Biology subjects

Gonzalez, S.

Publications and source records attributed to Gonzalez, S..

28 records · Page 2Linked to original sources

bioRxiv2020

Neuromotor impairment, hearing loss and blindness in a preclinical mouse model of Charcot Marie-Tooth disorder

Schwann cells produce myelin sheath around peripheral nerve axons. Myelination is critical for rapid propagation of action potentials, as illustrated by the large number of acquired and hereditary peripheral neuropathies, such as diabetic neuropathy or Charcot-Marie-Tooth (CMT) diseases, that are commonly associated with a process of demyelination. Peripheral neuropathy is a major complication of diabetes, and the pathomechanism of the disease remains poorly studied. Here, we studied the progressive demyelinating process, hearing impairment and blindness observed in the CMT1A mouse model C3. Our results confirm that these mice represent a robust and validated model to study the peripheral neuropathy induced by CMT disorder allowing to determine the efficacy of new pharmacological candidates targeting demyelinating diseases such as CMT1A disorder.

neuroscience↗

bioRxiv2020

A peptidergic amygdala microcircuit modulates sexually dimorphic contextual fear

Trauma can cause dysfunctional fear regulation leading some to develop disorders like post-traumatic stress disorder (PTSD). The amygdala regulates fear, and, PACAP and PAC1 receptors are linked to PTSD symptom severity at genetic/epigenetic levels, with a strong link in females with PTSD. We discovered a PACAPergic projection from the basomedial amygdala (BMA) to the medial intercalated cells (mICCs). In vivo optogenetic stimulation of this pathway increased cfos expression in mICCs, decreased fear retention and increased fear extinction. Selective deletion of PAC1 receptors from the mICCs in females reduced fear acquisition, but enhanced fear generalization and reduced fear extinction in males. Optogenetic stimulation of the BMA-mICCs PACAPergic pathway produced excitatory postsynaptic currents (EPSCs) in mICCs neurons, which was enhanced by PAC1 receptor antagonist, PACAP 6-38. Our findings show that mICCs modulate contextual fear in a dynamic and sex-dependent manner via the microcircuit containing the BMA and mICCs, dependent on behavioral state.

neuroscience↗

bioRxiv2019

Pan-cancer computational histopathology reveals mutations, tumor composition and prognosis

The diagnosis of cancer is typically based on histopathological assessment of tissue sections, and supplemented by genetic and other molecular tests1-6. Modern computer vision algorithms have high diagnostic accuracy and potential to augment histopathology workflows7-9. Here we use deep transfer learning to quantify histopathological patterns across 17,396 hematoxylin and eosin (H&E) stained histopathology slide images from 28 cancer types and correlate these with matched genomic, transcriptomic and survival data. This approach accurately classifies cancer types and provides spatially resolved tumor and normal distinction. Automatically learned computational histopathological features correlate with a large range of recurrent genetic aberrations pan-cancer. This includes whole genome duplications, which display universal features across cancer types, individual chromosomal aneuploidies, focal amplifications and deletions as well as driver gene mutations. There are wide-spread associations between bulk gene expression levels and histopathology, which reflect tumour composition and enables localising transcriptomically defined tumour infiltrating lymphocytes. Computational histopathology augments prognosis based on histopathological subtyping and grading and highlights prognostically relevant areas such as necrosis or lymphocytic aggregates. These findings demonstrate the large potential of computer vision to characterise the molecular basis of tumour histopathology and lay out a rationale for integrating molecular and histopathological data to augment diagnostic and prognostic workflows.

bioinformatics↗

bioRxiv2019

FACT mediates cohesin function on chromatin

Cohesin is a key regulator of genome architecture with roles in sister chromatid cohesion 1,2 and the organisation of higher-order structures during interphase 3 and mitosis 4,5. The recruitment and mobility of cohesin complexes on DNA is restricted by nucleosomes 6-8. Here we show that cohesin role in chromosome organisation requires the histone chaperone FACT. Depletion of FACT in metaphase cells affects cohesin stability on chromatin reducing its accumulation at pericentric regions and binding on chromosome arms. Using Hi-C, we show that cohesin-dependent TAD (Topological Associated Domains)-like structures in G1 and metaphase chromosomes are disrupted in the absence of FACT. Surprisingly, sister chromatid cohesion is intact in FACT-depleted cells, although chromosome segregation failure is observed. Our results uncover a role for FACT in genome organisation by facilitating cohesin-dependent compartmentalization of chromosomes into loop domains.

molecular biology↗

bioRxiv2019

The GATA transcription factor Gaf1 represses tRNA genes, inhibits growth, and extends chronological lifespan downstream of fission yeast TORC1

Target of Rapamycin Complex 1 (TORC1) signaling promotes growth and ageing. Inhibition of TORC1 leads to a down-regulation of factors that stimulate protein translation, including RNA polymerase III, which in turn contributes to longevity. TORC1-mediated post-transcriptional regulation of protein translation has been well studied, while analogous transcriptional regulation is less well understood. Here we screened fission yeast deletion mutants for resistance to Torin1, which inhibits TORC1 and cell growth. Mutants lacking the GATA transcription factor Gaf1 (gaf1{Delta}) grew normally even in high doses of Torin1. The gaf1{Delta} mutants shortened the chronological lifespan of non-dividing cells and diminished the lifespan extension triggered by Torin1 treatment. Expression profiling and genome-wide binding experiments showed that, after TORC1 inhibition, Gaf1 directly up-regulated genes for small-molecule metabolic pathways and indirectly repressed genes for protein translation. Surprisingly, Gaf1 bound to, and down-regulated the tRNA genes, so also functions as a transcription factor for genes transcribed by RNA polymerase III. We conclude that Gaf1 controls the transcription of both coding and tRNA genes to inhibit translation and growth downstream of TORC1.

genetics↗

bioRxiv2019

Schwann cell demyelination is triggered by a transient mitochondrial calcium release through Voltage Dependent Anion Channel 1

The maintenance of the myelin sheath by Schwann cells around peripheral nerve axons is essential for the rapid propagation of action potentials. A large number of peripheral neuropathies results for the loss of this myelin sheath, a process called demyelination. Demyelination is a program of cell dedifferentiation characterized by reprograming and several catabolic and anabolic events. This process was best characterized in Wallerian demyelination that occurs following nerve injury. In this model, the earliest well characterized steps are MAPK pathways activation and cJun phosphorylation and nuclear localization starting around 4hrs after nerve injury. Here we show, using in vivo imaging of virally-delivered fluorescent probes to mitochondria, that Schwann cell mitochondria pH, motility and calcium are altered as soon as 1hr after nerve injury. Mitochondrial calcium release through VDAC1 mitochondrial channel and mPTP directly induced Schwann cell demyelination via MAPK and c-Jun activation. Decreasing mitochondrial calcium release through VDAC1 silencing or TRO19622 blocking prevented MAPK and cJun activation and demyelination. VDAC1 opening with Methyl Jasmonate induced these cellular mechanisms in absence of nerve injury. Taken together, these data indicate that mitochondria calcium homeostasis through VDAC1 is instrumental in the Schwann cell demyelination process and therefore provide a molecular basis for an anti-demyelinating drug approach.

neuroscience↗

bioRxiv2018

Genomic landscape and chronological reconstruction of driver events in multiple myeloma

Multiple myeloma (MM) has a heterogeneous genome, evolving through both pre-clinical and post-diagnosis phases. Here, using sequences from 67 MM genomes serially collected from 30 patients together with public datasets, we establish a hierarchy of driver lesions. Point mutations, structural variants and copy number aberrations define at least 7 genomic subgroups of MM, each with distinct sets of co-operating driver mutations. Complex structural events are major drivers of MM, including chromothripsis, chromoplexy and a replication-based mechanism of templated insertions: these typically occur early. Hyperdiploidy also occurs early, with individual chromosomes often gained in more than one chronological epoch of MM evolution, showing a preferred order of acquisition. Positively selected point mutations frequently occur in later phases of disease development, as do structural variants involving MYC. Thus, initiating driver events of MM, drawn from a limited repertoire of structural and numerical chromosomal changes, shape preferred trajectories of subsequent evolution.

cancer biology↗

bioRxiv2017

The evolutionary history of 2,658 cancers

Cancer develops through a process of somatic evolution. Here, we use whole-genome sequencing of 2,778 tumour samples from 2,658 donors to reconstruct the life history, evolution of mutational processes, and driver mutation sequences of 39 cancer types. The early phases of oncogenesis are driven by point mutations in a small set of driver genes, often including biallelic inactivation of tumour suppressors. Early oncogenesis is also characterised by specific copy number gains, such as trisomy 7 in glioblastoma or isochromosome 17q in medulloblastoma. By contrast, increased genomic instability, a nearly four-fold diversification of driver genes, and an acceleration of point mutation processes are features of later stages. Copy-number alterations often occur in mitotic crises leading to simultaneous gains of multiple chromosomal segments. Timing analysis suggests that driver mutations often precede diagnosis by many years, and in some cases decades, providing a window of opportunity for early cancer detection.

cancer biology↗

bioRxiv2017

A Comprehensive Reanalysis Of Publicly Available GWAS Datasets Reveals An X Chromosome Rare Regulatory Variant Associated With High Risk For Type 2 Diabetes.

The reanalysis of publicly available GWAS data represents a powerful and cost-effective opportunity to gain insights into the genetics and pathophysiology of complex diseases. We demonstrate this by gathering and reanalyzing public type 2 diabetes (T2D) GWAS data for 70,127 subjects, using an innovative imputation and association strategy based on multiple reference panels (1000G and UK10K). This approach led us replicate and fine map 50 known T2D loci, and identify seven novel associated regions: five driven by common variants in or near LYPLAL1, NEUROG3, CAMKK2, ABO and GIP genes; one by a low frequency variant near EHMT2; and one driven by a rare variant in chromosome Xq23, associated with a 2.7-fold increased risk for T2D in males, and located within an active enhancer associated with the expression of Angiotensin II Receptor type 2 gene (AGTR2), a known modulator of insulin sensitivity. We further show that the risk T allele reduces binding of a nuclear protein, resulting in increased enhancer activity in muscle cells. Beyond providing novel insights into the genetics and pathophysiology of T2D, these results also underscore the value of reanalyzing publicly available data using novel analytical approaches.

genetics↗

bioRxiv2017

Human PGBD5 DNA transposase promotes site-specific oncogenic mutations in rhabdoid tumors

Genomic rearrangements are a hallmark of childhood solid tumors, but their mutational causes remain poorly understood. Here, we identify the piggyBac transposable element derived 5 (PGBD5) gene as an enzymatically active human DNA transposase expressed in the majority of rhabdoid tumors, a lethal childhood cancer. Using assembly-based whole-genome DNA sequencing, we observed previously unknown somatic genomic rearrangements in primary human rhabdoid tumors. These rearrangements were characterized by deletions and inversions involving PGBD5-specific signal (PSS) sequences at their breakpoints, with some recurrently targeting tumor suppressor genes, leading to their inactivation. PGBD5 was found to be physically associated with human genomic PSS sequences that were also sufficient to mediate PGBD5-induced DNA rearrangements in rhabdoid tumor cells. We found that ectopic expression of PGBD5 in primary immortalized human cells was sufficient to promote penetrant cell transformation in vitro and in immunodeficient mice in vivo. This activity required specific catalytic residues in the PGBD5 transposase domain, as well as end-joining DNA repair, and induced distinct structural rearrangements, involving PSS-associated breakpoints, similar to those found in primary human rhabdoid tumors. This defines PGBD5 as an oncogenic mutator and provides a plausible mechanism for site-specific DNA rearrangements in childhood and adult solid tumors.

cancer biology↗