalling while being subject to an increase of chromatin accessibility. Finally, our data indicate that, following release from replication stress conditions, replication timing advances can be inherited by the next cellular generation, suggesting a new mechanism by which cancer cells would adapt to cellular or environmental stress.

cancer biology↗

bioRxiv2020

STAG2 loss-of-function affects short-range genomic contacts and modulates urothelial differentiation in bladder cancer cells

Cohesin exists in two variants, containing either STAG1 or STAG2. STAG2 is one of the most commonly mutated genes in human cancer, and a major bladder cancer tumor suppressor. Little is known about how its inactivation contributes to tumor development. Here, we analyze the genomic distribution of STAG1 and STAG2 and perform STAG2 loss-of-function experiments using RT112 bladder cancer cells; we then analyze the resulting genomic effects by integrating gene expression and chromatin interaction data. Cohesin-STAG2 is required for DNA contacts within topological domains, but not for compartment maintenance of domain boundary integrity. Cohesin-STAG2-mediated interactions are short-ranged and engage promoters and gene bodies with higher frequency than those mediated by cohesin-STAG1. STAG2 knockdown resulted in a modest but consistent down-regulation of the luminal urothelial differentiation signature, mirroring differences between STAG2-high and STAG2-low bladder tumors. Both lost and gained contacts were enriched among STAG1/STAG2 common sites as well as STAG2-enriched sites. Contacts lost upon depletion of STAG2 were significantly assortative, indicating their proximity at the 3D level, and were associated with changes in gene expression. Overall, our findings indicate that, in urothelial cells, STAG2 is required for the establishment and/or maintenance of DNA looping that, in turn, sustains the luminal differentiation program. This mechanism may contribute to the tumor suppressor function of STAG2 in bladder cancer.

cancer biology↗

bioRxiv2020

The antitumoral activity of TLR7 ligands is corrupted by the microenvironment of pancreatic tumors

Toll like receptors are key players in the innate immune system. Recent studies have suggested that they may impact the growth of pancreatic cancer, a disease with no cure. Among them, Toll like receptor-7 shows promise for therapy but may also promote tumor growth. Thus, we aimed to better understand the mechanism of action of Toll like receptor-7 ligands in pancreatic cancer, to open the door for clinical applications. In vitro, Toll like receptor-7 ligands strongly inhibit the proliferation and induce cell death by apoptosis of pancreatic cancer cells. In vivo, while Toll like receptor-7 agonists significantly delay the growth of aggressive tumors engrafted in immunodeficient mice, they instead surprisingly promote tumor growth and accelerate animal death in immunocompetent models. Molecular investigations revealed that Toll like receptor-7 agonists strongly increase the number of tumor-promoting macrophages to drive pancreatic tumorigenesis in immunocompetent mice. This is in stark contrast with Toll like receptor-7 ligands great potential to inhibit pancreatic cancer cell proliferation in vitro and tumor growth in vivo in immunosuppressed models. Collectively, our findings shine a light on the duality of action of Toll like receptor-7 agonists in experimental cancer models, and calls into question their use for pancreatic cancer therapy.

cancer biology↗

bioRxiv2019

GARDEN-NET and ChAseR: a suite of tools for the analysis of chromatin networks

We introduce an R package and a web-based visualization tool for the representation, analysis and integration of epigenomic data in the context of 3D chromatin interaction networks. GARDEN-NET allows for the projection of user-submitted genomic features on pre-loaded chromatin interaction networks exploiting the functionalities of the ChAseR package to explore the features in combination with chromatin network topology. We demonstrate the approach on epigenomic and chromatin structure datasets in haematopoietic cells.

genomics↗

bioRxiv2019

Three-dimensional connectivity and chromatin environment mediate the activation efficiency of mammalian DNA replication origins

In mammalian cells, chromosomal replication starts at thousands of origins at which replisomes are assembled and bidirectional DNA synthesis is established. The slowdown of DNA polymerases at endogenous or exogenous obstacles triggers the activation of additional dormant origins whose genomic positions and regulation are not well understood. Here we report a comparative study of origin activity in mouse embryonic stem cells growing in control conditions or in the presence of mild replication stress. While stress-responsive origins can be identified, we find that the majority of them are also active, albeit with lower frequency, in the control population. To gain insights into the molecular and structural determinants of origin efficiency, we have analyzed the genetic and epigenetic features of origins stratified according to their frequency of activation. We have also integrated the linear origin maps into three-dimensional (3D) chromatin interaction networks, revealing a hierarchical organization in which clusters of connected origins are brought together by longer-range chromatin contacts. Origin efficiency is proportional to the number of connections established with other origin-containing fragments. Interacting origins tend to be activated with similar efficiency and share their timing of replication even when located in different topologically associated domains. Our results are consistent with a model in which clusters of origins are arranged in 3D in replication factories. Within each factory, main and dormant origins are functionally defined by a combination of chromatin environment and 3D connectivity.

genomics↗

bioRxiv2019

Molecular Inverse Comorbidity between Alzheimer’s disease and Lung Cancer: new insights from Matrix Factorization

Matrix Factorization (MF) is an established paradigm for large-scale biological data analysis with tremendous potential in computational biology.\n\nWe here challenge MF in depicting the molecular bases of epidemiologically described Disease-Disease (DD) relationships. As use case, we focus on the inverse comorbidity association between Alzheimers disease (AD) and lung cancer (LC), described as a lower than expected probability of developing LC in AD patients. To the day, the molecular mechanisms underlying DD relationships remain poorly explained and their better characterization might offer unprecedented clinical opportunities.\n\nTo this goal, we extend our previously designed MF-based framework for the molecular characterization of DD relationships. Considering AD-LC inverse comorbidity as a case study, we highlight multiple molecular mechanisms, among which the previously identified immune system and mitochondrial metabolism. We then discriminate mechanisms specific to LC from those shared with other cancers through a pancancer analysis. Additionally, new candidate molecular players, such as Estrogen Receptor (ER), CDH1 and HDAC, are pinpointed as factors that might underlie the inverse relationship, opening the way to new investigations. Finally, some lung cancer subtype-specific factors are also detected, suggesting the existence of heterogeneity across patients also in the context of inverse comorbidity.

systems biology↗

bioRxiv2018

ChiCMaxima: a robust and simple pipeline for detection and visualization of chromatin looping in Capture Hi-C

Capture Hi-C (CHi-C) is a new technique for assessing genome organization, based on chromosome conformation capture coupled to oligonucleotide capture of regions of interest such as gene promoters. Chromatin loop detection is challenging, since existing Hi-C/4C-like analyses, which make different assumptions about the technical biases presented, are often unsuitable. We describe a new approach, ChiCMaxima, which uses local maxima combined with a background model to detect DNA looping interactions, integrating information from biological replicates. ChiCMaxima shows more stringency and robustness compared to previously developed tools. The tool includes a GUI browser for flexible visualization of CHi-C profiles alongside epigenomic tracks.

genomics↗

bioRxiv2018

Transcriptomic metaanalyses of autistic brains reveals shared gene expression and biological pathway abnormalities with cancer.

Epidemiological and clinical evidence points to cancer as a comorbidity in people with autism spectrum disorders (ASD). A significant overlap of genes and biological processes between both diseases has also been reported. Here, for the first time, we compared the gene expression profiles of ASD frontal cortex tissues and 22 cancer types obtained by differential expression meta-analysis. Four cancer types (brain, thyroid, kidney, and pancreatic cancers) presented a significant overlap in gene expression deregulations in the same direction as ASD whereas two cancer types (lung and prostate cancers) showed differential expression profiles significantly deregulated in the opposite direction from ASD. Functional enrichment and LINCS L1000 based drug set enrichment analyses revealed the implication of several biological processes and pathways that were affected jointly in both diseases, including impairments of the immune system, and impairments in oxidative phosphorylation and ATP synthesis among others. Our data also suggest that brain and kidney cancer have patterns of transcriptomic dysregulation in the PI3K/AKT/MTOR axis that are similar to those found in ASD. These shared transcriptomic alterations could help explain epidemiological observations suggesting direct and inverse comorbid associations between ASD and particular cancer types.

systems biology↗

bioRxiv2018

Unveiling the molecular basis of disease co-occurrence: towards personalized comorbidity profiles

Comorbidity is an impactful medical problem that is attracting increasing attention in healthcare and biomedical research. However, little is known about the molecular processes leading to the development of a specific disease in patients affected by other conditions. We present a disease interaction network inferred from similarities in patients molecular profiles, which significantly recapitulates epidemiologically documented comorbidities, providing the basis for their interpretation at a molecular level. Furthermore, expanding on the analysis of subgroups of patients with similar molecular profiles, our approach discovers comorbidity relations not previously described, implicates distinct genes in such relations, and identifies drugs whose side effects are potentially associated to the observed comorbidities.

bioinformatics↗

bioRxiv2017

Comparative analysis of neutrophil and monocyte epigenomes

Neutrophils and monocytes provide a first line of defense against infections as part of the innate immune system. Here we report the integrated analysis of transcriptomic and epigenetic landscapes for circulating monocytes and neutrophils with the aim to enable downstream interpretation and functional validation of key regulatory elements in health and disease. We collected RNA-seq data, ChIP-seq of six histone modifications and of DNA methylation by bisulfite sequencing at base pair resolution from up to 6 individuals per cell type. Chromatin segmentation analyses suggested that monocytes have a higher number of cell-specific enhancer regions (4-fold) compared to neutrophils. This highly plastic epigenome is likely indicative of the greater differentiation potential of monocytes into macrophages, dendritic cells and osteoclasts. In contrast, most of the neutrophil-specific features tend to be characterized by repressed chromatin, reflective of their status as terminally differentiated cells. Enhancers were the regions where most of differences in DNA methylation between cells were observed, with monocyte-specific enhancers being generally hypomethylated. Monocytes show a substantially higher gene expression levels than neutrophils, in line with epigenomic analysis revealing that gene more active elements in monocytes. Our analyses suggest that the overexpression of c-Myc in monocytes and its binding to monocyte-specific enhancers could be an important contributor to these differences. Altogether, our study provides a comprehensive epigenetic chart of chromatin states in primary human neutrophils and monocytes, thus providing a valuable resource for studying the regulation of the human innate immune system.

genomics↗

bioRxiv2016

Genome-wide Analysis of Differential Transcriptional and Epigenetic Variability Across Human Immune Cell Types

BackgroundA healthy immune system requires immune cells that adapt rapidly to environmental challenges. This phenotypic plasticity can be mediated by transcriptional and epigenetic variability.\n\nResultsWe applied a novel analytical approach to measure and compare transcriptional and epigenetic variability genome-wide across CD14+CD16- monocytes, CD66b+CD16+ neutrophils, and CD4+CD45RA+ naive T cells, from the same 125 healthy individuals. We discovered substantially increased variability in neutrophils compared to monocytes and T cells. In neutrophils, genes with hypervariable expression were found to be implicated in key immune pathways and to associate with cellular properties and environmental exposure. We also observed increased sex-specific gene expression differences in neutrophils. Neutrophil-specific DNA methylation hypervariable sites were enriched at dynamic chromatin regions and active enhancers.\n\nConclusionsOur data highlight the importance of transcriptional and epigenetic variability for the neutrophils key role as the first responders to inflammatory stimuli. We provide a resource to enable further functional studies into the plasticity of immune cells, which can be accessed from: http://blueprint-dev.bioinfo.cnio.es/WP10/hypervariability.

molecular biology↗

bioRxiv2016

Searching for the chromatin determinants of human hematopoiesis

Hematopoiesis is one of the best characterized biological systems but the connection between chromatin changes and lineage differentiation is not yet well understood. We have developed a bioinformatic workflow to generate a chromatin space that allows to classify forty-two human healthy blood epigenomes from the BLUEPRINT, NIH ROADMAP and ENCODE consortia by their cell type. This approach let us to distinguish different cells types based on their epigenomic profiles, thus recapitulating important aspects of human hematopoiesis. The analysis of the orthogonal dimension of the chromatin space identify 32,662 chromatin determinant regions (CDRs), genomic regions with different epigenetic characteristics between the cell types. Functional analysis revealed that these regions are linked with cell identities. The inclusion of leukemia epigenomes in the healthy hematological chromatin sample space gives us insights on the healthy cell types that are more epigenetically similar to the disease samples. Further analysis of tumoral epigenetic alterations in hematopoietic CDRs points to sets of genes that are tightly regulated in leukemic transformations and commonly mutated in other tumors. Our method provides an analytical approach to study the relationship between epigenomic changes and cell lineage differentiation. Method availability: https://github.com/david-juan/ChromDet

genomics↗