Biology subjects

Gabriele, M.

Publications and source records attributed to Gabriele, M..

10 recordsLinked to original sources

bioRxiv2025

Mining and e-waste recycling influence the spatial distribution of technology-critical elements, but not rare earth elements, in boreal lakes

Mining and more recent e-waste recycling have contributed trace elements (TEs) to the environment. However, the occurrence of emerging technology-critical elements (TCEs), including rare earth elements (REEs), remains poorly reported. Our study aims to i) investigate the spatial distribution of TEs, including TCEs, across different environmental matrices; ii) compare measured concentrations in water and sediment against environmental quality guidelines; and iii) assess potential risks to human health from fish consumption. In this study, we sampled water, sediment, and fish tissues (muscle and liver) across six boreal lakes near the historically mining region of Rouyn-Noranda, home to North Americas largest copper smelting and recycling facility (Horne Smelter). Concentrations of TEs (e.g., Cu, Se) were higher in lakes closest to the smelter. Similarly, some TCEs (i.e., Ti, Co, Tl) followed this same spatial distribution pattern, suggesting that their release may be linked to historical and current mining activities. Conversely, REEs displayed distinct spatial patterns, likely influenced by geological sources rather than pollution. Several TEs (e.g., Zn, Cd, Pb) exceeded Canadian water and sediment quality guidelines in lakes closer to the mining area. Muscle tissue from walleye or yellow perch showed Zn, Cd, or Pb concentrations above safety limits in at least one lake. This study highlights the importance of including emerging TCEs (e.g., Sr, Tl, Co) in biomonitoring programs. Our findings provide critical insights into the environmental distribution of TEs across multiple matrices of boreal lake ecosystems, contributing to global efforts in risk assessment and sustainable freshwater management in the context of growing electronic waste recycling. Highlights{blacksquare} First report of various TCEs and REEs in 3 matrices of boreal lakes {blacksquare}The spatial distribution of several newly reported TCEs is similar to that of historical TEs {blacksquare}REE concentrations are associated with geology rather than mining sources {blacksquare}Some TE concentrations in water and sediment are above guidelines in closest lakes {blacksquare}All lakes exceeded safety limits for at least one element (Zn, Cd, or Pb) in the muscle tissue of either walleye or yellow perch

ecology↗

bioRxiv2025

Live fast and die young: walleye populations adapt their life cycle to degraded lakes of the Canadian clay belt.

Despite its widespread distribution in North America, many populations of walleye (Sander vitreus) declined to the point where restoration measures, including restocking, are necessary. In this study, we compared population structure and dietary composition of walleye populations in two degraded lakes and two non-degraded lakes in the Abitibi-Temiscamingue region of Quebec, Canada. Food resources were assessed for walleye larvae, young-of-the-year, juveniles, and adults. Growth and relative abundance were also quantified for young-of-the-year, juvenile, and adult walleye. Young-of-the-year were more abundant and grew faster in degraded lakes compared to non-degraded controls, benefiting from high populations of spring zooplankton, which are a critical larval resource. The simplified food webs in degraded lakes lacked pollution-sensitive macroinvertebrates, which resulted in walleye diets being even more dominated by fish. Although juveniles and adults were equally or more abundant in degraded lakes compared to control lakes, premature adult mortality compromised population stability. We recommend focusing on improving adult fish habitat, manage for prey species, and review fishing regulations to enhance the survival of mature walleye and ensure sustainable populations.

ecology↗

bioRxiv2025

Disruption of ADNP-KDM1A-GTF2I complex drives neural differentiation imbalance in Helsmoortel-Van der Aa syndrome

Mutations in ADNP (Activity-Dependent Neuroprotective Protein) are among the most frequent monogenic causes of autism spectrum disorder (ASD) and lead to Helsmoortel-Van der Aa syndrome (HVDAS). Yet how ADNP dysfunction leads to HVDAS is unclear. We employed patient-derived induced pluripotent stem cells, cortical organoids and ADNP KO human neural stem cells (hNSCs) to clarify the cellular and molecular mechanism of HVDAS onset. We purified an ADNP-KDM1A-GTF2I (AKG) protein complex from hNSCs and show that it targets transposable elements (TEs) to repress nearby gene transcription. Upon ADNP KO, KDM1A binding is lost at promoters targeted by AKG, pointing to ADNP as the anchoring subunit of the AKG complex. HVDAS cortical organoids show impaired progenitor proliferation and accelerated neuronal differentiation, coupled with a sustained upregulation of neurogenesis transcriptional programs, including key transcription factors normally repressed by AKG. This work suggests that the AKG complex acts as the relevant ADNP unit in the molecular onset of HVDAS.

neuroscience↗

bioRxiv2025

Genome-wide absolute quantification of chromatin looping

3D genomics methods such as Hi-C and Micro-C have uncovered chromatin loops across the genome and linked these loops to gene regulation. However, these methods only measure 3D interaction probabilities on a relative scale. Here, we overcome this limitation by using live imaging data to calibrate Micro-C in mouse embryonic stem cells, thus obtaining absolute looping probabilities for 36,804 chromatin loops across the genome. We find that the looped state is generally rare, with a mean probability of 2.3% and a maximum of 26% across the quantified loops. On average, CTCF-CTCF loops are stronger than loops between cis-regulatory elements (3.2% vs. 1.1%). Our findings can be extended to human stem cells and differentiated cells under certain assumptions. Overall, we establish an approach for genome-wide absolute loop quantification and report that loops generally occur with low probabilities, generalizing recent live imaging results to the whole genome.

biophysics↗

bioRxiv2024

YY1 mutations disrupt corticogenesis and cytoarchitecture through a cell-type specific rewiring of cell-autonomous and non-cell-autonomous transcriptional programs

Germline mutations of YY1 cause Gabriele-de Vries syndrome (GADEVS), a neurodevelopmental disorder featuring intellectual disability and a wide range of systemic manifestations. To dissect the cellular and molecular mechanisms underlying GADEVS, we combined large-scale imaging, single-cell multiomics and gene regulatory network reconstruction in 2D and 3D patient-derived physiopathologically relevant cell lineages. YY1 haploinsufficiency causes a pervasive alteration of cell type specific transcriptional networks, disrupting corticogenesis at the level of neural progenitors and terminally differentiated neurons, including cytoarchitectural defects reminiscent of GADEVS clinical features. Transcriptional alterations in neurons propagated to neighboring astrocytes through a major non-cell autonomous pro-inflammatory effect that grounds the rationale for modulatory interventions. Together, neurodevelopmental trajectories, synaptic formation and neuronal-astrocyte cross talk emerged as salient domains of YY1 dosage-dependent vulnerability. Mechanistically, cell-type resolved reconstruction of gene regulatory networks uncovered the regulatory interplay between YY1, NEUROG2 and ETV5 and its aberrant rewiring in GADEVS. Our findings underscore the reach of advanced in vitro models in capturing developmental antecedents of clinical features and exposing their underlying mechanisms to guide the search for targeted interventions.

neuroscience↗

bioRxiv2022

Benchmarking brain organoid recapitulation of fetal corticogenesis

Brain organoids are becoming increasingly relevant to dissect the molecular mechanisms underlying psychiatric and neurological conditions. The in vitro recapitulation of key features of human brain development affords the unique opportunity of investigating the developmental antecedents of neuropsychiatric conditions in the context of the actual patients genetic backgrounds. Specifically, multiple strategies of brain organoid (BO) differentiation have enabled the investigation of human cerebral corticogenesis in vitro with increasing accuracy. However, the field lacks a systematic investigation of how closely the gene co-expression patterns seen in cultured BO from different protocols match those observed in fetal cortex, a paramount information for ensuring the sensitivity and accuracy of modeling disease trajectories. Here we benchmark BO against fetal corticogenesis by integrating transcriptomes from in-house differentiated cortical BO (CBO), other BO systems, human fetal brain samples processed in-house, and prenatal cortices from the BrainSpan Atlas. We identified co-expression patterns and prioritized hubs of human corticogenesis and CBO differentiation, highlighting both well-preserved and discordant trends across BO protocols, including different degrees of heterochronicity in differentiation across BO models compared to fetal cortex. Our approach provides a framework to directly compare the extent of in vivo/in vitro alignment of neurodevelopmentally relevant processes and their attending temporalities, structured as an accessible resource to query for modelling human corticogenesis and the neuropsychiatric outcomes of its alterations.

developmental biology↗

bioRxiv2021

Dynamics of CTCF and cohesin mediated chromatin looping revealed by live-cell imaging

Animal genomes are folded into loops and topologically associating domains (TADs) by CTCF and cohesin, but whether these loops are stable or dynamic is unknown. Here, we directly visualize chromatin looping at the Fbn2 TAD in mouse embryonic stem cells using super-resolution live-cell imaging and quantify looping dynamics by Bayesian inference. Our results are consistent with cohesin-mediated loop extrusion in cells, and with CTCF both stopping and stabilizing cohesin. Surprisingly, the Fbn2 loop is both rare and dynamic, with a looped fraction of ~3-6.5% and a median loop lifetime of ~10-30 minutes. Instead of a stable loop, our results establish a highly dynamic view of TADs and loops where the Fbn2 TAD exists predominantly in a partially extruded conformation. This dynamic and quantitative view of TADs may facilitate a mechanistic understanding of their functions.

biophysics↗

bioRxiv2021

KMT2D haploinsufficiency in Kabuki Syndrome disrupts neuronal function through transcriptional and chromatin rewiring independent of H3K4-monomethylation

Kabuki syndrome (KS) is a rare multisystem disorder, characterized by intellectual disability, growth delay, and distinctive craniofacial features. It is mostly caused by de novo mutations of KMT2D, which is responsible for histone H3lysine 4 mono-methylation (H3K4me1) that marks active and poised enhancers. We assessed the impact of KMT2D mutations on chromatin and transcriptional regulation in a cohort of multiple KS1 tissues, including primary patient samples and disease-relevant lineages, namely cortical neurons (iN), neural crest stem cells (NCSC), and mesenchymal cells (MC). In parallel, we generated an isogenic line derived from human embryonic stem cells (hESC) for the stepwise characterization of neural precursors and mature neurons. We found that transcriptional dysregulation was particularly pronounced in cortical neurons and widely affected synapse activity pathways. This was consistent with highly specific alterations of spontaneous network-bursts patterns evidenced by Micro-electrode-array (MEA)-based neural network. Profiling of H3K4me1 unveiled the almost complete uncoupling between this chromatin mark and the effects on transcription, which is instead reflected by defects in H3K27ac. Finally, we identified the direct targets of KMT2D in mature cortical neurons, uncovering TEAD2 as the main mediator of KMT2D haploinsufficiency. Our results uncover the multi-tissue architecture of KS1 dysregulation and define a unique electrical phenotype and its molecular underpinnings for the cortical neuronal lineage.

genetics↗

bioRxiv2020

CHD8 haploinsufficiency alters the developmental trajectories of human excitatory and inhibitory neurons linking autism phenotypes with transient cellular defects

Chromodomain helicase DNA-binding 8 (CHD8) is one of the most frequently mutated genes causative of autism spectrum disorder (ASD). While its phenotypic spectrum often encompasses macrocephaly and hence implicates cortical abnormalities in this form of ASD, the neurodevelopmental impact of human CHD8 haploinsufficiency remains unexplored. Here we combined human cerebral organoids and single cell transcriptomics to define the effect of ASD-linked CHD8 mutations on human cortical development. We found that CHD8 haploinsufficiency causes a major disruption of neurodevelopmental trajectories with an accelerated generation of inhibitory neurons and a delayed production of excitatory neurons alongside the ensuing protraction of the proliferation phase. This imbalance leads to a significant enlargement of cerebral organoids aligned to the macrocephaly observed in patients with CHD8 mutations. By adopting an isogenic design of patient-specific mutations and mosaic cerebral organoids, we define genotype-phenotype relationships and uncover their cell-autonomous nature. Finally, our results assign different CHD8-dependent molecular defects to particular cell types, pointing to an abnormal and extended program of proliferation and alternative splicing specifically affected in, respectively, the radial glial and immature neuronal compartments. By identifying temporally restricted cell-type specific effects of human CHD8 mutations, our study uncovers developmental alterations as reproducible endophenotypes for neurodevelopmental disease modelling.

neuroscience↗

bioRxiv2020

KANSL1 Deficiency Causes Neuronal Dysfunction by Oxidative Stress-Induced Autophagy

Autophagy is a finely tuned process of programmed degradation and recycling of proteins and cellular components, which is crucial in neuronal function and synaptic integrity. Mounting evidence implicates chromatin remodelling in fine-tuning autophagy pathways. However, this epigenetic regulation is poorly understood in neurons. Here, we investigate the role in autophagy of KANSL1, a member of the nonspecific lethal complex, which acetylates histone H4 on lysine 16 (H4K16ac) to facilitate transcriptional activation. Loss-of-function of KANSL1 is strongly associated with the neurodevelopmental disorder Koolen-de Vries Syndrome (KdVS). Starting from KANSL1-deficient human induced-pluripotent stem cells, both from KdVS patients and genome-edited lines, we identified superoxide dismutase 1, an antioxidant enzyme, to be significantly decreased, leading to a subsequent increase in oxidative stress and autophagosome accumulation. In KANSL1-deficient neurons, autophagosome accumulation at excitatory synapses resulted in reduced synaptic density, reduced AMPA receptor-mediated transmission and impaired neuronal network activity. Furthermore, we found that increased oxidative stress-mediated autophagosome accumulation leads to increased mTOR activation and decreased lysosome function, further preventing the clearing of autophagosomes. Finally, by pharmacologically reducing oxidative stress, we could rescue the aberrant autophagosome formation as well as synaptic and neuronal network activity in KANSL1-deficient neurons. Our findings thus point towards an important relation between oxidative stress-induced autophagy and synapse function, and demonstrate the importance of H4K16ac-mediated changes in chromatin structure to balance reactive oxygen species- and mTOR-dependent autophagy.

neuroscience↗