Biology subjects

Kong, Y.

Publications and source records attributed to Kong, Y..

At least 91 records · Page 5Linked to original sources

bioRxiv2021

Neural dynamics of parametrically modulated human mechanical pain determined using whole-brain quantitative perfusion imaging.

Arterial spin labelling (ASL) FMRI is a powerful tool to noninvasively image tonic and ongoing pain states in both healthy participants and patients. We used ASL to image the neural correlates of extended, parametrically modulated mechanical pain in healthy human participants. The aims of this study were to: i) assess if force-calibrated pin-prick probes could safely and robustly evoke tonic mechanical pain; ii) determine the neural correlates of the parametric changes in both the "force" of the stimulus and the "intensity" of the perception that this elicits using ASL; and iii) provide an initial assessment of the capacity for ALFF to differentiate painful versus non-painful tonic stimuli based on changes in the dynamics of the evoked signal. Our data confirm that it is possible to employ a stimulus force-locked design to induce robust, well maintained ongoing mechanical pain and to observe significant changes in rCBF relative to underlying component processes such as monitoring graded changes in the force applied to the skin (dACC, aMCC, pMCC, PCC, SI, SII, putamen, thalamus and the insula (anterior and posterior subsections); ipsilateral amygdala and hypothalamus; and the contralateral DLPFC) and tracking changes in the perceived intensity of the experience (: bilateral dACC, aMCC, pMCC, PCC, thalamus, SII and the cerebellum; and contralateral SI, insula (including the dpIns). Further exploration of the data using analyses targeting the spectral frequency aspects of the rCBF signal observed reveals that a collection of regions (e.g. the contralateral VLPFC, inferior frontal gyrus, insula (anterior, mid and posterior subsections), SII, putamen, OFC, amygdala, and the hippocampus) exhibit unique perfusion dynamics during extended painful stimulation compared to non-painful touch. Results from this study provide further validation for the application of ASL to image experimental pain in healthy human subjects while interrogation of the data offers unique insight into the dynamic signal changes underlying the perception of a tonic mechanical pain experience.

neuroscience↗

bioRxiv2020

Phytochrome contributes to blue-light-mediated stem elongation and associated shade-avoidance response in mature Arabidopsis plants

Our recent studies on ornamental plants and microgreens indicate that blue-light-mediated stem elongation is related to phytochrome activity, which was based on the calculated phytochrome photoequilibrium. To examine whether phytochromes really contribute to the blue lights effect, plant phenotypic responses were investigated in wild type Arabidopsis (Col-0), and its quintuple phytochrome (phyA phyB phyC phyD phyE) mutant plants under the following light treatments: (1) R, a pure red light from 660-nm LED; (2) B, a pure blue light from 455-nm LED; (3) BR, a impure blue light from LED combination of 94% B and 6% R; and (4) BRF, another impure blue light from LED combination of BR and 6 {micro}mol m-2 s-1 of FR (735 nm). For all the light treatments, a photosynthetic photon flux density of {approx}100 mol m-2 s-1 were provided by 24-h lighting daily inside a walk-in growth chamber, which had an air temperature of {approx} 23 {degrees}C. The calculated phytochrome photoequilibrium was 0.89, 0.50, 0.69, and 0.60 for R, B, BR, and BRF, respectively, indicating a higher phytochrome activity under R and BR than B and BRF. After 18 days of light treatment, B or BRF increased main stem length in wild-type plants compared with R, but BR had an inhibition effect similar to R. Also, B and BRF relative to R or BR induced earlier flowering and reduced leaf size in wild type plants, showing typical shade-avoidance responses. In phytochrome-deficient mutant plants, the above shade-avoidance responses were inhibited under B or BRF, and induced under BR. However, as an exception, hypocotyl length, a growth trait during the de-etiolation stage, was reduced under B, BR and BRF vs. R regardless of phytochrome absence. It suggests that for mature Arabidopsis plants, phytochrome plays an active role in blue-light-mediated stem elongation and associated shade-avoidance response.

plant biology↗

bioRxiv2020

IL-4-induced hysteresis in naive T cell activation

Naive T cells are generally considered to be a homogeneous population, but for their unique T cell receptors (TCRs). Naive T cells are activated within a specific cytokine milieu upon interaction with antigen-presenting cells through cognate TCR::MHC-peptide interaction and co-stimulation. Here we demonstrate that naive T cells are transcriptionally heterogeneous, and that the relative proportions of transcriptionally distinct naive T cell subpopulations are modified by immune responses, such as during helminth infection. Not only are cognate naive T cells activated during an immune response, but the cytokine produced - such as IL-4 during helminth infection - changes the transcriptome of bystander naive T cells. Such changes in gene expression and population level heterogeneity in bystander naive T cells result in altered responses to a concurrent immune challenge, for instance, hypo-responsiveness to vaccination. Thus, naive T cell activation is not the result of a singular temporal event, but is characterized by hysteresis. Our studies suggest that antigen-agnostic, cytokine-dependent naive T cell conditioning and resulting hysteresis is a mechanism that integrates input signals from concurrent infections for the regulation of the overall magnitude of the immune response.

immunology↗

bioRxiv2020

Laser Ablation of the Pia Mater for Insertion of High-Density Microelectrode Arrays in a Translational Sheep Model

The safe insertion of high density intracortical electrode arrays has been a long-standing practical challenge for neural interface engineering and applications such as brain-computer interfaces (BCIs). Here we describe a surgical procedure, inspired by laser corneal ablation, that can be used in large mammals to thin the pia mater, the innermost meningeal layer encapsulating the brain. This procedure allows for microelectrode arrays to be inserted into the cortex with less force, thus reducing deformation of underlying tissue during placement of the microelectrodes. We demonstrate that controlled pia removal over a small area of cortex allows for insertion of high-density electrode arrays and subsequent acute recordings of spiking neuron activity in sheep cortex. We also show histological and electrophysiological evidence that laser removal of the pia does not acutely affect neuronal viability in the region. This approach suggests a promising new path for clinical BCI with high-density microelectrode arrays.

neuroscience↗

bioRxiv2020

The Argo: A 65,536 channel recording system for high density neural recording in vivo

Here we demonstrate the Argo System, a massively parallel neural recording system based on platinum-iridium microwire electrode arrays bonded to a CMOS voltage amplifier array. The Argo system is the highest channel count in vivo neural recording system built to date, supporting simultaneous recording from 65,536 channels, sampled at over 32 kHz and 12-bit resolution. This system is designed for cortical recordings, compatible with both penetrating and surface microelectrodes. We have validated this system by recording spiking activity from 791 neurons in rats and cortical surface Local Field Potential (LFP) activity from over 30,000 channels in sheep. While currently adapted for head-fixed recording, the microwire-CMOS architecture is well suited for clinical translation. Thus, this demonstration helps pave the way for a future high data rate intracortical implant.

neuroscience↗

bioRxiv2020

The genome analysis of Tripterygium wilfordii reveals TwCYP712K1 and TwCYP712K2 responsible for oxidation of friedelin in celastrol biosynthesis pathway

ABSTRACTTripterygium wilfordii is a Traditional Chinese Medicine (TCM) from family Celastraceae and celastrol is one of the strongest active ingredients belonging to friedelane-type pentacyclic triterpenoid, which has a large clinical application value of anti-tumor, immunosuppression, and obesity treatment. The first committed biosynthesis step of celastrol is the cyclization of 2, 3-oxidosqualene to friedelin, catalyzed by the oxidosqualene cyclase, while the rest of this pathway is still unclear. In this study, we reported a reference genome assembly of T. wilfordii with high-quality annotation by using a hybrid sequencing strategy (Nanopore, Bionano, Illumina HiSeq, and Pacbio), which obtained a 340.12 Mb total size and contig N50 reached 3.09 Mb. In addition, we successfully anchored 91.02% sequences into 23 pseudochromosomes using Hi-C technology and the super-scaffold N50 reached 13.03 Mb. Based on integration genome, transcriptom and metabolite analyses, as well as in vivo and in vitro enzyme assays, two CYP450 genes, TwCYP712K1 and TwCYP712K2 have been proven for C-29 position oxidation of friedelin to produce polpunonic acid, which clarifies the second biosynthesis step of celastrol. Syntenic analysis revealed that TwCYP712K1 and TwCYP712K2 derived from the common ancestor. These results have provided insight into illustrating pathways for both celastrol and other bioactive compounds found in this plant.Competing Interest StatementThe authors have declared no competing interest.View Full Text

plant biology↗

bioRxiv2020

Blocking antibodies against SARS-CoV-2 RBD isolated from a phage display antibody library using a competitive biopanning strategy

The infection of the novel coronavirus SARS-CoV-2 have caused more than 150,000 deaths, but no vaccine or specific therapeutic antibody is currently available. SARS-CoV-2 relies on its spike protein, in particular the receptor binding domain (RBD), to bind human cell receptor angiotensin-converting enzyme 2 (ACE2) for viral entry, and thus targeting RBD holds the promise for preventing SARS-CoV-2 infection. In this work, a competitive biopanning strategy of a phage display antibody library was applied to screen blocking antibodies against RBD. High-affinity antibodies were enriched after the first round using a standard panning process in which RBD-His recombinant protein was immobilized as a bait. At the next two rounds, immobilized ACE2-Fc and free RBD-His proteins were mixed with the enriched phage antibodies. Antibodies binding to RBD at epitopes different from ACE2-binding site were captured by the immobilized ACE2-Fc, forming a "sandwich" complex. Only antibodies competed with ACE2 for recognizing RBD at the same or similar epitopes can bind to the free RBD-His in the supernatant and be subsequently separated by the Ni-NTA magnetic beads. Top 1 lead from the competitive biopanning of a synthetic antibody library, Lib AB1, was produced as the full-length IgG1 format. It was proved to competitively block the binding of RBD to ACE2 protein, and potently inhibit SARS-CoV-2 pseudovirus infection of ACE2-overexpressing Hela cells with IC50 values of 12nM. Nevertheless, top 1 lead from the standard biopanning of Lib AB1, can only bind to RBD in vitro but not have the blocking or neutralization activity. Our strategy can efficiently isolate the blocking antibodies of RBD, and it would speed up the discovery of neutralizing antibodies against SARS-CoV-2.

microbiology↗

bioRxiv2020

Ratio of the interferon-γ signature to the immunosuppression signature predicts anti-PD-1 therapy response in melanoma

Immune checkpoint inhibitor (ICI) treatments produce clinical benefit in many patients. However, better pretreatment predictive biomarkers for ICI are still needed to help match individual patients to the treatment most likely to be of benefit. Existing gene expression profiling (GEP)-based biomarkers for ICI are primarily focused on measuring a T cell-inflamed tumour microenvironment that contributes positively to the response to ICI. Here, we identified an immunosuppression signature (IMS) through analysing RNA sequencing data from a combined discovery cohort (n = 120) consisting of three publicly available melanoma datasets. Using the ratio of an established IFN-{gamma} signature and IMS led to consistently better prediction of the ICI therapy outcome compared to a collection of nine published GEP signatures from the literature on a newly generated internal validation cohort (n = 55) and three published datasets of metastatic melanoma treated with anti-PD-1 (n = 48) and anti-CTLA-4 (n = 42) as well as in patients with gastric cancer treated with antiPD-1 (n = 45), demonstrating the potential utility of IMS as a predictive/prognostic biomarker that complements existing GEP signatures for immunotherapy.

immunology↗

bioRxiv2020

Fully human single-domain antibodies against SARS-CoV-2

The COVID-19 pandemic is spreading rapidly, highlighting the urgent need for an efficient approach to rapidly develop therapeutics and prophylactics against SARS-CoV-2. We describe here the development of a phage-displayed single-domain antibody library by grafting naive CDRs into framework regions of an identified human germline IGHV allele. This enabled the isolation of high-affinity single-domain antibodies of fully human origin. The panning using SARS-CoV-2 RBD and S1 as antigens resulted in the identification of antibodies targeting five types of neutralizing or non-neutralizing epitopes on SARS-CoV-2 RBD. These fully human single-domain antibodies bound specifically to SARS-CoV-2 RBD with subnanomolar to low nanomolar affinities. Some of them were found to potently neutralize pseudotyped and live virus, and therefore may represent promising candidates for prophylaxis and therapy of COVID-19. This study also reports unique immunogenic profile of SARS-CoV-2 RBD compared to that of SARS-CoV and MERS-CoV, which may have important implications for the development of effective vaccines against SARS-CoV-2.

microbiology↗

bioRxiv2020

Chromatin-Bound PARP1 Correlates with Upregulation of Inflammatory Genes in Response to Long-Term Treatment with Veliparib

Poly-ADP-ribose polymerase (PARP) inhibitors are active against cells and tumors with defects in homology-directed repair as a result of synthetic lethality. PARP inhibitors have been suggested to act by either catalytic inhibition or by PARP localization in chromatin. In this study, we treat human HCC1937 BRCA1 mutant and isogenic BRCA1-complemented cells for three weeks with veliparib, a PARP inhibitor. We show that long-term treatment with veliparib results in chromatin-bound PARP1 in the BRCA1 mutant cells, and that this correlates with significant upregulation of inflammatory genes and activation of the cyclic GMP-AMP synthase (cGAS)/ signalling effector stimulator of interferon genes (STING) pathway. In contrast, long-term treatment of isogenic BRCA1-complemented cells with veliparib does not result in chromatin-associated PARP or significant upregulation of the inflammatory response. Our results suggest that long-term veliparib treatment may prime BRCA1 mutant tumors for positive responses to immune checkpoint blockade.

cancer biology↗

bioRxiv2020

Arabidopsis ERF4 and MYB52 Transcription Factors Play Antagonistic Roles in Regulating Homogalacturonan De-methylesterification in Seed Coat Mucilage

The Arabidopsis (Arabidopsis thaliana) seed coat mucilage is a specialized cell wall with pectin as its major component. Pectin is synthesized in the Golgi apparatus with homogalacturonan fully methylesterified, but it must undergo de-methylesterification by pectin methylesterase (PME) after being secreted into the cell wall. This reaction is critical for pectin maturation, but the mechanisms of its transcriptional regulation remain largely unknown. Here, we show that the Arabidopsis ERF4 transcription factor positively regulates pectin de-methylesterification during seed development and directly suppresses the expression of PME INHIBITOR13 (PMEI13), 14, 15 and SUBTILISIN-LIKE SERINE PROTEASE 1.7 (SBT1.7). The erf4 mutant seeds showed repartitioning of mucilage between soluble and adherent layers as a result of decreased PME activity and increased degree of pectin methylesterification. ERF4 physically associates with and antagonizes MYB52 in activating PMEI6, 14 and SBT1.7 and MYB52 also antagonizes ERF4 activity in the regulation of downstream targets. Gene expression studies revealed that ERF4 and MYB52 have opposite effects on pectin de-methylesterification. Genetic analysis indicated that the erf4-2 myb52 double mutant seeds show mucilage phenotype similar to wild-type. Taken together, this study demonstrates that ERF4 and MYB52 antagonize each others activity to maintain the appropriate degree of pectin methylesterification, expanding our understanding of how pectin de-methylesterification is fine-tuned by the ERF4-MYB52 transcriptional complex in the seed mucilage. One-sentence summaryArabidopsis ERF4 and MYB52 transcription factors interact and play antagonistic roles in regulating homogalacturonan de-methylesterification related genes in the seed coat mucilage.

plant biology↗

bioRxiv2019

Semaphorin 3A induces cytoskeletal paralysis in tumor-specific CD8+ T cells

Semaphorin-3A (Sema3A) regulates tumor angiogenesis, but its role in modulating anti-tumor immunity is unclear. We demonstrate that Sema3A secreted within the tumor microenvironment (TME) suppresses tumor-specific CD8+ T cell function via Neuropilin-1 (NRP1), a receptor that is upregulated upon activation with T cells cognate antigen. Sema3A inhibits T cell migration, assembly of the immunological synapse, and tumor killing. It achieves these functional effects through hyper-activating the acto-myosin system in T cells leading to cellular paralysis. Finally, using a clear cell renal cell carcinoma patient cohort, we demonstrate that human tumor-specific CD8+ T cells express NRP1 and are trapped in Sema3A rich regions of tumors. Our study establishes Sema3A as a potent inhibitor of anti-tumor immunity.

immunology↗

bioRxiv2019

Loss of AKAP1 triggers Drp1 dephosphorylation-mediated mitochondrial fragmentation and loss in retinal ganglion cells

Impairment of mitochondrial structure and function is strongly linked to glaucoma pathogenesis. Despite the widely appreciated disease relevance of mitochondrial dysfunction and loss, the molecular mechanisms underlying mitochondrial fragmentation and metabolic stress in glaucoma are poorly understood. We demonstrate here that glaucomatous retinal ganglion cells (RGCs) show loss of A-kinase anchoring protein 1 (AKAP1), activation of calcineurin (CaN) and reduction of dynamin-related protein 1 (Drp1) phosphorylation at serine 637 (Ser637). These findings suggest that AKAP1-mediated phosphorylation of Drp1 at Ser637 has a critical role in RGC survival in glaucomatous neurodegeneration. Male mice lacking AKAP1 show increases of CaN and total Drp1 level, as well as a decrease of Drp1 phosphorylation at Ser637 in the retina. Ultrastructural analysis of mitochondria shows that loss of AKAP1 triggers mitochondrial fragmentation and loss, as well as mitophagosome formation in RGCs. Loss of AKAP1 deregulates oxidative phosphorylation (OXPHOS) complexes (Cxs) by increasing CxII and decreasing CxIII-V, leading to metabolic and oxidative stress. Also, loss of AKAP1 decreases Akt phosphorylation at Serine 473 (Ser473) and threonine 308 (Thr308) and activates the Bim/Bax signaling pathway in the retina. These results suggest that loss of AKAP1 has a critical role in RGC dysfunction by decreasing Drp1 phosphorylation at Ser637, deregulating OXPHOS, decreasing Akt phosphorylation at Ser473 and Thr308, and activating the Bim/Bax pathway in glaucomatous neurodegeneration. Thus, we propose that overexpression of AKAP1 or modulation of Drp1 phosphorylation at Ser637 are potential therapeutic strategies for neuroprotective intervention in glaucoma and other mitochondria-related optic neuropathies.

neuroscience↗

bioRxiv2019

Kinetic Inference Resolves Epigenetic Mechanism of Drug Resistance in Melanoma

Drug-induced dedifferentiation towards a drug-tolerant persister state is a common mechanism cancer cells exploit to escape therapies, posing a significant obstacle to sustained therapeutic efficacy. The dynamic coordination of epigenomic and transcriptomic programs at the early-stage of drug exposure, which initiates and orchestrates these reversible dedifferentiation events, remains largely unexplored. Here we employ high-temporal-resolution multi-omics profiling, information-theoretic approaches, and dynamic system modeling to probe these processes in BRAF-mutant melanoma models and patient specimens. We uncover a hysteretic transition trajectory of melanoma cells in response to oncogene inhibition and subsequent release, driven by the sequential operation of two tightly coupled transcriptional waves, which orchestrate genome-scale chromatin state reconfiguration. Modeling of the transcriptional wave interactions predicts NF-{kappa}B/RelA-driven chromatin remodeling as the underlying mechanism of cell-state dedifferentiation, a finding we validate experimentally. Our results identify critical RelA-target genes that are epigenetically modulated to drive this process, establishing a quantitative epigenome gauge to measure cell-state plasticity in melanomas, which supports the potential use of drugs targeting epigenetic machineries to potentiate oncogene inhibition. Extending our investigation to other cancer models, we identify oxidative stress-mediated NF-{kappa}B/RelA activation as a common mechanism driving cellular transitions towards drug-tolerant persister states, revealing a novel and pivotal role for the NF-{kappa}B signaling axis in linking cellular oxidative stress to cancer progression.

cancer biology↗

bioRxiv2019

Dolosigranulum pigrum cooperation and competition in human nasal microbiota

BackgroundMultiple epidemiological studies identify Dolosigranulum pigrum as a candidate beneficial bacterium based on its positive association with health, including negative associations with nasal/nasopharyngeal colonization by the pathogenic species Staphylococcus aureus and Streptococcus pneumoniae. ResultsUsing a multipronged approach to gain new insights into D. pigrum function, we observed phenotypic interactions and predictions of genomic capacity that support a role for microbe-microbe interactions involving D. pigrum in shaping the composition of human nasal microbiota. We identified in vivo community-level and in vitro phenotypic cooperation by specific nasal Corynebacterium species. Also, D. pigrum inhibited S. aureus growth in vitro. Whereas, robust inhibition of S. pneumoniae required both D. pigrum and a nasal Corynebacterium together, and not either alone. D. pigrum L-lactic-acid production was insufficient to account for these inhibitions. Genomic analysis of 11 strains revealed that D. pigrum has a small genome (average 1.86 Mb) and multiple predicted auxotrophies consistent with D. pigrum relying on its human host and cocolonizing bacteria for key nutrients. Further, the accessory genome of D. pigrum encoded a diverse repertoire of biosynthetic gene clusters, some of which may have a role in microbe-microbe interactions. ConclusionsThese new insights into D. pigrums functions advance the field from compositional analysis to genomic and phenotypic experimentation on a potentially beneficial bacterial resident of the human upper respiratory tract and lay the foundation for future animal and clinical experiments.

microbiology↗

bioRxiv2019

CHIME: CMOS-hosted in-vivo microelectrodes for massively scalable neuronal recordings

Mammalian brains consist of 10s of millions to 100s of billions of neurons operating at millisecond time scales, of which current recording techniques only capture a tiny fraction. Recording techniques capable of sampling neural activity at such temporal resolution have been difficult to scale: The most intensively studied mammalian neuronal networks, such as the neocortex, show layered architecture, where the optimal recording technology samples densely over large areas. However, the need for application-specific designs as well as the mismatch between the threedimensional architecture of the brain and largely two-dimensional microfabrication techniques profoundly limits both neurophysiological research and neural prosthetics.\n\nHere, we propose a novel strategy for scalable neuronal recording by combining bundles of glass-ensheathed microwires with large-scale amplifier arrays derived from commercial CMOS of in-vitro MEA systems or high-speed infrared cameras. High signal-to-noise ratio (<20 V RMS noise floor, SNR up to 25) is achieved due to the high conductivity of core metals in glass-ensheathed microwires allowing for ultrathin metal cores (down to <1 m) and negligible stray capacitance. Multi-step electrochemical modification of the tip enables ultra-low access impedance with minimal geometric area and largely independent of core diameter. We show that microwire size can be reduced to virtually eliminate damage to the blood-brain-barrier upon insertion and demonstrate that microwire arrays can stably record single unit activity.\n\nCombining microwire bundles and CMOS arrays allows for a highly scalable neuronal recording approach, linking the progress of electrical neuronal recording to the rapid scaling of silicon microfabrication. The modular design of the system allows for custom arrangement of recording sites. Our approach of employing bundles of minimally invasive, highly insulated and functionalized microwires to lift a 2-dimensional CMOS architecture into the 3rd dimension can be translated to other CMOS arrays such as electrical stimulation devices.

neuroscience↗

bioRxiv2018

To examine environmental pollution by economic growth and their impact in an environmental Kuznets curve (EKC) among developed and developing countries.

This study analyzes the core energy consumption among countries specific variables by Environmental Kuznets Curve hypothesis (EKC), for a panel data of 29 (14 developed and 15 developing) countries during the period of 1977-2014. By assessing Generalized Method of Moments (GMM) regressions with first generation test such as common root, individual Augmented Dickey-Fuller (ADF), and individual root-Fisher-PP have been computed individually, the results confirm the EKC hypothesis in the case of emissions of solid, liquid, gases, manufacturing industries and also construction. Hence, we computed the cointegration test by Pedroni Kao from Engle-Granger based and Fisher. Onward, since the variable are co-integrated, a panel vector error correction model is estimated in GDP per capita, emission from manufacturing industries, arms import, commercial service export and coal rent, order to perform Pairwise Granger Causality test and indicate Vector Error Correction (VEC), with co-integration restrictions. Moreover, the statistical finding from VEC short-run unidirectional causality from GDP per capita growth to manufacturing industries and coat rent, as well as the causal link with manufacturing industries and commercial service export. Additionally, since there occurred no causal link among economic growth, arm import and coal rent.

ecology↗

bioRxiv2018

The lupus susceptibility locus Sgp3 encodes the suppressor of endogenous retrovirus expression SNERV

Elevated endogenous retrovirus (ERV) transcription and anti-ERV antibody reactivity are implicated in lupus pathogenesis. Overproduction of non-ecotropic ERV (NEERV) envelope glycoprotein, gp70, and resultant nephritis occur in lupus-prone mice. However, a NEERV repressor has not been identified to test if this association is causal. Here we identified suppressor of NEERV (Snerv) 1 & 2, Kruppel-associated box zinc finger proteins (KRAB-ZFP) that repressed NEERV by binding the NEERV long terminal repeat to recruit the transcriptional regulator KAP1. Germline Snerv1/2 deletion increased activating chromatin modifications, transcription, and gp70 expression from NEERV loci. F1 crosses of lupus-prone NZB and 129 mice to Snerv1/2-/- mice failed to restore NEERV repression, demonstrating that loss of SNERV underlies the lupus autoantigen gp70 overproduction that promotes nephritis in susceptible mice. Increased ERV expression in lupus patients was inversely correlated with expression of three putative ERV-suppressing KRAB-ZFP, suggesting that KRAB-ZFP-mediated ERV misexpression may contribute to human lupus pathogenesis.

immunology↗