133 research outputs found
Transcription Factor Activity Inference in Systemic Lupus Erythematosus
Background: Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease with
diverse clinical manifestations. Although most of the SLE-associated loci are located in regulatory
regions, there is a lack of global information about transcription factor (TFs) activities, the mode of
regulation of the TFs, or the cell or sample-specific regulatory circuits. The aim of this work is to
decipher TFs implicated in SLE. Methods: In order to decipher regulatory mechanisms in SLE, we
have inferred TF activities from transcriptomic data for almost all human TFs, defined clusters of SLE
patients based on the estimated TF activities and analyzed the differential activity patterns among
SLE and healthy samples in two different cohorts. The Transcription Factor activity matrix was used
to stratify SLE patients and define sets of TFs with statistically significant differential activity among
the disease and control samples. Results: TF activities were able to identify two main subgroups of
patients characterized by distinct neutrophil-to-lymphocyte ratio (NLR), with consistent patterns
in two independent datasets—one from pediatric patients and other from adults. Furthermore,
after contrasting all subgroups of patients and controls, we obtained a significant and robust list
of 14 TFs implicated in the dysregulation of SLE by different mechanisms and pathways. Among
them, well-known regulators of SLE, such as STAT or IRF, were found, but others suggest new
pathways that might have important roles in SLE. Conclusions: These results provide a foundation
to comprehend the regulatory mechanism underlying SLE and the established regulatory factors
behind SLE heterogeneity that could be potential therapeutic targets.Innovative Medicines Initiative 2 Joint Undertaking (JU) - 831434 (3TR)European
Union’s Horizon 2020 research and innovation program and EFPIANIH AR69572 and NIH RO-1 grant AR06957
Differential Treatments Based on Drug-induced Gene Expression Signatures and Longitudinal Systemic Lupus Erythematosus Stratification
Daniel Toro is at
present supported by structural funds to MEAR from the Fundación Pública Andaluza Progreso y Salud of the
Junta de AndalucíaSupplementary information is available for this paper at https://doi.org/10.1038/s41598-019-51616-9.Systemic lupus erythematosus (SLE) is a heterogeneous disease with unpredictable patterns of activity. Patients with similar activity levels may have different prognosis and molecular abnormalities. In this study, we aimed to measure the main differences in drug-induced gene expression signatures across SLE patients and to evaluate the potential for clinical data to build a machine learning classifier able to predict the SLE subset for individual patients. SLE transcriptomic data from two cohorts were compared with drug-induced gene signatures from the CLUE database to compute a connectivity score that reflects the capability of a drug to revert the patient signatures. Patient stratification based on drug connectivity scores revealed robust clusters of SLE patients identical to the clusters previously obtained through longitudinal gene expression data, implying that differential treatment depends on the cluster to which patients belongs. The best drug candidates found, mTOR inhibitors or those reducing oxidative stress, showed stronger cluster specificity. We report that drug patterns for reverting disease gene expression follow the cell-specificity of the disease clusters. We used 2 cohorts to train and test a logistic regression model that we employed to classify patients from 3 independent cohorts into the SLE subsets and provide a clinically useful model to predict subset assignment and drug efficacy.This work has been partially supported by Junta de Andalucía through grant PI-0173–2017. The Hopkins Lupus Cohort is supported by NIH AR RO1069572
Computational Methods and Software Tools for Functional Analysis of miRNA Data
miRNAs are important regulators of gene expression that play a key role in many biological
processes. High-throughput techniques allow researchers to discover and characterize large sets of
miRNAs, and enrichment analysis tools are becoming increasingly important in decoding which
miRNAs are implicated in biological processes. Enrichment analysis of miRNA targets is the standard
technique for functional analysis, but this approach carries limitations and bias; alternatives are
currently being proposed, based on direct and curated annotations. In this review, we describe the two
workflows of miRNAs enrichment analysis, based on target gene or miRNA annotations, highlighting
statistical tests, software tools, up-to-date databases, and functional annotations resources in the
study of metazoan miRNAs.Junta de Andalucia
PI-0173-2017
CV20.3672
NoMeplot: analysis of DNA methylation and nucleosome occupancy at the single molecule
Supplementary information accompanies this paper at https://doi.org/10.1038/s41598-019-44597-2.We are very grateful to Peter A. Jones for sharing protocols and advice and we thank Serafin Moral for constructive
and useful discussion.Recent technical advances highlight that to understand mammalian development and human disease we need to consider transcriptional and epigenetic cell-to-cell differences within cell populations. This is particularly important in key areas of biomedicine like stem cell differentiation and intratumor heterogeneity. The recently developed nucleosome occupancy and methylome (NOMe) assay facilitates the simultaneous study of DNA methylation and nucleosome positioning on the same DNA strand. NOMe-treated DNA can be sequenced by sanger (NOMe-PCR) or high throughput approaches (NOMe-seq). NOMe-PCR provides information for a single locus at the single molecule while NOMe-seq delivers genome-wide data that is usually interrogated to obtain population-averaged measures. Here, we have developed a bioinformatic tool that allow us to easily obtain locus-specific information at the single molecule using genome-wide NOMe-seq datasets obtained from bulk populations. We have used NOMePlot to study mouse embryonic stem cells and found that polycomb-repressed bivalent gene promoters coexist in two different epigenetic states, as defined by the nucleosome binding pattern detected around their transcriptional start site.This study was supported by the Spanish ministry of economy and competitiveness
(SAF2013-40891-R; BFU2016-75233-P) and the andalusian regional government (PC-0246-2017). David
Landeira is a Ramón y Cajal researcher of the Spanish ministry of economy and competitiveness (RYC-2012-
10019)
DExMA: An R Package for Performing Gene Expression Meta-Analysis with Missing Genes
Meta-analysis techniques allow researchers to jointly analyse different studies to determine
common effects. In the field of transcriptomics, these methods have gained popularity in recent
years due to the increasing number of datasets that are available in public repositories. Despite
this, there is a limited number of statistical software packages that implement proper meta-analysis
functionalities for this type of data. This article describes DExMA, an R package that provides a
set of functions for performing gene expression meta-analyses, from data downloading to results
visualization. Additionally, we implemented functions to control the number of missing genes, which
can be a major issue when comparing studies generated with different analytical platforms. DExMA
is freely available in the Bioconductor repository.Teaching Staff Programme by the Ministerio de Universidades FPU19/01999
MCIN/AEI PID2020119032RB-I00FEDER/Junta de Andalucia-Consejeria de Transformacion Economica, Industria, Conocimiento y Universidades P20_00335
B-CTS-40-UGR20'Consejeria de Transformacion Economica, Industria, Conocimiento y Universidades' (CTEICU)European Union through the European Social Fund (ESF) named 'Andalucia se mueve con Europa"
European Union-NextGenerationEU, Ministerio de Universidades (Spain's Government)Recovery, Transformation and Resilience Plan, through a call from the University of Granad
Polycomb regulation is coupled to cell cycle transition in pluripotent stem cells
When self-renewing pluripotent cells receive a differentiation signal, ongoing cell duplication needs to be coordinated
with entry into a differentiation program. Accordingly, transcriptional activation of lineage specifier genes and
cell differentiation is confined to the G1 phase of the cell cycle by unknown mechanisms. We found that Polycomb
repressive complex 2 (PRC2) subunits are differentially recruited to lineage specifier gene promoters across cell cycle in
mouse embryonic stem cells (mESCs). Jarid2 and the catalytic subunit Ezh2 are markedly accumulated at target
promoters during S and G2 phases, while the transcriptionally activating subunits EPOP and EloB are enriched
during G1 phase. Fluctuations in the recruitment of PRC2 subunits promote changes in RNA synthesis and RNA
polymerase II binding that are compromised in Jarid2 −/− mESCs. Overall, we show that differential recruitment of
PRC2 subunits across cell cycle enables the establishment of a chromatin state that facilitates the induction of cell
differentiation in G1 phase.This study was
supported by the Spanish Ministry of Economy and Competitiveness (SAF2013-40891-R and
BFU2016-75233-P) and the Andalusian Regional Government (PC-0246-2017). D.L. is a Ramón
y Cajal researcher of the Spanish Ministry of Economy and Competitiveness (RYC-2012-10019)
Metagene projection characterizes GEN2.2 and CAL-1 as relevant human plasmacytoid dendritic cell models
A meta-analysis of pre-pregnancy maternal body mass index and placental DNA methylation identifies 27 CpG sites with implications for mother-child health
Higher maternal pre-pregnancy body mass index (ppBMI) is associated with increased
neonatal morbidity, as well as with pregnancy complications and metabolic outcomes in
offspring later in life. The placenta is a key organ in fetal development and has been proposed
to act as a mediator between the mother and different health outcomes in children. The
overall aim of the present work is to investigate the association of ppBMI with epigenomewide
placental DNA methylation (DNAm) in 10 studies from the PACE consortium,
amounting to 2631 mother-child pairs. We identify 27 CpG sites at which we observe placental
DNAm variations of up to 2.0% per 10 ppBMI-unit. The CpGs that are differentially
methylated in placenta do not overlap with CpGs identified in previous studies in cord blood
DNAm related to ppBMI. Many of the identified CpGs are located in open sea regions, are
often close to obesity-related genes such as GPX1 and LGR4 and altogether, are enriched in
cancer and oxidative stress pathways. Our findings suggest that placental DNAm could be
one of the mechanisms by which maternal obesity is associated with metabolic health outcomes
in newborns and children, although further studies will be needed in order to corroborate
these findings.French Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences de l'Univers (INSU)Swiss National Science Foundation (SNSF)European CommissionMinistry of Science and Innovation, Spain (MICINN)Spanish Government FJC2018-036729European Development FundEuropean Social Fund (ESF
sRNAbench and sRNAtoolbox 2022 update: accurate miRNA and sncRNA profiling for model and non-model organisms
European Union [765492 to M.H.]; Spanish Government [AGL2017-88702-C2-2-R to M.H.]; Chair 'Doctors Galera-Requena in cancer stem cell research' (to J.A.M.); Tromsoforskningsstiftelse (TFS) [20 SG BF 'MIRevolution' to B.F.]; Stichting Cancer Center Amsterdam [CCA2021-9-77 to C.G]; TKI-Health Holland ['AQrate' project to C.G. and M.P.]. This publication is part of a project that has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No. 765492.The NCBI Sequence Read Archive currently hosts
microRNA sequencing data for over 800 different
species, evidencing the existence of a broad taxonomic
distribution in the field of small RNA research.
Simultaneously, the number of samples per
miRNA-seq study continues to increase resulting in
a vast amount of data that requires accurate, fast
and user-friendly analysis methods. Since the previous
release of sRNAtoolbox in 2019, 55 000 sRNAbench
jobs have been submitted which has motivated
many improvements in its usability and the
scope of the underlying annotation database. With
this update, users can upload an unlimited number
of samples or import them from Google Drive,
Dropbox or URLs. Micro- and small RNA profiling
can now be carried out using high-confidence Metazoan
and plant specific databases, MirGeneDB and
PmiREN respectively, together with genome assemblies
and libraries from 441 Ensembl species. The
new results page includes straightforward sample
annotation to allow downstream differential expression
analysis with sRNAde. Unassigned reads can
also be explored by means of a new tool that performsmapping
to microbial references, which can reveal
contamination events or biologically meaningful
findings as we describe in the example. sRNAtoolbox
is available at: https://arn.ugr.es/srnatoolbox/.European Commission 765492Spanish GovernmentEuropean Commission AGL2017-88702-C2-2-RChair 'Doctors Galera-Requena in cancer stem cell research'Stichting Cancer Center Amsterdam CCA2021-9-77Tromsoforskningsstiftelse (TFS) ['MIRevolution'] 20 SG BFTKI-Health Holland ['AQrate' project
Exploring the interplay between climate, population immunity and SARS-CoV-2 transmission dynamics in Mediterranean countries
The relationship between SARS-CoV-2 transmission and environmental factors has been analyzed in numerous studies
since the outbreak of the pandemic, resulting in heterogeneous results and conclusions. This may be due to differences
in methodology, considered variables, confounding factors, studied periods and/or lack of adequate data. Furthermore,
previous works have reported that the lack of population immunity is the fundamental driver in transmission dynamics
and can mask the potential impact of environmental variables. In this study, we aimed to investigate the association between climate variables and COVID-19 transmission considering the influence of population immunity. We analyzed
two different periods characterized by the absence of vaccination (low population immunity) and a high degree of vaccination (high level of population immunity), respectively. Although this study has some limitations, such us the restriction to
a specific climatic zone and the omission of other environmental factors, our results indicate that transmission of SARSCoV-2 may increase independently of temperature and specific humidity in periods with low levels of population immunity
while a negative association is found under conditions with higher levels of population immunity in the analyzed regions
- …