Biology subjects

Haider, S.

Publications and source records attributed to Haider, S..

At least 55 records · Page 3Linked to original sources

bioRxiv2023

Pandemic preparedness through genomic surveillance: Overview of mutations in SARS-CoV-2 over the course of COVID-19 outbreak

Genomic surveillance is a vital strategy for preparedness against the spread of infectious diseases and to aid in development of new treatments. In an unprecedented effort, millions of samples from COVID-19 patients have been sequenced worldwide for SARS-CoV-2. Using more than 8 million sequences that are currently available in GenBanks SARS-CoV-2 database, we report a comprehensive overview of mutations in all 26 proteins and open reading frames (ORFs) from the virus. The results indicate that the spike protein, NSP6, nucleocapsid protein, envelope protein and ORF7b have shown the highest mutational propensities so far (in that order). In particular, the spike protein has shown rapid acceleration in mutations in the post-vaccination period. Monitoring the rate of non-synonymous mutations (Ka) provides a fairly reliable signal for genomic surveillance, successfully predicting surges in 2022. Further, the external proteins (spike, membrane, envelope, and nucleocapsid proteins) show a significant number of mutations compared to the NSPs. Interestingly, these four proteins showed significant changes in Ka typically 2 to 4 weeks before the increase in number of human infections ("surges"). Therefore, our analysis provides real time surveillance of mutations of SARS-CoV-2, accessible through the project website http://pandemics.okstate.edu/covid19/. Based on ongoing mutation trends of the virus, predictions of what proteins are likely to mutate next are also made possible by our approach. The proposed framework is general and is thus applicable to other pathogens. The approach is fully automated and provides the needed genomic surveillance to address a fast-moving pandemic such as COVID-19.

genomics↗

bioRxiv2023

NOTCH3 signalling controls human trophoblast stem cell expansion and differentiation

Failures in growth and differentiation of the early human placenta are associated with severe pregnancy disorders such as preeclampsia and fetal growth restriction. However, regulatory mechanisms controlling development of its epithelial cells, the trophoblasts, remain poorly elucidated. Using trophoblast stem cells (TSCs), trophoblast organoids (TB-ORGs) and primary cytotrophoblasts (CTBs) of early pregnancy, we herein show that autocrine NOTCH3 signalling controls human placental expansion and differentiation. NOTCH3 receptor was specifically expressed in proliferative CTB progenitors and its active form, the nuclear NOTCH3 intracellular domain (NOTCH3-ICD), interacted with the transcriptional co-activator Mastermind-like 1 (MAML1). Doxycyclin-inducible expression of dominant-negative MAML1 in TSC lines provoked cell fusion and upregulation of genes specific for multinucleated syncytiotrophoblasts, the differentiated hormone-producing cell type of the placenta. However, progenitor expansion and markers of trophoblast stemness and proliferation were suppressed. Accordingly, inhibition of NOTCH3 signalling diminished growth of TB-ORGs whereas overexpression of NOTCH3-ICD in primary CTBs and TSCs showed opposite effects. In conclusion, the data suggest that canonical NOTCH3 signalling plays a key role in human placental development promoting self-renewal of CTB progenitors.

developmental biology↗

bioRxiv2023

Structural Insights into Regulation of Insulin Expression Involving i-Motif DNA Structures in the Insulin-Linked Polymorphic Region.

The insulin linked polymorphic region (ILPR) is a variable number of tandem repeats (VNTR) region of DNA in the promoter of the insulin gene that regulates transcription of insulin. This region is known to form the alternative DNA structures, i-motifs and G-quadruplexes. Individuals have different sequence variants of VNTR repeats and although previous work investigated the effects of some variants on G-quadruplex formation, there is not a clear picture of the relationship between the sequence diversity, the DNA structures formed, and the functional effects on insulin gene expression. Here we show that different sequence variants of the ILPR form different DNA secondary structures and insulin expression is dependent on formation of i-motif and G-quadruplex structures. The first crystal structure and dynamics of an intramolecular i-motif also reveal sequences within the loop regions forming additional stabilising interactions, which are critical to formation of the stable i-motif structures that modulate insulin expression. The outcomes of this work reveal the detail in formation of stable i-motif DNA structures, with potential for rational based drug design for compounds to alter insulin gene expression.

biophysics↗

bioRxiv2023

The Structural Role of N170 in Substrate-assisted Deacylation in KPC-2 β-Lactamase

The amino acid substitutions in Klebsiella pneumoniae carbapenemase 2 (KPC-2) that have arisen in the clinic are observed to lead to the development of resistance to ceftazidime-avibactam, a preferred treatment for KPC bearing Gram-negative bacteria. Specific substitutions in the omega loop (R164-D179) results in changes in the structure and function of the enzyme, leading to alterations in substrate specificity, decreased stability, and more recently observed, increased resistance to ceftazidime/avibactam. Using accelerated rare-event sampling well-tempered metadynamics simulations, we explored in detail the structural role of R164 and D179 variants that are described to confer ceftazidime/avibactam resistance. The buried conformation of D179 substitutions produce a pronounced structural disorder in the omega loop - more than R164 mutants, where the crystallographic omega loop structure remains mostly intact. Our findings also reveal that the conformation of N170 plays an underappreciated role impacting drug binding and restricting deacylation. The results further support the hypothesis that KPC-2 D179 variants employ substrate-assisted catalysis for ceftazidime hydrolysis, involving the ring amine of the aminothiazole group to promote deacylation and catalytic turnover. Moreover, the shift in the WT conformation of N170 contributes to reduced deacylation and altered spectrum of enzymatic activity.

biophysics↗

bioRxiv2023

High within-tree leaf trait variation and its response to species diversity and soil nutrients

O_LILeaf functional traits provide important insights into plants responses to different environments. Leaf traits have been increasingly studied within-species in the last decade, following the growing realisation that neglecting the intra-specific scale can result in misreading plants response to environmental change. However, while likely to lead to similar pitfalls, within-individual leaf traits are under-researched despite being the scale at which elementary interactions shape ecosystem processes. C_LIO_LITo address this critical lack of understanding at the local scale, we assessed leaf trait variation in a large biodiversity-ecosystem functioning experiment in subtropical China. We used optical spectroscopy to determine nine morphological and biochemical traits of >5800 leaves from 414 trees representing 14 species. We evaluated the relative importance of the intra-individual level for total leaf trait variation, and the interacting effect of two trait variations drivers, soil nutrient availability, and a local species richness gradient. C_LIO_LIComparing the amount of trait variation at the between-species, between-individuals and intra-individual levels, we found that intra-individual variation accounted on average for >25% of total trait variation. Additionally, intra-individual variation was the most prominent component of intra-specific variation. We found partial support for positive effects of soil nutrient availability and species diversity on intra-individual trait variation, and a strong interdependence of both effects. Contrary to the amplifying effects we expected, trait variation increased with soil nutrient availability at intermediate diversity, but decreased at low and high diversity. C_LIO_LIOur findings quantify the relevance of intra-individual level for leaf trait variation, and expose a complex interaction between its drivers. In particular, interactive effects of soil nutrient availability and local species diversity on trait variation suggest responses ranging from alleviating competition to enhancing complementarity. Taken together, our work highlights the importance of integrating an intra-individual perspective to understand trait-based mechanisms in biodiversity-ecosystem functioning relationships. C_LI

ecology↗

bioRxiv2023

Genomic profiling and pre-clinical modelling of breast cancer leptomeningeal metastasis (BCLM) reveals acquisition of a lobular-like phenotype

Breast cancer leptomeningeal metastasis (BCLM), where tumour cells grow along the lining of the brain and spinal cord, is a devastating development for patients. Investigating this metastatic site is hampered by difficulty in accessing tumour material. Here, we utilise cerebrospinal fluid (CSF) cell-free DNA (cfDNA) and CSF disseminated tumour cells (DTCs) to explore the clonal evolution of BCLM and heterogeneity between leptomeningeal and extracranial metastatic sites. Somatic alterations with potential therapeutic actionability were detected in 81% (17/21) of BCLM cases, with 19% detectable in CSF cfDNA only. BCLM was enriched in genomic aberrations in adherens junction and cytoskeletal genes, revealing a lobular-like breast cancer phenotype. CSF DTCs were cultured in 3D to establish BCLM patient-derived organoids, and used for the successful generation of BCLM in vivo models. These data reveal that BCLM possess a unique genomic aberration profile and highlights potential cellular dependencies in this hard-to-treat form of metastatic disease.

cancer biology↗

bioRxiv2022

Emerging variants of SARS-CoV-2 NSP10 highlight strong functional conservation of its binding to two non-structural proteins, NSP14 and NSP16

The coronavirus SARS-CoV-2 protects its RNA from being recognized by host immune responses by methylation of its 5 end, also known as capping. This process is carried out by two enzymes, non-structural protein 16 (NSP16) containing 2-O-methyltransferase and NSP14 through its N7 methyltransferase activity, which are essential for the replication of the viral genome as well as evading the hosts innate immunity. NSP10 acts as a crucial cofactor and stimulator of NSP14 and NSP16. To further understand the role of NSP10, we carried out a comprehensive analysis of >13 million globally collected whole-genome sequences (WGS) of SARS-CoV-2 obtained from the Global Initiative Sharing All Influenza Data (GISAID) and compared it with the reference genome Wuhan/WIV04/2019 to identify all currently known variants in NSP10. T12I, T102I, and A104V in NSP10 have been identified as the three most frequent variants and characterized using X-ray crystallography, biophysical assays and enhanced sampling simulations. In contrast to other proteins such as spike and NSP6, NSP10 is significantly less prone to mutation due to its crucial role in replication. The functional effects of the variants were examined for their impact on the binding affinity and stability of both NSP14-NSP10 and NSP16-NSP10 complexes. These results highlight the limited changes induced by variant evolution in NSP10 and reflect on the critical roles NSP10 plays during the SARS-CoV-2 life cycle. These results also indicate that there is limited capacity for the virus to overcome inhibitors targeting NSP10 via the generation of variants in inhibitor binding pockets. Significance StatementThe SARS-CoV-2 proteins have constantly been evolving. These variants assist the virus to survive, adapt and evade the host immune responses. While the main focus has been on structural proteins like Spike, there is very limited structural and functional information on the effects of emerging mutations on other essential non-structural viral proteins. One such protein is NSP10, an essential cofactor for NSP14 and NSP16. This study demonstrates that NSP10 is more resistant to genetic variations than other SARS-CoV-2 non-structural proteins and that the presence of mutations conserve structural and dynamic changes in NSP10. The effects of naturally occurring mutations reflect the evolutionary relationship between structurally conserved essential cofactors, their function and the role they play in the survival of the virus.

biophysics↗

bioRxiv2022

Gating interactions steer loop conformational changes in the active site of the L1 metallo-β-lactamase

{beta}-lactam antibiotics are the most important and widely used antibacterial agents across the world. However, the widespread dissemination of {beta}-lactamases among pathogenic bacteria limits the efficacy of {beta}-lactam antibiotics. This has created a major public health crisis. The use of {beta}-lactamase inhibitors has proven useful in restoring the activity of {beta}-lactam antibiotics, yet, effective clinically approved inhibitors against class B metallo-{beta}-lactamases (MBLs) are not available. L1, a class B3 enzyme expressed by Stenotrophomonas maltophilia, is a significant contributor to the {beta}-lactam resistance displayed by this opportunistic pathogen. Structurally, L1 is a tetramer with two elongated loops, 3-{beta}7 and {beta}12-5, present around the active site of each monomer. Residues in these two loops influence substrate/inhibitor binding. To study how the conformational changes of the elongated loops affect the active site in each monomer, enhanced sampling molecular dynamics (MD) simulations were performed, Markov State Models (MSM) were built, and convolutional variational autoencoder (CVAE)-based deep learning was applied. The key identified residues (D150a, H151, P225, Y227, R236) were mutated and the activity of the generated L1 variants was evaluated in cell-based experiments. The results demonstrate that there are extremely significant gating interactions between 3-{beta}7 and {beta}12-5 loops. Taken together, the gating interactions with the conformational changes of the key residues play an important role in the structural remodeling of the active site. These observations offer insights into the potential for novel drug development exploiting these gating interactions.

biophysics↗

bioRxiv2022

Disturbed trophoblast transition links preeclampsia progression from placenta to the maternal syndrome

Pre-eclampsia (PE) is a syndrome that affects multiple organ systems and is the most severe hypertensive disorder in pregnancy. It frequently leads to preterm delivery, maternal and fetal morbidity and mortality and life-long complications1. We currently lack efficient screening tools2, 3 and early therapies4, 5 to address PE. To investigate the early stages of early onset PE, and identify candidate markers and pathways, we performed spatio-temporal multi-omics profiling of human PE placentae and healthy controls and validated targets in early gestation in a longitudinal clinical cohort. We used a single-nuclei RNA-seq approach combined with spatial proteo- and transcriptomics and mechanistic in vitro signalling analyses to bridge the gap from late pregnancy disease to early pregnancy pathomechanisms. We discovered a key disruption in villous trophoblast differentiation, which is driven by the increase of transcriptional coactivator p300, that ultimately ends with a senescence-associated secretory phenotype (SASP) of trophoblasts. We found a significant increase in the senescence marker activin A in preeclamptic maternal serum in early gestation, before the development of clinical symptoms, indicating a translation of the placental syndrome to the maternal side. Our work describes a new disease progression, starting with a disturbed transition in villous trophoblast differentiation. Our study identifies potential pathophysiology-relevant biomarkers for the early diagnosis of the disease as well as possible targets for interventions, which would be crucial steps toward protecting the mother and child from gestational mortality and morbidity and an increased risk of cardiovascular disease later in life.

systems biology↗

bioRxiv2022

Future COVID-19 surges prediction based on SARS-CoV-2 mutations surveillance

COVID19 has aptly revealed that airborne viruses such as SARS-CoV-2 with the ability to rapidly mutate, combined with high rates of transmission and fatality can cause a deadly world-wide pandemic in a matter of weeks.1 Apart from vaccines and post-infection treatment options, strategies for preparedness will be vital in responding to the current and future pandemics. Therefore, there is wide interest in approaches that allow predictions of increase in infections ("surges") before they occur. We describe here real time genomic surveillance particularly based on mutation analysis, of viral proteins as a methodology for a priori determination of surge in number of infection cases. The full results are available for SARS-CoV-2 at http://pandemics.okstate.edu/covid19/, and are updated daily as new virus sequences become available. This approach is generic and will also be applicable to other pathogens.

genomics↗

bioRxiv2022

MND1 and PSMC3IP control PARP inhibitor sensitivity in mitotic cells

The PSMC3IP-MND1 heterodimer promotes RAD51 and DMC1-dependent D-loop formation during meiosis in yeast and mammalian organisms. For this purpose, it catalyzes the DNA strand exchange activities of the recombinases. Interestingly, in a panel of genome-scale CRISPR-Cas9 mutagenesis and interference screens in mitotic cells, we found that depletion of either PSMC3IP or MND1 caused sensitivity to clinical Poly (ADP-Ribose) Polymerase inhibitors (PARPi). A retroviral mutagenesis screen in mitotic cells also identified PSMC3IP and MND1 as genetic determinants of ionizing radiation sensitivity. The role PSMC3IP and MND1 play in preventing PARPi sensitivity in mitotic cells appears to be independent of a previously described role in alternative lengthening of telomeres (ALT). PSMC3IP or MND1 depleted cells accumulate toxic RAD51 foci in response to DNA damage, show impaired homology-directed DNA repair, and become PARPi sensitive, even in cells lacking both BRCA1 and TP53BP1. Although replication fork reversal is also affected, the epistatic relationship between PSMC3IP-MND1 and BRCA1/BRCA2 suggests that the abrogated D-loop formation is the major cause of PARPi sensitivity. This is corroborated by the fact that a PSMC3IP p.Glu201del D-loop formation mutant associated with ovarian dysgenesis fails to reverse PARPi sensitivity. These observations suggest that meiotic proteins such as MND1 and PSMC3IP could have a greater role in mitotic cells in determining the response to therapeutic DNA damage.

cancer biology↗

bioRxiv2022

Monkey Pox Virus (MPXV): Phylogenomics, Host-Pathogen Interactome, and Mutational Cascade

While the world is still managing to recover from Covid-19 pandemic, Monkeypox awaits to bring in another global outbreak as a challenge to the entire mankind. However, Covid-19 pandemic have taught us lessons to move fast in viral genomic research to implement prevention and treatment strategies. One of the important aspects in Monkeypox virus should be immediately taken up is to gather insights of its evolutionary lineage based on the genomic studies. We have thus analysed the genome sequences of reported isolates of Monkeypox in the present study through phylogenomics. Host-pathogen interactions, mutation prevalence and evolutionary dynamics of this virus were investigated for all the documented isolates. Phylogenetic exploration revealed the clustering of strain Israel 2018 (MN 648051.1) from Clade I with the four isolates reported from the recent outbreak. An in-depth scrutiny of the host-pathogen interactome identified protein E3, serine protease inhibitor-2 (SPI-2), protein K7, and cytokine response-modifying protein B (CrmB) as the major regulatory hubs. Among these, the CrmB protein (dN/dS {approx} 1.61) was detected to be operating through positive selection. It possibly attests a selective advantage with the monkeypox virus in protecting the infected cells from antiviral responses elicited by the host. Studies also revealed that CrmB protein exhibited several mutations, the majority of which were destabilizing ({Delta}{Delta}G >0). While this study identified a large number of mutations within the newly outbreak clade, it also reflected that we need to move fast with the genomic analysis of the newly detected strains from around the world to develop better prevention and treatment methods

microbiology↗

bioRxiv2022

Two ligand-binding sites on SARS-CoV-2 non-structural protein 1 revealed by fragment-based x-ray screening

The regular reappearance of coronavirus (CoV) outbreaks over the past 20 years has caused significant health consequences and financial burdens worldwide. The most recent and still ongoing novel CoV pandemic, caused by Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) has brought a range of devastating consequences. Due to the exceptionally fast development of vaccines, the mortality rate of the virus has been curbed to a significant extent. However, the limitations of vaccination efficiency and applicability, coupled with the still high infection rate, emphasise the urgent need for discovering safe and effective antivirals against SARS-CoV-2 through suppressing its replication and or attenuating its virulence. Non-structural protein 1 (nsp1), a unique viral and conserved leader protein, is a crucial virulence factor for causing host mRNA degradation, suppressing interferon (IFN) expression and host antiviral signalling pathways. In view of the essential role of nsp1 in the CoV life cycle, it is regarded as an exploitable target for antiviral drug discovery. Here, we report a variety of fragment hits against SARS-CoV-2 nsp1 identified by fragment-based screening via X-ray crystallography. We also determined the structure of nsp1 at atomic resolution (0.95 [A]). Binding affinities of hits against nsp1 were determined by orthogonal biophysical assays such as microscale thermophoresis and thermal sift assays. We identified two ligand-binding sites on nsp1, one deep and one shallow pocket, which are not conserved between the three medially relevant SARS, SARS-CoV-2 and MERS coronaviruses. Our study provides an excellent starting point for the development of more potent nsp1-targeting inhibitors and functional studies on SARS-CoV-2 nsp1.

biochemistry↗

bioRxiv2022

Fully Transient CRISPR/Cas12f system in plants capable of broad-spectrum resistance against Begomovirus

CRISPR/Cas system has emerged as the most efficient genome editing technology for both eukaryotic and prokaryotic cells. Recently, biologist have started using CRISPR/Cas9 as a defence machinery in plants against DNA viruses by targeting conserve regions of their genome. Considerable resistance requires formation of stable transgenic lines with multiple gRNAs, targeting specific viruses. Development of such transgenic plants is not only time consuming but also there will always be some uncertainty of their efficiency and off targets in plant genome. Newly discovered miniature CRISPR/Cas12f (Cas14a) system has unique ability to chop down every ssDNA fragment once activated through targeted cleavage. Here we report first fully functional transient CRISPR/Cas12f system in plants. We also show that Cas12f with just one gRNA is enough for substantial broad-spectrum resistance against Gemini viruses. Plant phenotype showed nearly complete recovery and qPCR results showed multifold decrease infection of CLCuV in CRISPR/Cas12f treated plants compare to the infected plants (infected with CLCuMuV and CLCuKV). Smaller size, broad range and more efficiency make Cas12f a superior alternative of Cas9 against diverse group of ssDNA viruses.

plant biology↗

bioRxiv2022

ReSurveyGermany: Vegetation-plot time-series over the past hundred years in Germany

Vegetation-plot resurvey data are a main source of information on terrestrial biodiversity change, with records reaching back more than one century. Although more and more data from re-sampled plots have been published, there is not yet a comprehensive open-access dataset available for analysis. Here, we compiled and harmonised vegetation-plot resurvey data from Germany covering almost 100 years. We show the distribution of the plot data in space, time and across habitat types of the European Nature Information System (EUNIS). In addition, we include metadata on geographic location, plot size and vegetation structure. The data allow calculating temporal biodiversity change at the community scale and reach back further into the past than most comparable data yet available. They also enable tracking changes in the incidence and distribution of individual species across Germany. In summary, the data come at a level of detail that holds promise for broadening our understanding of the mechanisms and drivers behind plant diversity change over the last century.

ecology↗

bioRxiv2022

Revealing druggable cryptic pockets in the Nsp-1 of SARS-CoV-2 and other β-coronaviruses by simulations and crystallography

Non-structural protein 1 (Nsp1) is a main pathogenicity factor of - and {beta}-coronaviruses. Nsp1 of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) suppresses the host gene expression by sterically blocking 40S host ribosomal subunits and promoting host mRNA degradation. This mechanism leads to the downregulation of the translation-mediated innate immune response in host cells, ultimately mediating the observed immune evasion capabilities of SARS-CoV-2. Here, by combining extensive Molecular Dynamics simulations, fragment screening and crystallography, we reveal druggable pockets in Nsp1. Structural and computational solvent mapping analyses indicate the partial crypticity of these newly discovered and druggable binding sites. The results of fragment-based screening via X-ray crystallography confirm the druggability of the major pocket of Nsp1. Finally, we show how the targeting of this pocket could disrupt the Nsp1-mRNA complex and open a novel avenue to design new inhibitors for other Nsp1s present in homologous {beta}-coronaviruses.

biophysics↗

bioRxiv2022

The human placenta dictates the phenotype of decidual macrophages.

During human pregnancy, placenta-derived extravillous trophoblasts (EVT) invade the decidua and communicate with maternal immune cells. The decidua can be distinguished into basalis (decB) and parietalis (decP), the latter being unaffected by placentation. By defining a novel gating strategy, we report accumulation of myeloid cells in decB. We identified a decidua basalis-associated macrophage (decBAM) population with a differential transcriptome and secretome when compared to decidua parietalis-associated macrophages (decPAMs). decBAMs are CD11chi and efficient inducers of Tregs, proliferate in situ and secrete high levels of CXCL1, CXCL5, M-CSF, and IL-10. In contrast, decPAMs exert a dendritic cell-like, motile phenotype characterized by induced expression of HLA class II molecules, enhanced phagocytosis, and the ability to activate T cells. Strikingly, EVT-conditioned media are able to convert decPAMs into a decBAM phenotype. Cumulatively, these findings assign distinct macrophage phenotypes to decidual areas depending on placentation and further highlight a critical role for EVTs in the induction of pregnancy-tolerant macrophage polarization. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=131 SRC="FIGDIR/small/486171v3_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@130f55dorg.highwire.dtl.DTLVardef@13cad47org.highwire.dtl.DTLVardef@942b9forg.highwire.dtl.DTLVardef@1bbe575_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsIn this study, we identified so far unrecognized, placenta-induced immune responses at the maternal-fetal interface. Altogether, we imply that placenta-derived trophoblasts induce a pregnancy-tolerant phenotype by suppressing antigen-presenting cell-like functions in maternal tissue macrophages.

immunology↗

bioRxiv2022

Abnormal molecular signatures of inflammation, energy metabolism and vesicle biology in human Huntington disease peripheral tissues

BackgroundA major challenge in neurodegenerative diseases concerns identifying biological disease signatures that track with disease progression or respond to an intervention. Several clinical trials in Huntington disease (HD), an inherited, progressive neurodegenerative disease, are currently ongoing. Therefore, we examined whether peripheral tissues can serve as a source of readily accessible biological signatures at the RNA and protein level in HD patients. ResultsWe generated large, high-quality human datasets from skeletal muscle, skin and adipose tissue to probe molecular changes in human premanifest and early manifest HD patients - those most likely involved in clinical trials. In-depth single nucleotide polymorphism data across the HTT gene will facilitate the use of the generated primary- and iPSC cell lines in allele-specific targeting approaches. The analysis of the transcriptomics and proteomics data shows robust, stage-dependent dysregulation. Gene ontology analysis confirmed the involvement of inflammation and energy metabolism in peripheral HD pathogenesis. Furthermore, we observed changes in the homeostasis of extracellular vesicles, where we found consistent changes of genes and proteins involved in this process. ConclusionsOur omics data document the involvement of inflammation, energy metabolism and extracellular vesicle homeostasis. This demonstrates the potential to identify biological signatures from peripheral tissues in HD suitable as biomarkers in clinical trials. Together with the primary cell lines established from peripheral tissues and a large panel of iPSC lines that can serve as human models of HD, the generated data are a valuable and unique resource to advance the current understanding of molecular mechanisms driving HD pathogenesis.

neuroscience↗