Biology subjects

Levy, D.

Publications and source records attributed to Levy, D..

At least 55 records · Page 3Linked to original sources

bioRxiv2022

The Impact of Storage Condition and Duration on Function of Native and Cargo-Loaded Mesenchymal Stromal Cell Extracellular Vesicles

As evidenced by ongoing clinical trials and increased activity in the commercial sector, extracellular vesicle (EV)-based therapies have begun the transition from bench to bedside. As this progression continues, one critical aspect to EV clinical translation is understanding the effects of storage and transport conditions. Several studies have assessed the impact of storage on EV characteristics such as morphology, uptake, and component content, but effects of storage duration and temperature on EV functional bioactivity and, especially, loaded cargo are scarcely reported. Here, EV outcomes following storage at different temperatures (room temperature, 4{degrees}C, -20{degrees}C, -80{degrees}C) for various durations as well as after lyophilization were assessed. Mesenchymal stem/stromal cell (MSC) EVs were observed to retain key aspects of their bioactivity (pro-vascularization, anti-inflammation) for up to 4-6 weeks at -20{degrees}C, -80{degrees}C, and after lyophilization. Furthermore, via in vitro assays and an in vivo wound healing model respectively, these same storage conditions were also demonstrated to enable preservation of the functionality of loaded microRNA (miRNA) as well as long non-coding RNA (lncRNA) cargo in MSC EVs. These findings extend the current understanding of how EV therapeutic potential is impacted by storage conditions and may inform best practices for handling and storage of MSC EVs for both basic research and translational purposes.

bioengineering↗

bioRxiv2022

VAP-A intrinsically disordered regions enable versatile tethering at membrane contact sites

Membrane contact sites (MCSs) between organelles are heterogeneous in shape, composition and dynamics. Despite this diversity, VAP proteins act as receptors for multiple FFAT motif-containing proteins and drive the formation of most MCSs involving the endoplasmic reticulum (ER). Although the VAP-FFAT interaction is well characterized, no model explains how VAP adapts to its partners in various MCSs. We report here that VAP-A localization to different MCSs depends on its intrinsically disordered regions (IDRs). We show that VAP-A interaction with PTPIP51 and VPS13A at ER-mitochondria MCS conditions mitochondria fusion by promoting lipid transfer and cardiolipin buildup. VAP-A also enables lipid exchange at ER-Golgi MCS by interacting with OSBP and CERT. However, removing IDRs from VAP-A restricts its distribution and function to ER- mitochondria MCS, at the expense of ER-Golgi MCS. Our data suggest that IDRs of VAP-A do not modulate its preference towards specific partners, but adjust its geometry to the constraints linked to different MCS organization and lifetime. Thus, VAP-A conformational flexibility mediated by its IDRs ensures membrane tethering plasticity and efficiency.

cell biology↗

bioRxiv2022

Structure-function conservation between the methyltransferases SETD3 and SETD6

Among the protein lysine methyltransferases family members, it appears that SETD6 is highly similar and closely related to SETD3. The two methyltransferases show high similarity in their structure, which raised the hypothesis that they share cellular functions. Using a proteomic screen, we identified 52 shared interacting-proteins. Gene Ontology (GO) analysis of the shared proteins revealed significant enrichment of proteins involved in transcription. Our RNA-seq data of SETD6 KO and SETD3 KO HeLa cells identified [~]100 up-regulated and down-regulated shared genes. We have also identified a substantial number of genes that changed dramatically in the double KO cells but did not significantly change in the single KO cells. GO analysis of these genes revealed enrichment of apoptotic genes. Accordingly, we show that the double KO cells displayed high apoptotic levels, suggesting that SETD6 and SETD3 inhibit apoptosis. Collectively, our data strongly suggest a functional link between SETD6 and SETD3 in the regulation of apoptosis.

cell biology↗

bioRxiv2021

Accurate measurement of microsatellite length by disrupting its tandem repeat structure

Replication of tandem repeats of simple sequence motifs, also known as microsatellites, is error prone and variable lengths frequently occur during population expansions. Therefore, microsatellite length variations could serve as markers for cancer. However, accurate error-free quantitation of microsatellite lengths is difficult with current methods because of a high error rate during amplification and sequencing. We have solved this problem by using partial mutagenesis to disrupt enough of the repeat structure so that it can replicate faithfully, yet not so much that the flanking regions cannot be reliably identified. In this work we use bisulfite mutagenesis to convert a C to a U, later read as T. Compared to untreated templates, we achieve three orders of magnitude reduction in the error rate per round of replication. By requiring two independent first copies of an initial template, we reach error rates below one in a million. We discuss potential clinical applications of this method.

genomics↗

bioRxiv2021

TWIST1 methylation by SETD6 selectively antagonizes LINC-PINT expression in Glioblastoma multiforme

Glioblastoma multiforme (GBM) is the most common and aggressive malignant brain tumor among adults, which is characterized by high invasion, migration and proliferation abilities. One important process that contributes to the invasiveness of GBM is the epithelial to mesenchymal transition (EMT). EMT is regulated by a set of defined transcription factors which tightly regulate this process, among them is the basic helix-loop-helix family member, TWIST1. Here we show that TWIST1 is methylated on lysine-33 at chromatin by SETD6, a methyltransferase with expression levels correlating with poor survival in GBM patients. RNA-seq analysis in U251 GBM cells suggested that both SETD6 and TWIST1 regulate cell adhesion and migration processes. We further show that TWIST1 methylation attenuates the expression of the long-non-coding RNA, LINC-PINT, thereby suppressing EMT in GBM. Mechanistically, TWIST1 methylation represses the transcription of LINC-PINT by increasing the occupancy of EZH2 and the catalysis of the repressive H3K27me3 mark at the LINC-PINT locus. Under un-methylated conditions, TWIST1 dissociates from the LINC-PINT locus, allowing the expression of LINC-PINT which leads to increased cell adhesion and decreased cell migration. Together, our findings unravel a new mechanistic dimension for selective expression of LINC-PINT mediated by TWIST1 methylation.

molecular biology↗

bioRxiv2021

PI4P and BLOC-1 remodel endosomal membranes into tubules

Intracellular trafficking is mediated by transport carriers that originate by membrane remodeling from donor organelles. Tubular carriers play major roles in the flux of membrane lipids and proteins to acceptor organelles. However, how lipids and proteins impose a tubular geometry on the carriers is incompletely understood. By exploiting imaging approaches at different scales on cells and in vitro membrane systems, we show that phosphatidylinositol-4-phosphate (PI4P) and biogenesis of lysosome-related organelles complex 1 (BLOC-1) govern the formation, stability and functions of recycling endosomal tubules. Endosomal PI4P production by type II PI4-kinases is needed to form nascent curved tubules through binding of BLOC-1 that stabilize and elongate them. Membrane remodeling by the PI4P/ BLOC-1 module functions not only in the recycling of endosomal cargoes, but also in the lifecycles of intracellular pathogens such as Chlamydia bacteria and influenza virus. This study demonstrates how a phospholipid and a protein complex coordinate as a minimal machinery to remodel cellular membranes into functional tubes.

cell biology↗

bioRxiv2021

Control of protein activity by photoinduced spin polarized charge reorganization

Considerable electric fields are present within living cells, and the role of bioelectricity has been well established at the organismal level. Yet little is known about electric-field effects on protein function. Here we use phototriggered charge injection from a site-specifically attached ruthenium photosensitizer to directly demonstrate the effects of charge redistribution within a protein. We find that binding of an antibody to phosphoglycerate kinase (PGK) is increased two folds under illumination. Remarkably, illumination is found to suppress the enzymatic activity of PGK by a factor as large as three. These responses are sensitive to the photosensitizer position on the protein. Surprisingly, left (but not right) circularly polarized light elicits these responses, indicating that the electrons involved in the observed dynamics are spin polarized, due to spin filtration by protein chiral structures. Our results directly establish the contribution of electrical polarization as an allosteric signal within proteins. Future experiments with phototriggered charge injection will allow delineation of charge rearrangement pathways within proteins and will further depict their effects on protein function. Significance StatementThe role of well-placed charges within proteins in mediating biological functions, from protein-protein association to enzyme kinetics, is well documented. Here we go beyond this static picture and show that charge motions can exert significant effects on protein function. Injecting charge from a photosensitizer, we demonstrate a three-fold decrease in enzymatic activity and a two-fold increase of antibody-antigen binding. These effects depend on the specific position of the photosensitizer on the protein. Our results point to charge reorganization as a form of allostery that complements known allosteric mechanisms such as conformational changes and dynamics.

biophysics↗

bioRxiv2021

Tonic interferon restricts pathogenic IL-17-driven inflammatory disease via balancing the microbiome

Maintenance of immune homeostasis involves a synergistic relationship between the host and the microbiome. Canonical interferon (IFN) signaling controls responses to acute microbial infection, through engagement of the STAT1 transcription factor. However, the contribution of tonic levels of IFN to immune homeostasis in absence of acute infection remains largely unexplored. We report that STAT1 KO mice spontaneously developed an inflammatory disease marked by myeloid hyperplasia and splenic accumulation of hematopoietic stem cells. Moreover, these animals developed inflammatory bowel disease. Profiling gut bacteria revealed a profound dysbiosis in absence of tonic IFN signaling, which triggered expansion of TH17 cells and loss of splenic Treg cells. Resolution of dysbiosis by antibiotic treatment averted the TH17 bias, and blocking IL17 signaling prevented myeloid expansion and splenic stem cell accumulation. Thus, tonic IFNs regulate gut microbial ecology, which is crucial for maintaining physiologic immune homeostasis and preventing inflammation.

immunology↗

bioRxiv2021

On-off transition and ultrafast decay of amino acid luminescence driven by modulation of supramolecular packing

It has been experimentally observed that various biomolecules exhibit clear luminescence in the visible upon aggregation, contrary their monomeric state. However, the physical basis for this phenomenon is still elusive. Here, we systematically examine all coded amino acids to provide non-biased insights into this phenomenon. Several amino acids, including non-aromatic, show intense visible luminescence. While lysine crystals display the highest signal, the very chemically similar non-coded ornithine does not, implying a role for molecular packing rather than the chemical characteristics of the molecule. Furthermore, cysteine show luminescence that is indeed crystal-packing-dependent as repeated rearrangements between two crystal structures result in a reversible on-off optical transition. In addition, ultrafast lifetime decay is experimentally validated, corroborating a recently raised hypothesis regarding the governing role of n{pi}* states in the emission formation. Collectively, our study supports the hypothesis that electronic interactions between molecules that are non-fluorescent and non-absorbing at the monomeric state may result in reversible optically-active states by the formation of supramolecular fluorophores.

biophysics↗

bioRxiv2021

Substrates modulate charge-reorganization allosteric effects in protein-protein association

Protein function may be modulated by an event occurring far away from the functional site, a phenomenon termed allostery. While classically allostery involves conformational changes, we recently observed that charge redistribution within an antibody can also lead to an allosteric effect, modulating the kinetics of binding to target antigen. In the present study, we study the association of a poly-histidine tagged enzyme (phosphoglycerate kinase, PGK) to surface-immobilized anti-His antibodies, finding a significant Charge-Reorganization Allostery (CRA) effect. We further observe that PGKs negatively charged nucleotide substrates modulate CRA substantially, even though they bind far away from the His-tag-antibody interaction interface. In particular, binding of ATP reduces CRA by more than 50%. The results indicate that CRA may be affected by charged substrates bound to a protein and provide further insight into the role of charge redistribution in protein function. TOC GRAPHIC O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

biophysics↗

bioRxiv2021

Genetically independent phenotype analysis identifies LPA and VCAM1 as drug targets for human ageing

The length and quality of life is important to us all, yet identification of promising drug targets for human ageing using genetics has had limited success. Here, we combine six large European-ancestry genome-wide association studies (GWAS) of human ageing traits--healthspan, father and mother lifespan, exceptional longevity, frailty index, and self-rated health--in a principal component framework that maximises their shared genetic architecture. The first principal component (GIP1) is more heritable than the original studies and shows strong genetic correlations with length of life as well as multiple indices of mental and physical wellbeing. We identify 27 genomic regions associated with GIP1, and provide additional, independent evidence for an effect on human ageing for loci near HTT and MAML3 using a study of Finnish and Japanese subject survival. Across the genome, GIP1 associations are enriched in genes involved in haem metabolism and pathways related to transcription, neurogenesis, homeostasis, proteolysis, intracellular signalling, immunity, and the muscle system. Finally, using proteome-wide two-sample Mendelian randomisation and colocalisation, we provide robust evidence for a detrimental effect of blood levels of apolipoprotein(a) (LPA) and vascular cell adhesion molecule 1 (VCAM1) on GIP1. Together, our results demonstrate that combining multiple ageing traits using genetic principal components enhances power to detect biological targets for human ageing.

genomics↗

bioRxiv2020

Overt visual attention and value computation in complex risky choice

Traditional models of decision making under uncertainty explain human behavior in simple situations with a minimal set of alternatives and attributes. Some of them, such as prospect theory, have been proven successful and robust in such simple situations. Yet, less is known about the preference formation during decision making in more complex cases. Furthermore, it is generally accepted that attention plays a role in the decision process but most theories make simplifying assumptions about where attention is deployed. In this study, we replace these assumptions by measuring where humans deploy overt attention, i.e. where they fixate. To assess the influence of task complexity, participants perform two tasks. The simpler of the two requires participants to choose between two alternatives with two attributes each (four items to consider). The more complex one requires a choice between four alternatives with four attributes each (16 items to consider). We then compare a large set of model classes, of different levels of complexity, by considering the dynamic interactions between uncertainty, attention and pairwise comparisons between attribute values. The task of all models is to predict what choices humans make, using the sequence of observed eye movements for each participant as input to the model. We find that two models outperform all others. The first is the two-layer leaky accumulator which predicts human choices on the simpler task better than any other model. We call the second model, which is introduced in this study, TNPRO. It is modified from a previous model from management science and designed to deal with highly complex decision problems. Our results show that this model performs well in the simpler of our two tasks (second best, after the accumulator model) and best for the complex task. Our results suggest that, when faced with complex choice problems, people prefer to accumulate preference based on attention-guided pairwise comparisons.

neuroscience↗

bioRxiv2020

Cardiovascular Disease Related Proteomic Biomarkers of Alcohol Consumption

The relationship between alcohol consumption, circulating proteins, and cardiovascular disease (CVD) risk has not been well studied. We performed association analyses of alcohol consumption with three CVD risk factors and 71 CVD-related circulating proteins measured in 6,745 Framingham Heart Study participants (mean age, 49 years; 53% women). We found that an increase in alcohol consumption was associated with a higher risk of incident hypertension (P=7.2E-3) but a lower risk of incident obesity (P=5.7E-4) and type 2 diabetes (P=1.4E-5) in a 14-year of follow-up. Using independent discovery (n=4,348) and validation (n=2,397) samples, we identified 20 alcohol-associated proteins (FDR<0.05 in discovery and P<0.05/n in validation), with majority (18 of 20 proteins) inversely associated with alcohol consumption. The alcohol-protein associations remained similar after removing heavy drinkers. Four proteins demonstrated consistent triangular relationships, as expected, with alcohol consumption and CVD risk factors. For example, a greater level of APOA1, which was associated with a higher alcohol consumption (P=1.2E-65), was associated with a lower risk of type 2 diabetes (P=3.1E-5). However, several others showed inconsistent triangular relationships, e.g., a greater level of GDF15, which was associated with a lower alcohol consumption (P=1.0E-13), was associated with an increased risk of hypertension (P=2.4E-4). In conclusion, we identified 20 alcohol-associated proteins and demonstrated complex relationships between alcohol consumption, circulating proteins and CVD risk factors. Future studies with integration of more proteomic markers and larger sample size are warranted to unravel the complex relationship between alcohol consumption and CVD risk.

bioinformatics↗

bioRxiv2020

Presence and Transmission of Mitochondrial Heteroplasmic Mutations in Human Populations of European and African Ancestry

We investigated the concordance of mitochondrial DNA heteroplasmic mutations (heteroplasmies) in different types of maternal pairs (n=6,745 pairs) of European (EA, n=4,718 pairs) and African (AA, n=2,027 pairs) Americans with whole genome sequences (WGSs). The average concordance rate of heteroplasmies was highest between mother-offspring pairs, followed by sibling-sibling pairs and more distantly related maternal pairs in both EA and AA participants. The allele fractions of concordant heteroplasmies exhibited high correlation (R2=0.8) between paired individuals. Compared to concordant heteroplasmies, discordant ones were more likely to locate in coding regions, be nonsynonymous or nonsynonymous-deleterious (p<0.001). The average number of heteroplasmies per individual (i.e. heteroplasmic burden) was at a similar level until older age (70-80 years old) and increased significantly thereafter (p<0.01). The burden of deleterious heteroplasmies (combined annotation-dependent depletion score[≥]15), however, was significantly correlated with advancing age (20-44, 45-64, [≥]65 years, p-trend=0.01). A genome-wide association analysis of the heteroplasmic burden identified many significant (P<5e-8) common variants (minor allele frequency>0.05) at 11p11.12. Many of the top SNPs act as strong long-range cis regulators of protein tyrosine phosphatase receptor type J. This study provides further evidence that mtDNA heteroplasmies may be inherited or somatic. Somatic heteroplasmic variants increase with advancing age and are more likely to have an adverse impact on mitochondrial function. Further studies are warranted for functional characterization of the deleterious heteroplasmies occurring with advancing age and the association of the 11p11.12 region of the nuclear genome with mtDNA heteroplasmy.

genetics↗

bioRxiv2020

Nanoscale architecture of a VAP-A-OSBP tethering complex at membrane contact site

Membrane contact sites (MCS) are subcellular regions where two organelles appose their membranes to exchange small molecules, including lipids. Structural information on how proteins form MCS is scarce. We designed an in vitro MCS with two membranes and a pair of tethering proteins suitable for cryo-tomography analysis. It includes VAP-A, an ER transmembrane protein interacting with a myriad of cytosolic proteins, and oxysterol-binding protein (OSBP), a lipid transfer protein that transports cholesterol from the ER to the trans Golgi network. We show that VAP-A is a highly flexible protein, allowing formation of MCS of variable intermembrane distance. The tethering part of OSBP contains a central, dimeric, and helical T-shape region. We propose that the molecular flexibility of VAP-A enables the recruitment of partners of different sizes within MCS of adjustable thickness, whereas the T geometry of the OSBP dimer facilitates the movement of the two lipid-transfer domains between membranes.

cell biology↗

bioRxiv2020

Increased severity of closed head injury or repetitive subconcussive head impacts enhances post-traumatic headache-like behaviors in a rat model.

IntroductionPosttraumatic headache (PTH) is one of the most common, debilitating and difficult symptoms to manage after a traumatic head injury. The development of novel therapeutic approaches is nevertheless hampered by the paucity of preclinical models and poor understanding of the mechanisms underlying PTH. To address these shortcomings, we previously characterized the development of PTH-like pain behaviors in rats subjected to a single mild closed head injury using a 250 g weight drop. Here, we conducted a follow-up study to further develop this preclinical model by exploring the development of headache-like pain behaviors in male rats subjected to a single, but more severe head trauma (450 g) as well as following repetitive, subconcussive head impacts (150 g). In addition, we tested whether these behaviors involve peripheral CGRP signaling by testing the effect of systemic anti-CGRP monoclonal antibody (anti-CGRP mAb). MethodsAdult male Sprague Dawley rats (total n=138) were subjected to diffuse closed head injury using a weight-drop device, or a sham procedure. Three injury paradigms were employed: a single hit, using 450 g or 150 g weight drop, and three successive 150 g weight drop events conducted 72 hours apart. Changes in open field activity and development of headache-related cephalic and extracephalic mechanical pain hypersensitivity were assessed up to 42 days post head trauma. Treatment included systemic administration of a mouse anti-calcitonin-gene-related peptide monoclonal antibody (30 mg/kg.). ResultsRats subjected to 450 g closed head injury displayed an acute decrease in rearing and increased thigmotaxis, together with cephalic and extracephalic mechanical pain hypersensitivity that resolved by 6 weeks post-injury. Repetitive subconcussive head impacts using the 150 g weight drop, but not a single event, led to decreased vertical rearing as well as prolonged cephalic and extracephalic mechanical pain hypersensitivity. Early and prolonged anti-CGRP mAb treatment inhibited the development of the cephalic, but not extracephalic pain hypersensitivities in both the severe and repetitive subconcussive head impact models. ConclusionsWhen compared to the data obtained from male rats in the previous study, a more severe head injury gives rise to a prolonged state of cephalic and extracephalic hyperalgesia. Such enhanced headache-like behaviors also occur following repetitive, subconcussive head impacts. Extended headache-like behaviors following severe and repetitive mild closed head injury are ameliorated by early and prolonged anti-CGRP mAb treatment, suggesting a mechanism linked to peripheral CGRP signaling.

neuroscience↗

bioRxiv2019

Enhanced post-traumatic headache-like behaviors and diminished contribution of peripheral CGRP in female rats following a mild closed head injury

IntroductionFemales are thought to have increased risk of developing posttraumatic headache (PTH) following a traumatic head injury, or concussion. However, the processes underlying this susceptibility remain unclear. We previously explored the development of PTH-like pain behaviors in a novel rat model of mild closed head injury, along with the ability of sumatriptan and an anti-calcitonin-gene-related peptide monoclonal antibody to ameliorate these behaviors. Here, we explored the development of PTH-like behaviors and the effectiveness of these headache therapies in females subjected to the same head trauma protocol. MethodsAdult female Sprague Dawley rats were subjected to a mild closed head injury using a weight-drop device. Characterization of headache and pain related behaviors included assessment of changes in cutaneous cephalic and extracephalic tactile pain sensitivity, using von Frey monofilaments. Sensitivity to headache/migraine triggers was tested by examining the effect of systemic administration of a low-dose of glyceryl trinitrate (GTN). Treatments included acute systemic administration of sumatriptan and repeated systemic administration of a mouse anti-calcitonin-gene-related peptide monoclonal antibody. Serum levels of calcitonin-gene-related peptide were measured at various time points in females and males after the head injury. ResultsFemale rats subjected to a mild closed head injury developed cutaneous mechanical hyperalgesia, that was limited to the cephalic region, and was resolved 4 weeks later. Cephalic pain hypersensitivity was ameliorated by treatment with sumatriptan, but was resistant to an early and prolonged treatment with the anti-CGRP monoclonal antibody. Following the resolution of the head injury-evoked cephalic hypersensitivity, administration of GTN produced a renewed and pronounced cephalic and extracephalic pain hypersensitivity that was inhibited by sumatriptan, but only partially by the anti-CGRP treatment. CGRP serum levels were elevated in females but not in males at 7 days post head injury. ConclusionsDevelopment of PTH-like pain behaviors following a mild closed head injury, and responsiveness to treatment in rats is sexually dimorphic. When compared to males, female rats display a prolonged state of cephalic hyperalgesia, increased responsiveness to a headache trigger, and a poorer effectiveness of an early and prolonged anti-CGRP treatment. The increased risk of females to develop PTH may be linked to enhanced responsiveness of peripheral and/or central pain pathways and a mechanism independent of peripheral CGRP signaling.

neuroscience↗

bioRxiv2019

Integrative Genomic Analysis and Functional Studies Reveal GP5, GRN, MPO and MCAM as Causal Protein Biomarkers for Platelet Traits

RationaleMean platelet volume (MPV) and platelet count (PLT) are platelet measures that have been linked to cardiovascular disease (CVD) and mortality risk. Identifying protein biomarkers for these measures may yield insights into CVD mechanisms. ObjectiveWe aimed to identify causal protein biomarkers for MPV and PLT among 71 CVD-related plasma proteins measured in Framingham Heart Study (FHS) participants. Methods and ResultsWe conducted integrative analyses of genetic variants associated with PLT and MPV with protein quantitative trait locus (pQTL) variants associated with plasma proteins followed by Mendelian randomization (MR) to infer causal relations of proteins for PLT/MPV, and tested protein-PLT/MPV association in FHS participants. Utilizing induced pluripotent stem cell (iPSC)-derived megakaryocyte (MK) clones that produce functional platelets, we conducted RNA-sequencing and analyzed transcriptome-wide differences between low- and high-platelet producing clones. We then performed small interfering RNA (siRNA) gene knockdown experiments targeting genes encoding proteins with putatively causal platelet effects in MK clones to examine effects on platelet production. Protein-trait association analyses were conducted for MPV (n = 4,348) and PLT (n = 4,272). Eleven proteins were associated with MPV and 31 with PLT. MR identified four putatively causal proteins for MPV and four for PLT. Glycoprotein V (GP5), granulin (GRN), and melanoma cell adhesion molecule (MCAM) were associated with PLT in both protein-trait and MR analyses. Myeloperoxidase (MPO) showed significant association with MPV in both analyses. MK RNA-sequencing analysis results were directionally concordant with observed and MR-inferred associations for GP5, GRN, and MCAM. In siRNA gene knockdown experiments, silencing GP5, GRN, and MPO decreased platelet counts. ConclusionsBy integrating population genomics data, epidemiological data, and iPSC-derived MK experiments, we identified four proteins that are causally linked to platelet counts. These proteins and genes may be further explored for their utility in increasing platelet production in bioreactors for transfusion medicine purposes as well as their roles in the pathogenesis of CVD via a platelet/blood coagulation-based mechanism.

genomics↗