Biology subjects

Dali, R.

Publications and source records attributed to Dali, R..

7 recordsLinked to original sources

bioRxiv2025

Tanycyte-mediated synapse pruning shapes hypothalamic circuits controlling metabolism.

Synaptic pruning by glial cells is critical for refining neural circuits, yet which glial populations mediate this process in hypothalamic networks controlling energy balance remains poorly understood. Here, using 3D-ultrastructural analyses and molecular approaches, we show that tanycytes --specialized glial cells lining the third ventricle-- actively engulf excitatory synapses in the mediobasal hypothalamus during a defined postnatal window. This phagocytic activity relies on tanycytic MFG-E8 and phosphatidylserine exposure on synaptic elements. Disruption of this pathway reduces synapse uptake in vitro and alters body weight control around weaning and glucose homeostasis in adulthood. These findings identify tanycytes as previously unrecognized glial mediators of synaptic pruning in hypothalamic circuits, establishing their active role in shaping neural networks underlying energy balance.

neuroscience↗

bioRxiv2025

Tanycytic annexinA1-containing extracellular vesicles control thermogenesis by orchestrating microglial and neuronal functions.

Obesity, a major global health issue, results from disrupted energy balance driven by chronic hypothalamic inflammation and altered intercellular communication. Among the diverse cells orchestrating this regulation, tanycytes--specialized ependymal cells at the brain-blood interface--have emerged as key modulators, yet the molecular mechanisms by which they influence surrounding cells remain poorly understood. Here, we identify Annexin A1 (ANXA1) as a tanycyte-derived anti-inflammatory signal whose expression, localization, and secretion are dynamically regulated by nutritional state and altered under high-fat diet. During positive energy balance, ANXA1 is secreted in CD9 extracellular vesicles (EV), remodeling hypothalamic networks by altering microglial morphology, synaptic density, and neuronal activation. These EV-mediated effects extend systemically to regulate brown adipose tissue thermogenesis, glucose homeostasis, and overall energy balance. Our findings reveal a previously unrecognized tanycyte-microglia-neuron signaling axis and highlight EV-mediated glial communication as a potential therapeutic target in obesity-associated neuroinflammation.

neuroscience↗

bioRxiv2023

H3K27me3 spreading organizes canonical PRC1 chromatin architecture to regulate developmental programs

Polycomb Repressive Complex 2 (PRC2)-mediated histone H3K27 tri-methylation (H3K27me3) recruits canonical PRC1 (cPRC1) to maintain heterochromatin. In early development, polycomb-regulated genes are connected through long-range 3D interactions which resolve upon differentiation. Here, we report that polycomb looping is controlled by H3K27me3 spreading and regulates target gene silencing and cell fate specification. Using glioma-derived H3 Lys-27-Met (H3K27M) mutations as tools to restrict H3K27me3 deposition, we show that H3K27me3 confinement concentrates the chromatin pool of cPRC1, resulting in heightened 3D interactions mirroring chromatin architecture of pluripotency, and stringent gene repression that maintains cells in progenitor states to facilitate tumor development. Conversely, H3K27me3 spread in pluripotent stem cells, following neural differentiation or loss of the H3K36 methyltransferase NSD1, dilutes cPRC1 concentration and dissolves polycomb loops. These results identify the regulatory principles and disease implications of polycomb looping and nominate histone modification-guided distribution of reader complexes as an important mechanism for nuclear compartment organization. Highlights{square} The confinement of H3K27me3 at PRC2 nucleation sites without its spreading correlates with increased 3D chromatin interactions. {square}The H3K27M oncohistone concentrates canonical PRC1 that anchors chromatin loop interactions in gliomas, silencing developmental programs. {square}Stem and progenitor cells require factors promoting H3K27me3 confinement, including H3K36me2, to maintain cPRC1 loop architecture. {square}The cPRC1-H3K27me3 interaction is a targetable driver of aberrant self-renewal in tumor cells.

molecular biology↗

bioRxiv2020

An Arf/Rab cascade controls the growth and invasiveness of glioblastoma

Glioblastoma is the most common and deadly malignant brain cancer. We now demonstrate that loss of function of the endosomal GTPase Rab35 in human brain tumor initiating cells (BTICs) increases glioblastoma growth and decreases animal survival following BTIC implantation in mouse brain. Mechanistically, we identify that the GTPase Arf5 interacts with the guanine nucleotide exchange factor (GEF) for Rab35, DENND1/connecdenn and allosterically enhances its GEF activity towards Rab35. Knockdown of either Rab35 or Arf5 increases cell migration, invasiveness and self-renewal in culture and enhances the growth and invasiveness of BTIC-initiated brain tumors in mice. RNAseq of the tumors reveals upregulation of the tumor-promoting transcription factor SPOCD1, and disruption of the Arf5/Rab35 axis in glioblastoma cells leads to strong activation of the epidermal growth factor receptor with resulting enhancement of SPOCD1 levels. These discoveries reveal an unexpected cascade between an Arf and a Rab and indicate a role for the cascade, and thus endosomal trafficking, in brain tumors.

cancer biology↗

bioRxiv2020

Groucho/TLE opposes axial to hypaxial motor neuron development

Spinal cord motor neuron diversity and the ensuing variety of motor circuits allow for the processing of elaborate muscular behaviours such as body posture and breathing. Little is known, however, about the molecular mechanisms behind the specification of axial and hypaxial motor neurons controlling postural and respiratory functions respectively. Here we show that the Groucho/TLE (TLE) transcriptional corepressor is a multi-step regulator of axial and hypaxial motor neuron diversification in the developing spinal cord. TLE first promotes axial motor neuron specification at the expense of hypaxial identity by cooperating with non-canonical WNT5A signalling within the motor neuron progenitor domain. TLE further acts during post-mitotic motor neuron diversification to promote axial motor neuron topology and axonal connectivity whilst suppressing hypaxial traits. These findings provide evidence for essential and sequential roles of TLE in the spatial and temporal coordination of events regulating the development of motor neurons influencing posture and controlling respiration. HIGHLIGHTSO_LIGroucho/TLE mediates non-canonical WNT signalling in developing motor neurons C_LIO_LINon canonical WNT:TLE pathway regulates thoracic motor neuron diversification C_LIO_LITLE promotes axial while inhibiting hypaxial motor neuron development C_LIO_LITLE influences developing motor neuron topology and muscle innervation C_LI IN BRIEFSalin-Cantegrel et al use in ovo engineered approaches to show that a non-canonical WNT:TLE pathway coordinates temporally and spatially separated elements of motor neuron diversification, repressing hypaxial motor neuron development to promote the axial fate. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=116 SRC="FIGDIR/small/986323v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@e2d96dorg.highwire.dtl.DTLVardef@130baf4org.highwire.dtl.DTLVardef@41fa32org.highwire.dtl.DTLVardef@190ebd3_HPS_FORMAT_FIGEXP M_FIG TLE contribution to the development of thoracic somatic motor columns Progenitor cells in the ventral pMN domain are exposed to higher concentrations of non-canonical WNTs and express more TLE. Cooperation of non-canonical WNTs and TLE renders ventral pMN progenitors refractory to a respiratory MN fate, thereby contributing to the separation of MMC and RMC MN lineages. Differentiating MNs that maintain high TLE expression also maintain LHX3 expression, adopt axial motor neuron topology and connect to axial muscles. TLE activity in differentiating MMC MNs prevents the acquisition of respiratory MN topology and innervation traits. C_FIG

neuroscience↗

bioRxiv2018

GenPipes: an open-source framework for distributed and scalable genomic analyses

With the decreasing cost of sequencing and the rapid developments in genomics technologies and protocols, the need for validated bioinformatics software that enables efficient large-scale data processing is growing. Here we present GenPipes, a flexible Python-based framework that facilitates the development and deployment of multi-step workflows optimized for High Performance Computing clusters and the cloud. GenPipes already implements 12 validated and scalable pipelines for various genomics applications, including RNA-Seq, ChIP-Seq, DNA-Seq, Methyl-Seq, Hi-C, capture Hi-C, metagenomics and PacBio long read assembly. The software is available under a GPLv3 open source license and is continuously updated to follow recent advances in genomics and bioinformatics. The framework has been already configured on several servers and a docker image is also available to facilitate additional installations. In summary, GenPipes offers genomic researchers a simple method to analyze different types of data, customizable to their needs and resources, as well as the flexibility to create their own workflows.

bioinformatics↗

bioRxiv2018

RobusTAD: A Tool for Robust Annotation ofTopologically Associating Domain Boundaries

MotivationTopologically Associating Domains (TADs) are chromatin structures that can be identified by analysis of Hi-C data. Tools currently available for TAD identification are sensitive to experimental conditions such as coverage, resolution and noise level.\n\nResultsHere, we present RobusTAD, a tool to score TAD boundaries in a manner that is robust to these parameters. In doing so, RobusTAD eases comparative analysis of TAD structures across multiple heterogeneous samples.\n\nAvailabilityRobusTAD is implemented in R and released under a GPL license. RobusTAD can be downloaded from https://github.com/rdali/RobusTAD and runs on any standard desktop computer.\n\nContactrola.dali@mail.mcgill.ca, blanchem@cs.mcgill.ca\n\nSupplementary informationSupplementary data are available at Bioinformatics online.

bioinformatics↗