Biology subjects

Heutink, P.

Publications and source records attributed to Heutink, P..

At least 19 recordsLinked to original sources

bioRxiv2025

Integrative analysis of pooled CRISPR screens provide functional insights into AD GWAS risk genes

Emerging research has implicated Alzheimers disease (AD) pathology with dysregulation of many key pathways in microglia, including lipid transport and metabolism, phagocytosis of plaques, and lysosomal function. However, the exact mechanisms underlying these pathways remain poorly understood. Leveraging high-throughput CRISPR screens to understand the interplay between these pathways may enable novel therapeutic strategies for AD and other neurological diseases. Here, we constructed activation and interference CRISPRa/i libraries targeting 203 genes, 71 of which were identified through neurodegenerative GWAS, and 132 additional genes linked to microglial functions. We used this library to conduct pooled CRISPRa/i screens across a range of functional assays relating to lipid metabolism and lysosomal function using a monocytic cell line, THP-1. We identified a core set of lipid and lysosome mediators and validated a subset in primary macrophages. To gain insights into transcriptional states modulated by these genes we also applied the CRISPRa/i libraries to Perturb-seq, enabling us to capture transcriptomic changes. Through non-negative matrix factorization, we identified five gene programs altered by our perturbation library. We then used an integrative analysis of functional screen data with Perturb-seq data that enabled us to uncover novel functions and genetic relationships between perturbations. This multidimensional resource links genetic perturbations to phenotypes and transcriptional programs, establishing a scalable framework for systematic gene discovery in neurodegeneration and beyond. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=162 SRC="FIGDIR/small/660041v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@5b2acborg.highwire.dtl.DTLVardef@156a0b1org.highwire.dtl.DTLVardef@4fdbb8org.highwire.dtl.DTLVardef@e2166c_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG

genetics↗

bioRxiv2025

Piccolo Regulates Secretion of the Extracellular Matrix Components Brevican and Tenascin R from Astrocytes to Drive Synapse Formation: Implications for Pontocerebellar Hypoplasia Type 3 (PCH3)

BackgroundAstrocytes are crucial for CNS health, for instance via the secretion of extracellular matrix (ECM) components that are vital for synapse formation and maturation. While the scaffolding protein Piccolo is known for its role at synapses, its function in astrocytes and contribution to neurodegenerative disorders like Pontocerebellar Hypoplasia Type 3 (PCH3) are largely unknown. Understanding these mechanisms is key to elucidating PCH3 pathology. MethodsWe used a multi-faceted approach with a Pclogt/gtrat model. Methods included RNA-sequencing for gene expression and GO analysis. Immunohistochemistry and immunocytochemistry assessed Piccolo localization, ECM component (Brevican [Bcan], Tenascin-R [TNR]) levels, distribution, and secretion in brain sections and primary astrocytes. Golgi morphology was evaluated via GM130 staining. Neuronal network formation and function were investigated by co-culturing wild-type neurons with Pclowt/wt or Pclogt/gt astrocytes in a Banker setup, assessing synapse density (immunostaining, RRP electrophysiology) and spontaneous activity (mEPSCs, mIPSCs). Astrocyte-conditioned media (ACM) experiments determined secreted factor roles. ResultsRNA-seq showed significant DEG increases in older versus young Pclogt/gt rats (P25 vs. P5), which were strongly enriched in cell communication, signaling, and ECM GO terms. We identified a novel astrocyte-specific Piccolo isoform that partially localizes at the Golgi. Piccolo gene trap transposon mutation led to impaired ECM secretion (reduced extracellular Bcan, altered TNR) from astrocytes, correlating with a fragmented Golgi in Pclogt/gt astrocytes. Functionally, Pclogt/gt astrocytes significantly reduced synapse density and altered intrinsic activity (increased mEPSC frequency) in neuronal networks. This synaptic deficit was substantially rescued by Pclowt/wtastrocyte conditioned media (ACM). ConclusionOur findings reveal a critical, unrecognized role for Piccolo in regulating astrocytic ECM secretion, essential for proper neuronal network formation and activity. Astrocytic Piccolo dysfunction disrupts this process, causing impaired synaptogenesis and altered intrinsic network activity, providing a novel cellular and molecular mechanism for neurodegenerative diseases like PCH3 and highlights astrocytes as potential therapeutic targets.

neuroscience↗

bioRxiv2025

The Insertion of an ATTTC Repeat in an Alu Element Hyperactivates a Primate-Specific Neurodevelopmental Enhancer in Spinocerebellar Ataxia Type 37

Alu are evolutionarily very old primate-specific interspersed repeat elements that constitute [~]11% of the human genome. They are a source of short tandem repeats (STRs), which often expand in size and originate inherited neuromuscular and neurodegenerative disorders. How expanded STR insertion mutations within Alu STRs culminate in disease remains unknown. Here we report an Alu STR located in an intron of DAB1 that functions as a neurodevelopmental enhancer. We demonstrated that an ATTTC repeat insertion in this DAB1 Alu STR, known to cause spinocerebellar ataxia type 37 (SCA37), hyperactivates a neurodevelopmental DAB1 enhancer. Importantly, we showed that neurons derived from SCA37 subjects have higher levels of DAB1 expression and DAB1 overexpression causes abnormal axonal pathfinding in vivo. Overall, these results establish that neuronal dysregulation of a developmental DAB1 Alu STR enhancer contributes to SCA37 pathogenesis, an unexplored mechanism likely acting in many Alu STR diseases, potentially reshaping the therapeutic landscape.

genetics↗

bioRxiv2024

The Alzheimers Disease Risk Genes MS4A4A And MS4A6A Cooperate to Negatively Regulate Trem2 and Microglia states

Genetic variations in MS4A4A and MS4A6A are linked to the regulation of cerebrospinal fluid soluble TREM2 (sTREM2) levels and are associated with Alzheimers disease (AD) risk and progression. Using CRISPR knockout and MS4A4A-degrading antibodies in primary human microglia, non-human primates (NHP), and a xenotransplantation model of amyloid pathology, we provide evidence that MS4A4A and MS4A6A are negative regulators of both the transmembrane and soluble TREM2 proteins. They also negatively regulate microglia proliferation, survival, metabolism, lysosomal function, energetics, phagocytosis, and disease-fighting states. Mechanistically, we find that MS4A4A exerts negative regulation by interacting with MS4A6A and protecting it from degradation. MS4A6A in turn forms a complex with and blocks the co-receptor DAP12, which is required for the stability, cell surface localization, and signaling of TREM2 and other receptors. Taken together, the data indicate that MS4A4A and MS4A6A are cooperating, post-transcriptional negative regulators of TREM2 and microglial function, and potential drug targets for AD.

neuroscience↗

bioRxiv2024

Direct and indirect regulation of β- glucocerebrosidase by the transcription factors USF2 and ONECUT2

Mutations in the GBA gene, which encodes the lysosomal enzyme {beta}-glucocerebrosidase (GCase), are the most prevalent genetic susceptibility factor for Parkinsons disease (PD). However, only approximately 20% of carriers develop the disease, suggesting the presence of genetic modifiers influencing the risk of developing PD in the presence of GBA mutations. Here we screened 1,634 human transcription factors (TFs) for their effect on GCase activity in cell lysates of the human glioblastoma line LN-229, into which we introduced the pathogenic GBA L444P variant via adenine base editing. Using a novel arrayed CRISPR activation library, we uncovered 11 TFs as regulators of GCase activity. Among these, activation of MITF and TFEC increased lysosomal GCase activity in live cells, while activation of ONECUT2 and USF2 decreased it. Conversely, ablating USF2 increased GBA mRNA and led to enhanced levels of GCase protein and activity. While MITF, TFEC, and USF2 affected GBA transcription, ONECUT2 was found to control GCase trafficking by modulating the guanine exchange factors PLEKHG4 and PLEKHG4B. Hence, our study provides a systematic approach to identifying modulators of GCase activity, expands the transcriptional landscape of GBA regulation, and deepens our understanding of the mechanisms involved in influencing GCase activity.

molecular biology↗

bioRxiv2024

A role for astrocytic miR-129-5p in Frontotemporal Dementia

Frontotemporal dementia is a debilitating neurodegenerative disorder characterized by frontal and temporal lobe degeneration, resulting in behavioral changes, language difficulties, and cognitive decline. In this study, smallRNA sequencing was conducted on postmortem brain tissues obtained from FTD patients with GRN, MAPT, or C9ORF72 mutations, focusing on the frontal and temporal lobes. Our analysis identified miR-129-5p as consistently deregulated across all mutation conditions and brain regions. Functional investigations revealed a novel role of miR-129-5p in astrocytes, where its loss led to neuroinflammation and impaired neuronal support functions, including reduced glutamate uptake. Depletion of miR-129-5p in astrocytes resulted in the loss of neuronal spines and altered neuronal network activity. These findings highlight miR-129-5p as a potential therapeutic target in neurodegenerative diseases and also sheds light on the role of astrocytes in Frontotemporal dementia pathogenesis.

neuroscience↗

bioRxiv2023

Epigenetic age acceleration in frontotemporal lobar degeneration: a comprehensive analysis in the blood and brain

Frontotemporal lobar degeneration (FTLD) includes a heterogeneous group of disorders pathologically characterized by the degeneration of the frontal and temporal lobes. In addition to major genetic contributors of FTLD such as mutations in MAPT, GRN, and C9orf72, recent work has identified several epigenetic modifications including significant differential DNA methylation in DLX1, and OTUD4 loci. As aging remains to be one of the major risk factors for FTLD, we investigated the presence of accelerated epigenetic aging in FTLD compared to controls. We calculated epigenetic age in both peripheral blood and brain tissues of multiple FTLD subtypes using several DNA methylation clocks, i.e., DNAmClockMulti, DNAmClockHannum, DNAmClockCortical, GrimAge and PhenoAge, and determined age acceleration and its association with different cellular proportions and clinical traits. Significant epigenetic age acceleration was observed in the peripheral blood of both frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP) patients compared to controls with DNAmClockHannum, even after accounting for confounding factors. A similar trend was observed with both DNAmClockMulti and DNAmClockCortical in post-mortem frontal cortex tissue of PSP patients and in FTLD cases harboring GRN mutations. Our findings support that increased epigenetic age acceleration in the peripheral blood could be an indicator for PSP and to a smaller extent, FTD.

neuroscience↗

bioRxiv2022

Rescue of the increased susceptibility to Mild Chronic Oxidative Stress of iNeurons carrying the MAPT Chromosome 17q21.3 H1/H1 risk allele by FDA-approved compounds

The microtubule associated protein tau (MAPT) chromosome 17q21.31 locus lies within a region of high linkage disequilibrium (LD) conferring two extended haplotypes commonly referred to as H1 and H2. The major haplotype, H1 has been genetically associated with an increased risk for multiple neurodegenerative disorders, including Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), APOE {varepsilon}4-negative Alzheimers disease (AD) and Parkinsons disease (PD). The mechanism causing this increased risk is largely unknown. Here, we investigated the role of Mild Chronic Oxidative Stress (MCOS) in neurogenin 2 (NGN2) induced neurons (iNeurons) derived from iPS (induced pluripotent stem cells) from carriers of both haplotypes. We identified that iNeurons of the H1 homozygous haplotype showed an increased susceptibility to MCOS compared to homozygous H2 carriers, leading to cell death through ferroptosis. We performed a cellular screen in H1 iNeurons using a FDA-approved Drug Library and identified candidate molecules that rescued the increased susceptibility to MCOS and prevented ferroptosis in H1 iNeurons. HighlightsO_LIMild Chronic Oxidative Stress induces neurotoxicity via ferroptosis on iNGN2 neurons C_LIO_LIAxonal degeneration, disordered microtubules, blebs precede neurotoxicity C_LIO_LIMAPT-17q21.3 locus H1/H1, risk allele for NDD is more vulnerable to MCOS C_LIO_LIFDA-approved drugs reverse MCOS induced ferroptosis on H1/H1 risk allele C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=158 SRC="FIGDIR/small/515284v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@eddb2eorg.highwire.dtl.DTLVardef@1d0c00dorg.highwire.dtl.DTLVardef@1f0b00eorg.highwire.dtl.DTLVardef@b68f1b_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

Brain DNA methylomic analysis of frontotemporal lobar degeneration reveals OTUD4 and CEBPZ in shared dysregulated signatures across pathological subtypes

Frontotemporal lobar degeneration (FTLD) is an umbrella term describing the neuropathology of a clinically, genetically and pathologically heterogeneous group of diseases, including frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP). Among the major FTLD pathological subgroups, FTLD with TDP-43 positive inclusions (FTLD-TDP) and FTLD with tau positive inclusions (FTLD-tau) are the most common, representing about 90% of the cases. Although alterations in DNA methylation have been consistently associated with neurodegenerative diseases, including Alzheimers disease and Parkinsons disease, little is known for FTLD and its heterogeneous subgroups and subtypes. The main goal of this study was to investigate DNA methylation variation in FTLD-TDP and FTLD-tau. We used frontal cortex genome-wide DNA methylation profiles from three FTLD cohorts (234 individuals), generated using the Illumina 450K or EPIC microarray. We performed epigenome-wide association studies (EWAS) for each cohort followed by meta-analysis to identify shared differential methylated loci across FTLD subgroups/subtypes. Additionally, we used weighted gene correlation network analysis to identify co-methylation signatures associated with FTLD and other disease-related traits. Wherever possible, we also incorporated relevant gene/protein expression data. After accounting for a conservative Bonferroni multiple testing correction, the EWAS meta-analysis revealed two differentially methylated loci in FTLD, one annotated to OTUD4 (5UTR-shore) and the other to NFATC1 (gene body-island). Of these loci, OTUD4 showed consistent upregulation of mRNA and protein expression in FTLD. Additionally, in the three independent co-methylation networks, OTUD4-containing modules were enriched for EWAS meta-analysis top loci and were strongly associated with the FTLD status. These co-methylation modules were enriched for genes implicated in the ubiquitin system, RNA/stress granule formation and glutamatergic synaptic signalling. Altogether, our findings identified novel FTLD-associated loci, and support a role for DNA methylation as a mechanism involved in the dysregulation of biological processes relevant to FTLD, highlighting novel potential avenues for therapeutic development.

neuroscience↗

bioRxiv2022

Robust and Versatile Arrayed Libraries for Human Genome-Wide CRISPR Activation, Deletion and Silencing

Arrayed CRISPR libraries extend the scope of gene-perturbation screens but require large numbers of efficacious sgRNA-expressing vectors. Using a newly invented liquid-phase plasmid cloning methodology, we constructed genome-wide arrayed libraries for human gene ablation (19,936 plasmids), activation, and epigenetic silencing (22,442 plasmids). At least 76% of each plasmid preparation encoded an intact array of 4 non-overlapping sgRNAs designed to tolerate most human DNA polymorphisms. We achieved perturbation efficacies of 75-99%, 76-92% and up to 10,000x in deletion, silencing and activation experiments, respectively. Upon conversion into massively parallel lentiviral vectors, an arrayed activation screen of 1,634 human transcription factors yielded 11 novel regulators of the cellular prion protein PrPC. Furthermore, a screen using a pooled version of the ablation library identified 5 novel modifiers of autophagy that went undetected with either of two 1sgRNA libraries. The CRISPR libraries described here represent a powerful resource for the targeted perturbation of human protein-coding genes.

genomics↗

bioRxiv2021

The Foundational data initiative for Parkinsons disease (FOUNDIN-PD): enabling efficient translation from genetic maps to mechanism

The FOUNdational Data INitiative for Parkinsons Disease (FOUNDIN-PD) is an international collaboration producing fundamental resources for Parkinsons disease (PD). FOUNDIN-PD generated a multi-layered molecular dataset in a cohort of induced pluripotent stem cell (iPSC) lines differentiated to dopaminergic (DA) neurons, a major affected cell type in PD. The lines were derived from the Parkinsons Progression Markers Initiative study including participants with PD carrying monogenic PD (SNCA) variants, variants with intermediate effects and variants identified by genome-wide association studies and unaffected individuals. We generated genetic, epigenetic, regulatory, transcriptomic, and longitudinal cellular imaging data from iPSC-derived DA neurons to understand molecular relationships between disease associated genetic variation and proximate molecular events. These data reveal that iPSC-derived DA neurons provide a valuable cellular context and foundational atlas for modelling PD genetic risk. We have integrated these data into a FOUNDIN-PD data browser (https://www.foundinpd.org) as a resource for understanding the molecular pathogenesis of PD.

genomics↗

bioRxiv2021

A multimodal 3D neuro-microphysiological system with neurite-trapping microelectrodes

Three-dimensional cell technologies as pre-clinical models are emerging tools for mimicking the structural and functional complexity of the nervous system. The accurate exploration of phenotypes in engineered 3D neuronal cultures, however, demands morphological, molecular and especially functional measurements. Particularly crucial is measurement of electrical activity of individual neurons with millisecond resolution. Current techniques rely on customized electrophysiological recording set-ups, characterized by limited throughput and poor integration with other readout modalities. Here we describe a novel approach, using multiwell glass microfluidic microelectrode arrays, allowing non-invasive electrical recording from engineered 3D neural tissues. We demonstrate parallelized studies with reference compounds, calcium imaging and optogenetic stimulation. Additionally, we show how microplate compatibility allows automated handling and high-content analysis of human induced pluripotent stem cell-derived neurons. This microphysiological platform opens up new avenues for high-throughput studies on the functional, morphological and molecular details of neurological diseases and their potential treatment by therapeutic compounds.

neuroscience↗

bioRxiv2021

The landscape of PrPC biosynthesis revealed by an arrayed genome-wide interference screen

The cellular prion protein PrPC is necessary for prion replication, and its reduction greatly increases life expectancy in animal models of prion infection. Hence the factors controlling the levels of PrPC may represent therapeutic targets against human prion diseases. Here we performed an arrayed whole-transcriptome RNA interference screen to identify modulators of PrPC expression. We cultured human U251-MG glioblastoma cells in the presence of 64752 unique siRNAs targeting 21584 annotated human genes, and measured PrPC using a one-pot fluorescence-resonance energy transfer immunoassay in 51128 individual microplate wells. This screen yielded 743 candidate regulators of PrPC. When downregulated, 563 of these candidates reduced and 180 enhanced PrPC expression. Recursive candidate attrition through multiple secondary screens yielded 54 novel regulators of PrPC, 9 of which were confirmed by CRISPR interference as robust regulators of PrPC biosynthesis and degradation. The phenotypes of 6 of the 9 candidates were inverted in response to transcriptional activation using CRISPRa. The RNA-binding post-transcriptional repressor Pumilio-1 was identified as a potent limiter of PrPC expression through the degradation of PRNP mRNA. Because of its hypothesis-free design, this comprehensive genetic-perturbation screen delivers an unbiased landscape of the genes regulating PrPC levels in cells, most of which were unanticipated, and some of which may be amenable to pharmacological targeting in the context of antiprion therapies.

neuroscience↗

bioRxiv2020

Integrated multi-omics analysis reveals common and distinct dysregulated pathways for genetic subtypes of Frontotemporal Dementia

Understanding the molecular mechanisms underlying frontotemporal dementia (FTD) is essential for the development of successful therapies. Systematic studies on human post-mortem brain tissue of patients with genetic subtypes of FTD are currently lacking. The Risk and Modyfing Factors of Frontotemporal Dementia (RiMod-FTD) consortium therefore has generated a multi-omics dataset for genetic subtypes of FTD to identify common and distinct molecular mechanisms disturbed in disease. Here, we present multi-omics datasets generated from the frontal lobe of post-mortem human brain tissue from patients with mutations in MAPT, GRN and C9orf72 and healthy controls. This data resource consists of four datasets generated with different technologies to capture the transcriptome by RNA-seq, and small RNA-seq, and supplemented this date with CAGE-seq, and methylation profiling. We show concrete examples on how to use the resulting data and confirm current knowledge about FTD and identify new processes for further investigation. This extensive multi-omics dataset holds great value to reveal new research avenues for this devastating disease.

neuroscience↗

bioRxiv2019

17q21.31 sub-haplotypes underlying H1-associated risk for Parkinson's disease and progressive supranuclear palsy converge on altered glial regulation

Parkinsons disease (PD) is genetically associated with the H1 haplotype of the MAPT 17q.21.31 locus, although the causal gene and variants underlying this association have not been identified. To better understand the genetic contribution of this region to PD, we fine-mapped the 17q21.31 locus in order to identify novel mechanisms conferring risk for the disease. We identified three novel H1 sub-haplotype blocks across the 17q21.31 locus associated with PD risk. Protective sub-haplotypes were associated with increased LRRC37A/2 copy number and expression in human brain tissue. We found that LRRC37A/2 is a membrane-associated protein that plays a role in cellular migration, chemotaxis and astroglial inflammation. In human substantia nigra, LRRC37A/2 was primarily expressed in astrocytes, interacted directly with soluble -synuclein, and co-localized with Lewy bodies in PD brain tissue. These data indicate that a novel candidate gene, LRRC37A/2, contributes to the association between the 17q21.31 locus and PD via its interaction with -synuclein and its effects on astrocytic function and inflammatory response. These data are the first to associate the genetic association at the 17q21.31 locus with PD pathology, and highlight the importance of variation at the 17q21.31 locus in the regulation of multiple genes other than MAPT and KANSL1, as well as its relevance to non-neuronal cell types.

neuroscience↗

bioRxiv2019

Regulation of neuronal mRNA splicing and Tau isoform ratio by ATXN3 through deubiquitylation of splicing factors

The ubiquitylation/deubiquitylation balance in cells is maintained by deubiquitylating enzymes, including ATXN3. The precise role of this protein, mutated in spinocerebellar ataxia type 3 (SCA3), remains elusive, as few substrates for its deubiquitylating activity were identified. Here, we characterized the ubiquitome of neuronal cells lacking ATXN3, and found altered polyubiquitylation in a large proportion of proteins involved in RNA metabolism, including splicing factors. Using transcriptomic analysis and reporter minigenes we confirmed that splicing was globally altered in these cells. Among the candidate targets of ATXN3 was SRSF7 (9G8), a key regulator of MAPT (Tau) exon 10 splicing. Loss-of-function of ATXN3 led to reduced SRSF7 levels and a deregulation of MAPT exon 10 splicing, resulting in a decreased 4R/3R-Tau ratio. Similar alterations were found in cellular models of expanded polyQ ATXN3 and SCA3 patient brains, pointing to a relevant role of this mechanism in SCA3, and establishing a previously unsuspected link between two key proteins involved in different neurodegenerative disorders.

neuroscience↗

bioRxiv2019

Functional Annotation of Human Long Non-Coding RNAs via Molecular Phenotyping

Long non-coding RNAs (lncRNAs) constitute the majority of transcripts in the mammalian genomes and yet, their functions remain largely unknown. We systematically knockdown 285 lncRNAs expression in human dermal fibroblasts and quantified cellular growth, morphological changes, and transcriptomic responses using Capped Analysis of Gene Expression (CAGE). Antisense oligonucleotides targeting the same lncRNA exhibited global concordance, and the molecular phenotype, measured by CAGE, recapitulated the observed cellular phenotypes while providing additional insights on the affected genes and pathways. Here, we disseminate the largest to-date lncRNA knockdown dataset with molecular phenotyping (over 1,000 CAGE deep-sequencing libraries) for further exploration and highlight functional roles for ZNF213-AS1 and lnc-KHDC3L-2.

genomics↗

bioRxiv2019

Deep-learning-based cell composition analysis from tissue expression profiles.

We present Scaden, a deep neural network for cell deconvolution that uses gene expression information to infer the cellular composition of tissues. Scaden is trained on single cell RNA-seq data to engineer discriminative features that confer robustness to bias and noise, making complex data preprocessing and feature selection unnecessary. We demonstrate that Scaden outperforms existing deconvolution algorithms in both precision and robustness. A single trained network reliably deconvolves bulk RNA-seq and microarray, human and mouse tissue expression data and leverages the combined information of multiple data sets. Due to this stability and flexibility, we surmise that deep learning will become an algorithmic mainstay for cell deconvolution of various data types. Scadens comprehensive software package is easy to use on novel as well as diverse existing expression datasets available in public resources, deepening the molecular and cellular understanding of developmental and disease processes.

bioinformatics↗