Biology subjects

Perez, G.

Publications and source records attributed to Perez, G..

17 recordsLinked to original sources

bioRxiv2026

Expanding Threat of Carbapenemase-Producing Escherichia coli and Klebsiella pneumoniae in Peru: Genomic and Phenotypic Evidence of High-Risk Clones Dissemination

Carbapenemase-producing Enterobacterales represent a growing global threat due to their extensive antimicrobial resistance and rapid dissemination. This study characterized the phenotypic and genomic features of Escherichia coli and Klebsiella pneumoniae isolates collected between 2020 and 2022 from four healthcare institutions in Lima, Peru. A total of 320 non-redundant isolates (61 E. coli and 259 K. pneumoniae) were analyzed through antimicrobial susceptibility testing, polymerase chain reaction, and whole-genome sequencing. The most frequent carbapenemase gene was blaNDM (69%), followed by blaKPC (16.9%) and blaOXA-48-like (4.6%). Eleven K. pneumoniae isolates co-produced NDM and KPC, and one E. coli isolate co-harbored NDM and OXA-48-like. All isolates were multidrug resistant, and 5% were pandrug resistant. Novel {beta}-lactam/{beta}-lactamase inhibitor combinations such as aztreonam/avibactam and cefiderocol showed complete activity against all classes of carbapenemases. Genomic analysis revealed predominant E. coli sequence types ST167 and ST410 and K. pneumoniae lineages ST147, ST15, ST45, and ST273. The blaNDM-5 allele was detected for the first time in Peru, mostly in E. coli ST167, carried on multireplicon IncF-type plasmids. In K. pneumoniae, ST147 was identified as a dominant clone associated with blaNDM-1, indicating sustained local dissemination of high-risk clonal groups. The coexistence of multiple carbapenemases and plasmid backbones highlights the ongoing evolution of resistance mechanisms. These findings provide actionable evidence to guide treatment strategies in settings with high prevalence of metallo-{beta}-lactamases and underscores the need for continuous genomic surveillance and antimicrobial stewardship to mitigate their clinical and epidemiological impact.

microbiology↗

bioRxiv2025

An annotated chromosome-level genome assembly ofthe Adzuki bean borer Ostrinia scapulalis (Lepidoptera: Crambidae)

The genus Ostrinia (Lepidoptera: Crambidae) comprises two of the most important maize pests worldwide, the Asian and the European corn borers. Here, we present an annotated, chromosome-level genome assembly for the most closely related species, the Adzuki bean borer Ostrinia scapulalis, which feeds on various dicotyledon plants. The previous reference genome assembly for this species was generated from short-read sequencing data, resulting in high fragmentation and low completeness. Combining PacBio long read and Hi-C sequencing, we generated a 476 Mb genome with 48 contigs organised into 31 chromosomes (30 autosomes and one Z sex chromosome), with a contig N50 of 16.1 Mbp and BUSCO completeness exceeding 98%. We further combined published and novel RNA-seq data encompassing multiple life stages, tissues, and sexes to annotate 14,261 gene models, reaching a proteome BUSCO completeness of 95%. This highly contiguous reference genome assembly provides a much-improved resource for carrying comparative genomic approaches and better understanding speciation and host plant adaptation in the Ostrinia genus.

evolutionary biology↗

bioRxiv2025

Map simulator of tick abundance in heterogeneous agricultural landscapes

Among vector-borne diseases, tick-borne diseases (TBD) are a major concern for human health. Mapping the distribution of important tick species is thus a major challenge for efficient prevention. Due to its specific ecological requirements, Ixodes ricinus, the main tick species in Europe responsible for TBD transmission, lives mostly in woodlands but also at the interface between woodlands and pastures or crops and along hedgerows. At the landscape scale, extensive variations in tick densities are observed but remain poorly understood. In that aim, we built a statistical model to identify the landscape variables influencing the abundance of questing I. ricinus nymphs, using GLMM approaches and MCMC estimates. This model was fitted on a data set based on a field sampling of ticks conducted during 3 years in 2 different agricultural landscapes in northwest and southwest France, for a total of 5390 sampling units. Among 12 variables investigated, 4 were finally kept in the model: woodland perimeter, woodland distance, road distance and building perimeter. Then, we developed a R package that simulates the abundance of questing nymphs within a given agricultural landscape, taking into account the influence of the different habitats as determined by the above statistical model. The maps obtained as an output from this simulator will be a useful tool for visualizing TBD risk, notably for stake-holders involved in landscape management and public health decisions. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=88 SRC="FIGDIR/small/663759v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@f950aborg.highwire.dtl.DTLVardef@1f0f27org.highwire.dtl.DTLVardef@11bde05org.highwire.dtl.DTLVardef@8d2202_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsIxodes ricinus abondance is influenced by landscape characteristics Tick sampling was carried out in heterogeneous agricultural landscapes Informative variables related to habitats were identified by statistical analysis Woodlands, roads and buildings influence tick densities The resulting model was used to build a simulator of tick at-risk zones

ecology↗

bioRxiv2025

Bidirectional regulation of glycoprotein nonmetastatic melanoma protein B by β-glucocerebrosidase deficiency in GBA1 isogenic dopaminergic neurons from a patient with Gaucher disease and parkinsonism

Variants in GBA1 are common genetic risk factors for several synucleinopathies. The increased risk has been attributed to the toxic effects of misfolded glucocerebrosidase (GCase) (gain-of-function), and the accumulation of lipid substrates due to reduced enzyme activity (loss-of-function). To delineate GBA1 pathogenicity, an iPSC line was generated from a patient with both type 1 Gaucher disease (GBA1: N370S/N370S; p.N409S/p.N409S) and Parkinson disease (PD). From this line, we created a reverted wild-type (WT) line and a GBA1 knockout (KO) line to eliminate misfolded GCase and intensify lipid accumulation. N370S/N370S and KO dopaminergic neurons (DANs) exhibited decreasing GCase levels and progressive accumulation of lipid substrates compared to WT DANs. Notably, the expression of GPNMB, whose levels correlate with PD risk, was upregulated by the mild lipid accumulation in N370S/N370S DANs but disrupted in KO DANs. These findings refine the loss-of-function mechanism by associating PD risk levels of GPNMB with lipid levels specific to GBA1 risk variants.

neuroscience↗

bioRxiv2025

Likely circulation of a coronavirus in roe deer (Capreolus capreolus) populations suggested by SARS-CoV-2 serological investigation in France

The risk of viral transmissions from domestic/wild animals to humans is a major public health concern. Humans can also transmit viruses back to domestic and wild animals, acting as reservoir for virus maintenance and sources of epidemic diseases re-emergence. The SARS-CoV-2, causing COVID-19, likely originated from wildlife and has been evidenced to transmit from humans to captive, domestic and wild animals. White-tailed deer (Odocoileus virginianus) show high SARS-CoV-2 prevalence following human contamination, suggesting they could act as an emerging virus reservoir. We completed recent research on European cervid species by investigating whether SARS-CoV-2 had emerged in longitudinally-monitored European roe deer (Capreolus capreolus) populations in direct contact with humans in France. We performed indirect tests (serological ELISAs and seroneutralization) on sera collected before and after the virus emergence in humans, and direct RT-PCR tests on nasal swabs collected in 2022. We also investigated the virus exposure and prevalence in three other cervid species. ELISA tests were positive for 2.20% of sera, pre- and post-pandemic, but seroneutralization and PCR tests were negative. Although one population showed increased seroprevalence post-2020, results suggest that SARS-CoV-2 has not emerged in those populations, and that ELISA cross-reaction with one or several unidentified circulating coronaviruses is possible.

immunology↗

bioRxiv2024

TRF1 and TRF2 form distinct shelterin subcomplexes at telomeres

The shelterin complex protects chromosome ends from the DNA damage repair machinery and regulates telomerase access to telomeres. Shelterin is composed of six proteins (TRF1, TRF2, TIN2, TPP1, POT1 and RAP1) that can assemble into various subcomplexes in vitro. However, the stoichiometry of the shelterin complex and its dynamic association with telomeres in cells is poorly defined. To quantitatively analyze the shelterin function in living cells we generated a panel of cancer cell lines expressing HaloTagged shelterin proteins from their endogenous loci. We systematically determined the total cellular abundance and telomeric copy number of each shelterin subunit, demonstrating that the shelterin proteins are present at telomeres in equal numbers. In addition, we used single-molecule live-cell imaging to analyze the dynamics of shelterin protein association with telomeres. Our results demonstrate that TRF1-TIN2-TPP1-POT1 and TRF2-RAP1 form distinct subcomplexes that occupy non-overlapping binding sites on telomeric chromatin. TRF1-TIN2-TPP1-POT1 tightly associates with chromatin, while TRF2-RAP1 binding to telomeres is more dynamic, allowing it to recruit a variety of co-factors to chromatin to protect chromosome ends from DNA repair factors. In total, our work provides critical mechanistic insight into how the shelterin proteins carry out multiple essential functions in telomere maintenance and significantly advances our understanding of macromolecular structure of telomeric chromatin.

cell biology↗

bioRxiv2024

Comparative study of enriched dopaminergic neurons from siblings with Gaucher disease discordant for parkinsonism

Inducible pluripotent stem cells (iPSCs) derived from patient samples have significantly enhanced our ability to model neurological diseases. Comparative studies of dopaminergic (DA) neurons differentiated from iPSCs derived from siblings with Gaucher disease discordant for parkinsonism provides a valuable avenue to explore genetic modifiers contributing to GBA1-associated parkinsonism in disease-relevant cells. However, such studies are often complicated by the inherent heterogeneity in differentiation efficiency among iPSC lines derived from different individuals. To address this technical challenge, we devised a selection strategy to enrich dopaminergic (DA) neurons expressing tyrosine hydroxylase (TH). A neomycin resistance gene (neo) was inserted at the C-terminus of the TH gene following a T2A self-cleavage peptide, placing its expression under the control of the TH promoter. This allows for TH+ DA neuron enrichment through geneticin selection. This method enabled us to generate comparable, high-purity DA neuron cultures from iPSC lines derived from three sisters that we followed for over a decade: one sibling is a healthy individual, and the other two have Gaucher disease (GD) with GBA1 genotype N370S/c.203delC+R257X (p.N409S/c.203delC+p.R296X). Notably, the younger sister with GD later developed Parkinson disease (PD). A comprehensive analysis of these high-purity DA neurons revealed that although GD DA neurons exhibited decreased levels of glucocerebrosidase (GCase), there was no substantial difference in GCase protein levels or lipid substrate accumulation between DA neurons from the GD and GD/PD sisters, suggesting that the PD discordance is related to of other genetic modifiers.

neuroscience↗

bioRxiv2023

The distribution, phenology, host range and pathogen prevalence of Ixodes ricinus in France: a systematic map and narrative review

The tick Ixodes ricinus is the most important vector species of infectious diseases in European France. Understanding its distribution, phenology, and host species use, along with the distribution and prevalence of associated pathogens at national scales is essential for developing prevention strategies. The aim of this paper is to provide a systematic map and narrative review of the existing knowledge on the eco-epidemiology of I. ricinus in France. Using literature published up to 2020, the present paper provides a distribution map for the species and a summary of environmental factors explaining observed geographical differences in phenology and temporal differences in abundance. The diversity of vertebrate host species used by this tick, along with their degree of infestation when available, are presented and discussed with respect to their potential contribution to the population dynamics of I. ricinus and the circulation of tick-borne zoonotic pathogens. Prevalence data of detected pathogens are summarised in different maps. Results from 187 identified references show that the species is present in most departments, but scarce under Mediterranean climate and in coastal habitats. Its phenology is generally bimodal with variations depending on climate. Abundance seems positively influenced by forest cover and host abundance. Rodents and ruminants are the most studied species groups, but the diversity of sampling protocols (e.g., location, season, exhaustivity of inspection) precluded direct comparisons between species groups. Data on pathogens are patchy, with most studies conducted near research units. Among pathogens, Borrelia burgdorferi sensu lato is the most searched for in ticks and seems more prevalent in north-eastern and central France. The review carried out here has made it possible to highlight the gaps in our knowledge of tick-host-pathogen interactions, their ecology and their distribution, and the need to address these gaps in order to optimize tick and tick-borne diseases prevention and control strategies.

ecology↗

bioRxiv2022

Using spatio-temporal information in weather radar data to detect and track communal bird roosts

O_LIThe exodus of swallows from communal nighttime roosts is often visible as an expanding ring-shaped pattern in weather radar data. The WSR-88D network operated by the National Weather Service archives more than 25 years of data across 143 stations in the contiguous US. However, access to information about the roosting behavior of swallows is limited by the cost of manual annotation of these scans. C_LIO_LIWe develop an AI system to detect and track swallow roosts in weather radar data. Our model is based on the Faster R-CNN architecture and is customized to incorporate multiple spatial and temporal channels in volumetric radar scans using novel adaptor layers. We systematically study the impact of network architecture and input representation for this task. We incorporate our detection outputs into an AI-assisted system with an interface for human screening to collect research-grade data about roosting behavior. We deploy the system to collect information from 12 radar stations in the Great Lakes region of the US spanning 21 years. C_LIO_LIThe addition of temporal information improves roost detection performance from 47.0% mean average precision to 54.7%. Temporal information helps the model recognize the expanding pattern of roosts and filter false positives due to rain and static structures. Our system allowed the annotation of 15,628 roost signatures with 64,620 single-frame detections in 612,786 radar scans with 183.6 total hours of human screening, or 1.08 seconds per radar scan. C_LIO_LIOur AI-assisted system provides research-quality roost data with far less human effort than manual annotation of radar scans. The data contains critical information about the phenology and population trends of swallows and martins, a declining group of aerial insectivores. Our successful deployment to collect historical data for 8% of the radar stations in the contiguous US lays the groundwork for continentscale analysis of swallow roosts, and provides a starting point for analysis of other family-specific phenomena in weather radar, such as bat roosts and mayfly hatches. C_LI

ecology↗

bioRxiv2022

When complex movement yields simple dispersal: behavioural heterogeneity, spatial spread and parasitism in groups of micro-wasps

O_LIUnderstanding how behavioural dynamics, inter-individual variability and individual interactions scale-up to shape the spatial spread and dispersal of animal populations is a major challenge in ecology. For biocontrol agents, such as the microscopic Trichogramma parasitic wasps, an understanding of movement strategies is also critical to predict pest-suppression performance in the field. C_LIO_LIWe experimentally studied the spatial propagation of groups of parasitoids and their patterns of parasitism. We investigated whether population spread is density-dependent, how it is affected by the presence of hosts, and whether the spatial distribution of parasitism (dispersal kernel) can be predicted from the observed spread of individuals. C_LIO_LIUsing a novel experimental device and high-throughput imaging techniques, we continuously tracked the spatial spread of groups of parasitoids over large temporal and spatial scales (eight hours; and six metres, ca. 12,000 body lengths). We could thus study how population density, the presence of hosts and their spatial distribution impacted the rate of population spread, the spatial distribution of individuals during population expansion, the overall rate of parasitism and the dispersal kernel (position of parasitism events). C_LIO_LIHigher population density accelerated population spread, but only transiently: the rate of spread reverted to low values after four hours, in a "tortoise-hare" effect. Interestingly, the presence of hosts suppressed this transiency and permitted a sustained high rate of population spread. Importantly, we found that population spread did not obey classical diffusion, but involved dynamical switches between resident and explorer movement modes. Population distribution was therefore not Gaussian, though surprisingly the distribution of parasitism (dispersal kernel) was. C_LIO_LIEven homogenous asexual groups of animals were shown to develop behavioral heterogeneties over a few hours. Explorer individuals were responsible for most parasitism and dispersal, and determined spatial spread and density-dependent dispersal. We showed that simple Gaussian dispersal did not emerge from simple diffusion, but rather from the interplay of several non-linearities at individual level. This suggests expectations from classical diffusion theory may not hold generally to active dispersers. These results highlight the need to take into account behaviour and inter-individual heterogeneity to understand population spread in animals. C_LI

ecology↗

bioRxiv2022

A double-spiral maze and hi-resolution tracking pipeline to study dispersal by groups of minute insects

Minute insects such as parasitic micro-wasps have high basic and applied importance, for their widespread use as biocontrol agents. Their dispersal is a phenotype of particular interest. Classically, it is evaluated using field releases, but those are time consuming, costly, and their results highly variable, preventing high-throughput and repeatability. Alternatively, dispersal can be studied using small-scale assays, but those neglect important higher-scale processes. Consequently, proper evaluation of dispersal is often complicated or lacking in academic studies and biocontrol breeding programs. Here we introduce a new method, the double-spiral maze, that allows the study of spatial propagation at relevant scales (several hours and meters), retaining high throughput and experimental power. The method records the location of every individual at every time, enabling accurate precise estimates of diffusion coefficients or other dispersal metrics. We describe this affordable, scalable, and easy-to-implement method, and illustrate its application with a species of agricultural interest.

ecology↗

bioRxiv2022

Non-target effects of ten essential oils on the egg-parasitoid Trichogramma evanescens

Essential oils (EOs) are increasingly used as biopesticides due to their insecticidal potential. This study addresses their non-target effects on a biological control agent: the egg parasitoid Trichogramma evanescens. In particular, we tested whether EOs affected parasitoid fitness either directly, by decreasing pre-imaginal survival, or indirectly, by disrupting parasitoids orientation abilities. The effect of Anise, Fennel, Sweet orange, Basil, Coriander, Oregano, Peppermint, Mugwort, Rosemary and Thyme EOs were studied on five strains of T. evanescens. Specific experimental setups were developed, and data obtained from image analysis were interpreted with phenomenological models fitted with Bayesian inference. Results highlight the fumigant toxicity of EOs on parasitoid development. Anise, Fennel, Basil, Coriander, Oregano, Peppermint and Thyme EOs are particularly toxic and drastically reduce the emergence rate of T. evanescens. Most EOs also affect parasitoid behavior: (i) Basil, Coriander, Oregano, Peppermint, Mugwort and Thyme EOs are highly repellent for naive female parasitoids; (ii) Anise and Fennel EOs can have repellent or attractive effects depending on strains; and (iii) Sweet orange, Oregano and Rosemary EOs have no detectable impact on orientation behavior. This study shows that EOs fumigation have non-target effects on egg parasitoids. This highlights the need to cautiously precise the deployment framework of biopesticides in an agroecological perspective.

ecology↗

bioRxiv2021

Let-7b-5p, miR-184, and miR-22-3p: Multianalyte Plasma Biomarkers for NSCLC Diagnosis and for Predicting Resistance to Osimertinib

Low-dose computed tomography (LDCT) Non-Small Cell Lung (NSCLC) screening is associated with high false-positive rates, leading to unnecessary expensive and invasive follow ups. There is a need for minimally invasive approaches to improve the accuracy of NSCLC diagnosis. Plasma extracellular vesicle (EV) and circulating microRNA (miRNA) have been proposed as cancer screening biomarkers. However, the identification of highly sensitive and broadly predictive core miRNA signatures remains a challenge. Also, how these systemic and diverse miRNAs impact cancer drug response is not well understood. Using an integrative approach, we examined plasma EV and circulating miRNA isolated from NSCLC patients versus screening controls with a similar risk profile. We found that combining EV (Hsa-miR-184, Let-7b-5p) and circulating (Hsa-miR-22-3p) miRNAs abundance robustly discriminates between NSCLC patients and high-risk cancer-free controls. Diagnosed NSCLC patients harboring sensitizing mutations in epidermal growth factor receptor EGFR (T790M, L578R) are treated with Osimertinib, a potent tyrosine kinase inhibitor (TKI). Nearly all patients develop TKI resistance via complex mechanisms and progress. We found that Hsa-miR-22-3p, Hsa-miR-184, and Let-7b-5p functionally converge on WNT/{beta}catenin and mTOR/AKT signaling axes, known cancer therapy resistance signals. Targeting Hsa-miR-22-3p and Hsa-miR-184 desensitized EGFR-mutated (T790M, L578R) NSCLC cells to Osimertinib. These findings suggest that the expression levels of circulating hsa-miR-22-3p combined with EV hsa-miR-184 and Let-7b-5p levels potentially define a core biomarker signature for improving the accuracy of NSCLC diagnosis. Importantly, these biomarkers have the potential to enable prospective identification of patients who are at risk of responding poorly to Osimertinib alone but likely to benefit from Osimertinib/AKT blockade combination treatments.

cancer biology↗

bioRxiv2021

Up and to the light: intra- and interspecific variability of photo- and geo-tactic oviposition preferences in genus Trichogramma

AO_SCPLOWBSTRACTC_SCPLOWTrichogramma are parasitic microwasps much used as biological control agents. The genus is known to harbor tremendous diversity, at both inter- and intra-specific levels. The successful selection of Trichogramma strains for biocontrol depends on characterizing the existing diversity in this group, especially regarding oviposition performance and behavior. Oviposition preferences in relation to environmental cues such as light and gravity have received little attention so far, although they are suspected to play an important role in microhabitat selection and parasitism patterns. The extent of their variability, and their potential correlated variations, is virtually unknown. Here we use a novel experimental approach relying on automatic image analysis to characterize the oviposition preferences in relation to light and gravity, as well as their interaction, in 25 populations of Trichogramma from five species. We show that most Trichogramma populations and species harbour preferences for light and preferences for elevated parts. However, the two traits harbor significant inter and intraspecific variation. The effects of light and gravity on oviposition patterns were found to be almost perfectly additive overall, with two exceptions. Oviposition preference patterns were not static but very plastic in time: preferences tended to relax over consecutive days, and the strongest preferences relaxed the fastest, presumably because of the density-dependent effect of resource depletion. A correlation of oviposition patterns with the vegetation stratum at which populations were sampled suggests that different species/populations may be associated with different strata with corresponding differentiation in light- and gravity-related oviposition preferences. This article has been peer-reviewed and recommended by Peer Community in Zoology doi: https://doi.org/10.24072/pci.zool.100008

ecology↗

bioRxiv2021

Local jasmonic acid cues drive systemic acquired resistance signal generation

The phytohormones salicylic acid (SA) and jasmonic acid (JA) promote two, mutually antagonistic immune pathways respectively protecting plants from biotrophic pathogens and necrotrophic pathogens or insects. This trade-off largely precludes the exploitation of SA and JA immune components for crop protection, raising the interest in immune signalling components that disrupt SA-JA antagonism. A local pathogen infection primes SA-dependent immunity in systemic tissues. This so-called systemic acquired resistance (SAR) ensures a long-lasting, broad-spectrum disease resistance that is not subject to SA-JA antagonism. Here, we show that two sequence-related LEGUME LECTIN-LIKE PROTEINs (LLPs) promote SAR through spatially separated functions with JA promoting local SAR signal generation through LLP3. In concert with LLP1, which is important for systemic recognition and propagation of SAR signals, LLP3 promotes both SA-dependent SAR and JA-mediated immunity. Thus, exploitation of LLP-associated signalling cues might allow application of plant innate immune signals to promote (crop) plant health.

plant biology↗

bioRxiv2019

Relationships between landscape structure and the prevalence of two tick-borne infectious agents, Anaplasma phagocytophilum and Borrelia burgdorferi sensu lato, in small mammal communities

ContextBy modifying ecosystems, land cover changes influence the emergence, the spread and the incidence of vector-borne diseases. ObjectiveThis study aimed at identifying associations between landscape structure and the prevalence of two tick-borne infectious agents, Anaplasma phagocytophilum and Borrelia burgdorferi s.l., in small mammal communities. MethodsSmall mammals were sampled in 24 sites along a gradient of woodland fragmentation and hedgerow network density, and screened for infectious agents with real-time PCR techniques. For each site, structural variables (composition and configuration) of the surrounding landscape at various scales (0-500 m) and variables of wooded habitats connectivity based on graph theory and least cost path distances for the two dominant species, bank voles (Myodes glareolus) and wood mice (Apodemus sylvaticus), were computed. ResultsThe A. phagocytophilum prevalence increased with wooded habitats cover (0-500 m), likely through host population size, and increased slightly with bank vole abundance, which has a higher reservoir competence than wood mouse. The B. burgdorferi s.l. prevalence increased with wooded ecotones only at local scales (50-100 m). Wooded habitats connectivity measures did not improve models built with simple land cover variables. A more marked spatial pattern was observed for the prevalence of A. phagocytophilum than B. burgdorferi s.l.. ConclusionsThis study highlights the interest of considering together the ecology of infectious agents (e.g. host specificity) and the host species community ecology to better understand the influence of the landscape structure on the spatial distribution of vector-borne infectious agents.

ecology↗

bioRxiv2018

In vivo epigenetic editing of sema6a promoter reverses impaired transcallosal connectivity caused by C11orf46/ARL14EP neurodevelopmental risk gene

Many neuropsychiatric risk genes contribute to epigenetic regulation of gene expression but very little is known about specific chromatin-associated mechanisms governing the formation and maintenance of neuronal connectivity. Here we show that transcallosal connectivity is critically dependent on C11orf46 (also known as ARL14EP), a small nuclear protein encoded in the chromosome 11p13 Wilms Tumor, Aniridia, Genitourinary Abnormalities, intellectual disability (formerly referred to as Mental Retardation) (WAGR) risk locus. C11orf46 haploinsufficiency in WAGR microdeletion cases was associated with severe hypoplasia of the corpus callosum. In utero short hairpin RNA-mediated C11orf46 knockdown disrupted transcallosal projections of cortical pyramidal neurons, a phenotype that was rescued by wild type C11orf46 but not the C11orf46R236H mutant associated with autosomal recessive intellectual disability. Multiple genes encoding key regulators of axonal growth and differentiation, including Sema6A, were hyperexpressed in C11orf46-knockdown neurons. Importantly, RNA-guided epigenetic editing of neuronal Sema6a gene promoters via a dCas9 protein-conjugated SunTag scaffold with multimeric (10x) C11orf46 binding during early developmental periods, resulted in normalization of expression and rescue of transcallosal dysconnectivity via repressive chromatin remodeling, including up-regulated histone H3K9 methylation by the KAP1-SETDB1 repressor complex. Our study demonstrates that interhemispheric communication is highly sensitive to locus-specific remodeling of neuronal chromatin, revealing the therapeutic potential for shaping the brains connectome via gene-targeted designer activators and repressor proteins.

developmental biology↗