C286, an orally available retinoic acid receptor β agonist drug, regulates multiple pathways to achieve spinal cord injury repair.

Retinoic acid receptor β2 (RARβ2) is an emerging therapeutic target for spinal cord injuries (SCIs) with a unique multimodal regenerative effect. We have developed a first-in-class RARβ agonist drug, C286, that modulates neuron-glial pathways to induce functional recovery in a rodent model of sensory root avulsion. Here, using genome-wide and pathway enrichment analysis of avulsed rats' spinal cords, we show that C286 also influences the extracellular milieu (ECM).

Retinoids: Mechanisms of Action in Neuronal Cell Fate Acquisition.

Neuronal differentiation has been shown to be directed by retinoid action during embryo development and has been exploited in various in vitro cell differentiation systems. In this review, we summarize the role of retinoids through the activation of their specific retinoic acid nuclear receptors during embryo development and also in a variety of in vitro strategies for neuronal differentiation, including recent efforts in driving cell specialization towards a range of neuronal subtypes and glial cells. Finally, we highlight the role of retinoic acid in recent protocols recapitulating nervous tissue complexity (cerebral organoids).

Three-dimensional molecular cartography of human cerebral organoids revealed by double-barcoded spatial transcriptomics.

Spatially resolved transcriptomics is revolutionizing our understanding of complex tissues, but scaling these approaches to multiple tissue sections and three-dimensional tissue reconstruction remains challenging and cost prohibitive. In this work, we present a low-cost strategy for manufacturing molecularly double-barcoded DNA arrays, enabling large-scale spatially resolved transcriptomics studies. We applied this technique to spatially resolve gene expression in several human brain organoids, including the reconstruction of a three-dimensional view from multiple consecutive sections, revealing gene expression heterogeneity throughout the tissue.

Synergistic activation of RARβ and RARγ nuclear receptors restores cell specialization during stem cell differentiation by hijacking RARα-controlled programs.

How cells respond to different external cues to develop along defined cell lineages to form complex tissues is a major question in systems biology. Here, we investigated the potential of retinoic acid receptor (RAR)-selective synthetic agonists to activate the gene regulatory programs driving cell specialization during nervous tissue formation from embryonic carcinoma (P19) and mouse embryonic (E14) stem cells. Specifically, we found that the synergistic activation of the RARβ and RARγ by selective ligands (BMS641 or BMS961) induces cell maturation to specialized neuronal subtypes, and to astrocytes and oligodendrocyte precursors.

Patient-matched analysis identifies deregulated networks in prostate cancer to guide personalized therapeutic intervention.

Prostate cancer (PrCa) is the second most common malignancy in men. More than 50% of advanced prostate cancers display the TMPRSS2-ERG fusion. Despite extensive cancer genome/transcriptome data, little is known about the impact of mutations and altered transcription on regulatory networks in the PrCa of individual patients.

A Core Transcription Regulatory Circuitry Defining Microglia Cell Identity Inferred from the Reanalysis of Multiple Human Microglia Differentiation Protocols.

Microglia, the immune cells in the brain involved in both homeostasis and injury/infection control, play a predominant role in neurodegenerative diseases. In vivo studies on microglia are limited due to the requirement of surgical intervention, which can lead to the destruction of the tissues. Over the last few years, multiple protocols-presenting a variety of strategies-have described microglia differentiation issued from human pluripotent stem cells.

Protocol for using MULTILAYER to reveal molecular tissue substructures from digitized spatial transcriptomes.

Spatially resolved transcriptomics (SrT) allow researchers to explore organ/tissue architecture from the angle of the gene programs involved in their molecular complexity. Here, we describe the use of MULTILAYER to reveal molecular tissue substructures from the analysis of localized transcriptomes (defined as gexels). MULTILAYER can process low- and high-resolution SrT data but also perform comparative analyses within multiple SrT readouts.

Real-time SARS-CoV-2 diagnostic and variants tracking over multiple candidates using nanopore DNA sequencing.

Since December 2019, a novel coronavirus responsible for a severe acute respiratory syndrome (SARS-CoV-2) is accountable for a major pandemic situation. The emergence of the B.1.

Inferring biologically relevant molecular tissue substructures by agglomerative clustering of digitized spatial transcriptomes with multilayer.

Spatially resolved transcriptomics (SrT) can investigate organ or tissue architecture from the angle of gene programs that define their molecular complexity. However, computational methods to analyze SrT data underexploit their spatial signature. Inspired by contextual pixel classification strategies applied to image analysis, we developed MULTILAYER to stratify maps into functionally relevant molecular substructures.

The NANOTUMOR consortium - Towards the Tumor Cell Atlas.

Cancer is a multi-step disease where an initial tumour progresses through critical steps shaping, in most cases, life-threatening secondary foci called metastases. The oncogenic cascade involves genetic, epigenetic, signalling pathways, intracellular trafficking and/or metabolic alterations within cancer cells. In addition, pre-malignant and malignant cells orchestrate complex and dynamic interactions with non-malignant cells and acellular matricial components or secreted factors within the tumour microenvironment that is instrumental in the progression of the disease.

CDYL2 Epigenetically Regulates MIR124 to Control NF-κB/STAT3-Dependent Breast Cancer Cell Plasticity.

Epigenetic deregulation of gene transcription is central to cancer cell plasticity and malignant progression but remains poorly understood. We found that the uncharacterized epigenetic factor chromodomain on Y-like 2 (CDYL2) is commonly over-expressed in breast cancer, and that high CDYL2 levels correlate with poor prognosis. Supporting a functional role for CDYL2 in malignancy, it positively regulated breast cancer cell migration, invasion, stem-like phenotypes, and epithelial-to-mesenchymal transition.

A comprehensive resource for retrieving, visualizing, and integrating functional genomics data.

The enormous amount of freely accessible functional genomics data is an invaluable resource for interrogating the biological function of multiple DNA-interacting players and chromatin modifications by large-scale comparative analyses. However, in practice, interrogating large collections of public data requires major efforts for (i) reprocessing available raw reads, (ii) incorporating quality assessments to exclude artefactual and low-quality data, and (iii) processing data by using high-performance computation. Here, we present qcGenomics, a user-friendly online resource for ultrafast retrieval, visualization, and comparative analysis of tens of thousands of genomics datasets to gain new functional insight from global or focused multidimensional data integration.

Modeling gene-regulatory networks to describe cell fate transitions and predict master regulators.

Complex organisms originate from and are maintained by the information encoded in the genome. A major challenge of systems biology is to develop algorithms that describe the dynamic regulation of genome functions from large omics datasets. Here, we describe TETRAMER, which reconstructs gene-regulatory networks from temporal transcriptome data during cell fate transitions to predict "master" regulators by simulating cascades of temporal transcription-regulatory events.

Development of biotin-retinoid conjugates as chemical probes for analysis of retinoid function.

Herein, we report the rational design, synthesis and biological evaluation of conjugates consisting of the synthetic retinoid Am580 and biotin connected via a linker moiety. We found that the linking substructure between the retinoid part and the biotin part is critical for retaining the biological activity. Conjugate 4 with a shorter linker showed similar potency to endogenous retinoid ATRA (1) and the parent compound Am580 (2) for neural differentiation of mouse embryotic carcinoma P19 cells, and showed the same pattern of induction of gene expression.

Senescence-associated reprogramming promotes cancer stemness.

Cellular senescence is a stress-responsive cell-cycle arrest program that terminates the further expansion of (pre-)malignant cells. Key signalling components of the senescence machinery, such as p16, p21 and p53, as well as trimethylation of lysine 9 at histone H3 (H3K9me3), also operate as critical regulators of stem-cell functions (which are collectively termed 'stemness'). In cancer cells, a gain of stemness may have profound implications for tumour aggressiveness and clinical outcome.

Reconstruction of gene regulatory networks reveals chromatin remodelers and key transcription factors in tumorigenesis.

Background: Alterations in genetic and epigenetic landscapes are known to contribute to the development of different types of cancer. However, the mechanistic links between transcription factors and the epigenome which coordinate the deregulation of gene networks during cell transformation are largely unknown.

Methods: We used an isogenic model of stepwise tumorigenic transformation of human primary cells to monitor the progressive deregulation of gene networks upon immortalization and oncogene-induced transformation.

NGS-QC Generator: A Quality Control System for ChIP-Seq and Related Deep Sequencing-Generated Datasets.

The combination of massive parallel sequencing with a variety of modern DNA/RNA enrichment technologies provides means for interrogating functional protein-genome interactions (ChIP-seq), genome-wide transcriptional activity (RNA-seq; GRO-seq), chromatin accessibility (DNase-seq, FAIRE-seq, MNase-seq), and more recently the three-dimensional organization of chromatin (Hi-C, ChIA-PET). In systems biology-based approaches several of these readouts are generally cumulated with the aim of describing living systems through a reconstitution of the genome-regulatory functions. However, an issue that is often underestimated is that conclusions drawn from such multidimensional analyses of NGS-derived datasets critically depend on the quality of the compared datasets.

Assessing quality standards for ChIP-seq and related massive parallel sequencing-generated datasets: When rating goes beyond avoiding the crisis.

Massive parallel DNA sequencing combined with chromatin immunoprecipitation and a large variety of DNA/RNA-enrichment methodologies is at the origin of data resources of major importance. Indeed these resources, available for multiple genomes, represent the most comprehensive catalogue of (i) cell, development and signal transduction-specified patterns of binding sites for transcription factors ('cistromes') and for transcription and chromatin modifying machineries and (ii) the patterns of specific local post-translational modifications of histones and DNA ('epigenome') or of regulatory chromatin binding factors. In addition, (iii) the resources specifying chromatin structure alterations are emerging.

Senescence-secreted factors activate Myc and sensitize pretransformed cells to TRAIL-induced apoptosis.

Senescent cells secrete a plethora of factors with potent paracrine signaling capacity. Strikingly, senescence, which acts as defense against cell transformation, exerts pro-tumorigenic activities through its secretome by promoting tumor-specific features, such as cellular proliferation, epithelial-mesenchymal transition and invasiveness. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has the unique activity of activating cell death exclusively in tumor cells.

POLYPHEMUS: R package for comparative analysis of RNA polymerase II ChIP-seq profiles by non-linear normalization.

Chromatin immunoprecipitation coupled with massive parallel sequencing (ChIP-seq) is increasingly used to map protein-chromatin interactions at global scale. The comparison of ChIP-seq profiles for RNA polymerase II (PolII) established in different biological contexts, such as specific developmental stages or specific time-points during cell differentiation, provides not only information about the presence/accumulation of PolII at transcription start sites (TSSs) but also about functional features of transcription, including PolII stalling, pausing and transcript elongation. However, annotation and normalization tools for comparative studies of multiple samples are currently missing.

Dissecting the retinoid-induced differentiation of F9 embryonal stem cells by integrative genomics.

Retinoic acid (RA) triggers physiological processes by activating heterodimeric transcription factors (TFs) comprising retinoic acid receptor (RARα, β, γ) and retinoid X receptor (RXRα, β, γ). How a single signal induces highly complex temporally controlled networks that ultimately orchestrate physiological processes is unclear. Using an RA-inducible differentiation model, we defined the temporal changes in the genome-wide binding patterns of RARγ and RXRα and correlated them with transcription regulation.