Biology subjects

Wu, J.

Publications and source records attributed to Wu, J..

At least 631 records · Page 35Linked to original sources

bioRxiv2021

3D reconstruction of cell nuclei in a full Drosophila brain

We reconstructed all cell nuclei in a 3D image of a Drosophila brain acquired by serial section electron microscopy (EM). The total number of nuclei is approximately 133,000, at least 87% of which belong to neurons. Neuronal nuclei vary from several hundred down to roughly 5 cubic micrometers. Glial nuclei can be even smaller. The optic lobes contain more than two times the number of cells than the central brain. Our nuclear reconstruction serves as a spatial map and index to the cells in a Drosophila brain.

neuroscience↗

bioRxiv2021

Clonal hematopoiesis detection in cancer patients using cell free DNA sequencing

In the context of cancer, clonal hematopoiesis of indeterminate potential (CHIP) is associated with the development of therapy-related myeloid neoplasms and shorter overall survival. Cell-free DNA (cfDNA) sequencing is becoming widely adopted for genomic screening of cancer patients but has not been used extensively to determine CHIP status due to a requirement for matched blood and tumor sequencing. Here we present an accurate machine learning approach to determine clonal hematopoiesis (CH) status from cfDNA sequencing alone and apply our model to 4,096 oncology clinical cfDNA samples. Using this method, we determine that 26% of patients in this cohort have evidence of CH and CH is most common in lung cancer patients. Matched RNAseq data shows signals of increased inflammation, especially neutrophil activation, within the tumor microenvironment of CH-positive patients. Additionally, CH patients showed evidence of neutrophil activation systemically, pointing to a potential mechanism of action for the worse outcomes associated with CH status. Neutrophil activation may be one of many mechanisms however, as estrogen positive breast cancer patients harboring TET2 frameshift mutations had worse outcomes but similar neutrophil levels to CH-negative patients. One Sentence SummaryWe train an accurate machine learning model to detect clonal hematopoiesis in cancer and characterize associated changes in the tumor microenvironment.

cancer biology↗

bioRxiv2021

The amount range of membrane cholesterol required for robust cell adhesion and proliferation in serum-free condition.

Serum-containing medium is widely used to support cell attachment, stable growth and serial passaging of various cancer cell lines. However, the presence of cholesterols and lipids in serum greatly hinders the analysis of the effects of cholesterol depletion on cells in culture. In this study, we develop a defined serum-free culture condition accessible to a variety of different types of adherent cancer cells. We tested different factors that are considered essential for cell culture and various extracellular matrix for plate coating, and found cells cultured in Dulbeccos Modified Eagles Medium (DMEM) basal media supplemented with Albumin (BSA) and insulin-transferrin-selenium-ethanolamine (ITS-X) on fibronectin-precoated well (called as "DA-X condition") showed comparable proliferation and survival to those in a serum-containing medium. Interestingly, we observed that DA-X condition could be adapted to a wide variety of adherent cancer cell lines, which enabled the analysis of how cholesterol depletion affected cancer cells in culture. Mechanistically, we found the beneficial effects of the DA-X condition in part can be attributed to the appropriate level of membrane cholesterol, and fibronectin-mediated signaling plays an important role in the suppression of cholesterol production.

cancer biology↗

bioRxiv2021

Impaired trigeminal control of ingestive behavior in the Prrxl1- / - mouse is associated with a lemniscal-biased orosensory deafferentation

Although peripheral deafferentation studies have demonstrated a critical role for trigeminal afference in modulating the orosensorimotor control of eating and drinking, the central trigeminal pathways mediating that control, as well as the timescale of control, remain to be elucidated. In rodents, three ascending somatosensory pathways process and relay orofacial mechanosensory input: the lemniscal, paralemniscal, and extralemniscal. Two of these pathways (the lemniscal and extralemniscal) exhibit highly structured topographic representations of the orofacial sensory surface, as exemplified by the one-to-one somatotopic mapping between vibrissae on the animals face and barrelettes in brainstem, barreloids in thalamus, and barrels in cortex. Here we use the Prrxl1 knockout mouse model to investigate ingestive behavior deficits associated with disruption of the lemniscal pathway. The Prrxl1 deletion disrupts somatotopic patterning and axonal projections throughout the lemniscal pathway but spares patterning in the extralemniscal nucleus. Our data reveal an imprecise and inefficient ingestive phenotype with deficits that span timescales from milliseconds to months, tightly linking trigeminal input with ingestion, from moment-to-moment consummatory to long term appetitive control. We suggest that ordered assembly of trigeminal sensory information along the lemniscal pathway is critical for the rapid and precise modulation of motor circuits driving eating and drinking action sequences.

neuroscience↗

bioRxiv2021

Brain networks in human conscious visual perception

Consciousness is not explained by a single mechanism, rather it involves multiple specialized neural systems overlapping in space and time. We hypothesize that synergistic, large-scale subcortical and cortical attention and signal processing networks encode conscious experiences. To identify brain activity in conscious perception without overt report, we classified visual stimuli as perceived or not using eye measurements. Report-independent event-related potentials and functional magnetic resonance imaging (fMRI) signals both occurred at early times after stimuli. Direct recordings revealed a novel thalamic awareness potential linked to conscious visual perception based on report. fMRI showed thalamic and cortical detection, arousal, attentional salience, task-positive, and default mode networks were involved independent of overt report. These findings identify a specific sequence of neural mechanisms in human conscious visual perception. One-Sentence SummaryHuman conscious visual perception engages large-scale subcortical and cortical networks even without overt report.

neuroscience↗

bioRxiv2021

Why can we detect lianas from space?

Lianas, woody vines acting as structural parasites of trees, have profound effects on the composition and structure of tropical forests, impacting tree growth, mortality, and forest succession. Remote sensing offers a powerful tool for quantifying the scale of liana infestation, provided the availability of robust detection methods. We analyze the consistency and global specificity of spectral signals from liana-infested tree crowns and forest stands, examining the underlying mechanisms. We compiled a database, including leaf reflectance spectra from 5424 leaves, fine-scale airborne reflectance data from 999 liana-infested canopies, and coarse-scale satellite reflectance data covering hectares of liana-infested forest stands. To unravel the mechanisms of the liana spectral signal, we applied mechanistic radiative transfer models across scales, corroborated by field data on liana leaf chemistry and canopy structure. We find a consistent liana spectral signature at canopy and stand scales across sites. This signature mainly arises at the canopy level due to direct effects of leaf angles, resulting in a larger apparent leaf area, and indirect effects from increased light scattering in the NIR and SWIR regions, linked to lianas less costly leaf construction compared to trees. The existence of a consistent global spectral signal for lianas suggests that large-scale quantification of liana infestation is feasible. However, because the traits identified are not exclusive to lianas, accurate large-scale detection requires rigorously validated remote sensing methods. Our models highlight challenges in automated detection, such as potential misidentification due to leaf phenology, tree life-history, topography, and climate, especially where the scale of liana infestation is less than a single remote sensing pixel. The observed cross-site patterns also prompt ecological questions about lianas adaptive similarities across environments, indicating possible convergent evolution due to shared constraints on leaf biochemical and structural traits. Open data statementOf the 17 datasets used, 10 are published and publicly accessible, with links provided in this submission (Appendix S1: Section S1). Upon acceptance, remaining seven datasets will be provided via Smithsonians Dspace. The open-source model code is available as R-package ccrtm (https://cran.r-project.org/web/packages/ccrtm/index.html) and on github (https://github.com/MarcoDVisser/ccrtm). Code will be archived in Zenodo should the manuscript be accepted for publication

plant biology↗

bioRxiv2021

De novo variants in Chinese ASD trios reveal genetic basis underlying autism without developmental delay and intellectual disabilities

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that causes a range of social communication and behavioral impairments. ASD typically manifests in young children, often with developmental delay or intellectual disabilities (DD/ID) as comorbidities. Accruing evidence indicates that ASD is highly heritable and genomewide studies on ASD cohorts have defined numerous genetic contributors. Notably, most of these studies have been performed with individuals of European and Hispanic ancestry and thus there is a paucity of genetic analyses of ASD in the East Asian population. Here, we performed whole-exome sequencing on 772 ASD trios from China, combining with a previous study of 369 Chinese ASD trios, to identify de novo variants in a total of 1141 ASD trios. We found that ASD probands without DD/ID carried less disruptive de novo variants, including protein-truncating and missense variants, than ASD with DD/ID. Surprisingly, we showed that expression of genes with de novo variants found in ASD probands without DD/ID were enriched in a specific group of neural progenitor cells, suggesting a potential mechanism underlying high-functioning autism. Importantly, some ASD risk genes from this study are not present in the current ASD gene database, suggesting that there are novel genetic contributors to ASD in East Asian populations. We validated one such novel ASD risk gene - SLC35G1 by showing that mice harboring heterozygous deletion of Slc35g1 exhibited defects in social interaction behaviors. Together, this work nominates novel ASD risk genes and indicates that ASD genetic studies in different geographic populations are essential to reveal the comprehensive genetic architecture of ASD.

neuroscience↗

bioRxiv2021

Two helices control the dynamic crosstalk between the catalytic domains of LRRK2

The two major molecular switches in biology, kinases and GTPases, are both contained in the Parkinsons Disease-related Leucine-rich repeat kinase 2 (LRRK2). Using hydrogen-deuterium exchange mass spectrometry (HDX-MS) and Molecular Dynamics (MD) simulations, we generated a comprehensive dynamic allosteric portrait of the C-terminal domains of LRRK2 (LRRK2RCKW). We identified two helices that shield the kinase domain and regulate LRRK2 conformation and function. One docking helix in COR-B (Dk-Helix) tethers the COR-B domain to the C helix of the kinase domain and faces its Activation Loop, while the C-terminal helix (Ct-Helix) extends from the WD40 domain and interacts with both kinase lobes. The Ct-Helix and the N-terminus of the Dk-Helix create a "cap" that regulates the N-Lobe of the kinase domain. Our analyses reveal allosteric sites for pharmacological intervention and confirm the kinase domain as the central hub for conformational control.

biochemistry↗

bioRxiv2021

Anisotropic Rod-Shaped Particles Influence Injectable Granular Hydrogel Properties and Cell Invasion

Granular hydrogels have emerged as a new class of injectable and porous biomaterials that improve integration with host tissue when compared to solid hydrogels. Granular hydrogels are typically prepared using spherical particles and this study considers whether particle shape (i.e., isotropic spheres versus anisotropic rods) influences granular hydrogel properties and cellular invasion. Simulations predict that anisotropic rods influence pore shape and interconnectivity, as well as bead transport through granular assemblies. Photocrosslinkable norbornene-modified hyaluronic acid is used to produce spherical and rod-shaped particles using microfluidic droplet generators and formed into shear-thinning and self-healing granular hydrogels at low and high particle packing. Rod-shaped particles form granular hydrogels that have anisotropic and interconnected pores, with pore number and size, storage moduli, and extrusion forces influenced by particle shape and packing. Robust in vitro sprouting of endothelial cells from embedded cellular spheroids is observed with rod-shaped particles, including higher sprouting densities and sprout lengths when compared to hydrogels with spherical particles. Cellular invasion into granular hydrogels when injected subcutaneously in vivo is significantly greater with rod-shaped particles, whereas a gradient of cellularity is observed with spherical particles. Overall, this work demonstrates potentially superior functional properties of granular hydrogels with rod-shaped particles for tissue repair.

bioengineering↗

bioRxiv2021

Purinergic receptor P2RY14 cAMP signaling regulates EGFR-driven Schwann cell precursor self-renewal and nerve tumor initiation in neurofibromatosis.

Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by nerve tumors called neurofibromas, in which Schwann cells (SCs) lack NF1 and show deregulated RAS signaling. NF1 is also implicated in regulation of cAMP. Gene expression profiling and protein expression identified P2RY14 in SCs and SC precursors (SCPs) implicating P2RY14 as a candidate upstream regulator of cAMP in EGF-dependent SCP. We found that SCP self-renewal was reduced by genetic or pharmacological inhibition of P2RY14. In NF1 deficient SCs and malignant peripheral nerve sheath tumor (MPNST) cells, P2RY14 inhibition decreased EGFR-driven phospho-Akt and increased cAMP signaling. In a neurofibroma mouse model, genetic deletion of P2RY14 increased mouse survival, delayed neurofibroma initiation and rescued cAMP signaling. Conversely, elevation of cAMP diminished SCP number in vitro and diminished SC proliferation in neurofibroma bearing mice in vivo. These studies identify the purinergic receptor P2RY14 as a critical G-protein-coupled receptor (GPCR) in NF1 mutant SCPs and SCs and suggest roles for EGFR-GPCR crosstalk in facilitating SCP self-renewal and neurofibroma initiation via cAMP and EGFR-driven phospho-Akt.

neuroscience↗

bioRxiv2021

Mosaic Evolution of Beta Barrel Porin Encoding Genes in Escherichia coli

Bacterial porins serve as the interface interacting with extracellular environment, and are often found under positive selection to fit in different environmental stresses. Local recombination has been identified in a handful of porin genes to facilitate the rapid adaptation of bacterial cells. It remains unknown whether it is a common evolutionary mechanism in gram-negative bacteria for all or a majority of the outer membrane proteins. In this research, we investigated the {beta}-barrel porin encoding genes in Escherichia coli that were reported under positive Darwinia selection. Besides fhuA that was found with ingenic local recombination predominantly previously, we identified four other genes, i.e., lamB, ompA, ompC and ompF, all showing the similar mosaic evolution patterns as in fhuA. Comparative analysis of the protein sequences disclosed a list of highly variable regions in each protein family, which are mostly located in the convex of extracellular loops and coinciding with the binding sites of various bacteriophages. For each of the porin family, mosaic recombination leads to various combinations of the HVRs with different sequence patterns, generating diverse protein groups. Structure modeling further indicated the conserved global topology for various groups of each porin family, but the extracellular surface varies a lot that is formed by individual or combinatorial HVRs. The conservation of global tertiary structure ensures the channel activity while the wide diversity of HVRs may assist bacteria avoiding the invasion of phages, antibiotics or immune surveillance factors. In summary, the study identified multiple bacterial porin genes with mosaic evolution, a likely general strategy, by which outer membrane proteins could facilitate the host bacteria to both maintain normal life processes and evade the attack of unflavored environmental factors rapidly. ImportanceMicroevolution studies can disclose more elaborate evolutionary mechanisms of genes, appearing especially important for genes with multifaceted function such as those encoding outer membrane proteins. However, in most cases, the gene is considered as a whole unit and the evolutionary patterns are disclosed. In this research, we reported that multiple bacterial porin proteins follow mosaic evolution, with local ingenic recombination combined with spontaneous mutations based positive Darwinia selection, and conservation for most of the other regions. It could represent a common mechanism for bacterial outer membrane proteins. The study also provides insights on development of new anti-bacterial agent or vaccines.

microbiology↗

bioRxiv2021

Long-term in vivo imaging of mouse spinal cord through an optically cleared intervertebral window

Spinal cord, as part of the central nervous system, accounts for the main communication pathway between the brain and the peripheral nervous system. Spinal cord injury is a devastating and largely irreversible neurological trauma, and can result in lifelong disability and paralysis with no available cure. In vivo spinal cord imaging in mouse models without introducing immunological artifacts is critical to understand spinal cord pathology and discover effective treatments. We developed a minimal-invasive intervertebral window by retaining ligamentum flavum to protect the underlying spinal cord. By introducing an optical clearing method, we achieved repeated two-photon fluorescence and stimulated Raman scattering imaging at subcellular resolution with up to 16 imaging sessions over 167 days and observed no inflammatory response. Using this optically cleared intervertebral window, we studied the neuron-glia dynamics following laser axotomy and observed strengthened contact of microglia with the nodes of Ranvier during axonal degeneration. By enabling long-term, repetitive, stable, high-resolution and inflammation-free imaging of mouse spinal cord, our method provides a reliable platform in the research aiming at understanding and treatment of spinal cord pathology.

neuroscience↗

bioRxiv2021

Integrating Transcriptomics, Genomics, and Imaging in Alzheimer's Disease: A Federated Model

Alzheimers disease (AD) affects more than 1 in 9 people age 65 and older and becomes an urgent public health concern as the global population ages. In clinical practice, structural magnetic resonance imaging (sMRI) is the most accessible and widely used diagnostic imaging modality. Additionally, genome-wide association studies (GWAS) and transcriptomics - the study of gene expression - also play an important role in understanding AD etiology and progression. Sophisticated imaging genetics systems have been developed to discover genetic factors that consistently affect brain function and structure. However, most studies to date focused on the relationships between brain sMRI and GWAS or brain sMRI and transcriptomics. To our knowledge, few methods have been developed to discover and infer multimodal relationships among sMRI, GWAS, and transcriptomics. To address this, we propose a novel federated model, Genotype-Expression-Imaging Data Integration (GEIDI), to identify genetic and transcriptomic influences on brain sMRI measures. The relationships between brain imaging measures and gene expression are allowed to depend on a persons genotype at the single-nucleotide polymorphism (SNP) level, making the inferences adaptive and personalized. We performed extensive experiments on publicly available Alzheimers Disease Neuroimaging Initiative (ADNI) dataset. Experimental results demonstrated our proposed method outperformed state-of-the-art expression quantitative trait loci (eQTL) methods for detecting genetic and transcriptomic factors related to AD and has stable performance when data are integrated from multiple sites. Our GEIDI approach may offer novel insights into the relationship among image biomarkers, genotypes, and gene expression and help discover novel genetic targets for potential AD drug treatments.

bioinformatics↗

bioRxiv2021

E3 ligase TRIM47 positively regulates endothelial activation and pulmonary inflammation through potentiating the K63-linked ubiquitination

Endothelial activation plays an essential role in the pathology of sepsis-induced acute lung injury, but the detailed regulatory mechanisms remain largely unknown. Here, we demonstrated that TRIM47, an ubiquitin E3 ligase of tripartite protein family, is highly expressed in vascular endothelial cells and is up-regulated during TNF-induced endothelial activation. Knockdown of TRIM47 in endothelial cells prevents the transcription of multiple pro-inflammatory cytokines, reduces monocyte adhesion and the expression of adhesion molecules, and inhibits the secretion of IL-1{beta} and IL-6 into the supernatant. By contrast, overexpression of TRIM47 promotes inflammatory response and monocyte adhesion upon TNF stimulation. TRIM47 modulates the activation of NF-{kappa}B and MAPK signaling pathways during endothelial activation. Further experiment confirmed that TRIM47 interacts with TRAF2 and mediates K63-linked ubiquitination. In addition, TRIM47-deficient mice are more resistant to lipopolysaccharide-induced acute lung injury and death, due to attenuated pulmonary inflammation. Taken together, our studies suggest that TRIM47 promotes pulmonary inflammation and injury at least partly through potentiating the K63-linked ubiquitination of TRAF2, which in turn activates NF-{kappa}B and MAPK signaling pathways to trigger inflammatory response in endothelial cells.

cell biology↗

bioRxiv2021

Detecting Phytophthora cinnamomi associated with dieback disease on Carya cathayensis using loop-mediated isothermal amplification

Chinese hickory (Carya cathayensis Sarg.) is an economically and ecologically important nut plant in China. Dieback and basal stem necrosis have been observed in the plants since 2016, and its recent spread has significantly affected plant growth and nut production. Therefore, a survey was conducted to evaluate the disease incidence at five sites in Linan County, China. The highest incidence was recorded at the Tuankou site at up to 11.39% in 2019. The oomycete, Phytophthora cinnamomi, was isolated from symptomatic plant tissue and plantation soil using baiting and selective media-based detection methods and identified. Artificial infection with the representative P. cinnamomi ST402 isolate produced vertically elongated discolorations in the outer xylem and necrotic symptoms in C. cathayensis seedlings in a greenhouse trial. Molecular detections based on loop-mediated isothermal amplification (LAMP) specific to P. cinnamomi ST402 were conducted. Result indicated that LAMP detection showed a high coherence level with the baiting assays for P. cinnamomi detection in the field. This study provides the evidence of existence of high-pathogenic P. cinnamomi in the C. cathayensis plantation soil in China and the insights into a convenient tool developed for conducting field monitoring of this aggressive pathogen.

plant biology↗

bioRxiv2021

A non-bactericidal cathelicidin provides prophylactic efficacy against bacterial infection by driving phagocyte influx

The roles of bactericidal cathelicidins against bacterial infection have been extensively studied. However, the anti-bacterial property and mechanism of action of non-bactericidal cathelicidins are rarely known. Herein, a novel naturally occurring cathelicidin (PopuCATH) from tree frog (Polypedates puerensis) didnt show any direct anti-bacterial activity in vitro. Intriguingly, intraperitoneal injection of PopuCATH before bacterial inoculation significantly reduced the bacterial load in tree frogs and mice, and reduced the inflammatory response induced by bacterial inoculation in mice. PopuCATH pretreatment also increased the survival rates of septic mice induced by a lethal dose of bacterial inoculation or cecal ligation and puncture (CLP). Intraperitoneal injection of PopuCATH significantly drove the leukocyte influx in both frogs and mice. In mice, PopuCATH rapidly drove neutrophil, monocyte/macrophage influx in mouse abdominal cavity and peripheral blood with a negligible impact on T and B lymphocytes, and neutrophils, monocytes/macrophages, but not T and B lymphocytes, were required for the preventive efficacy of PopuCATH. PopuCATH did not directly act as chemoattractant for phagocytes, but PopuCATH obviously drove phagocyte migration when it was cultured with macrophages. PopuCATH significantly elicited chemokine/cytokine production in macrophages through activating p38/ERK mitogen-activated protein kinases (MAPKs) and NF-{kappa}B p65. PopuCATH markedly enhanced neutrophil phagocytosis via promoting the release of neutrophil extracellular traps (NETs). Additionally, PopuCATH showed low side effects both in vitro and in vivo. Collectively, PopuCATH acts as a host-based immune defense regulator that provides prophylactic efficacy against bacterial infection without direct antimicrobial effects. Our findings reveal a non-bactericidal cathelicidin which possesses unique anti-bacterial action, and highlight the potential of PopuCATH to prevent bacterial infection.

immunology↗

bioRxiv2021

Peroxide antimalarial drugs target redox homeostasis in Plasmodium falciparum infected red blood cells

Plasmodium falciparum causes the most lethal form of malaria. Peroxide antimalarials based on artemisinin underpin the frontline treatments for malaria, but artemisinin resistance is rapidly spreading. Synthetic peroxide antimalarials, known as ozonides, are in clinical development and offer a potential alternative. Here, we used chemoproteomics to investigate the protein alkylation targets of artemisinin and ozonide probes, including an analogue of the ozonide clinical candidate, artefenomel. We greatly expanded the list of protein targets for peroxide antimalarials and identified significant enrichment of redox-related proteins for both artemisinins and ozonides. Disrupted redox homeostasis was confirmed by dynamic live imaging of the glutathione redox potential using a genetically encoded redox-sensitive fluorescence-based biosensor. Targeted LC-MS-based thiol metabolomics also confirmed changes in cellular thiol levels. This work shows that peroxide antimalarials disproportionately alkylate proteins involved in redox homeostasis and that disrupted redox processes are involved in the mechanism of action of these important antimalarials. ImportanceThe frontline treatments for malaria are combination therapies based on the peroxide antimalarial, artemisinin. Concerningly, artemisinin resistance has emerged in malaria-endemic regions, and now poses a major threat to malaria treatment and eradication efforts. New medicines are urgently required to replace the artemisinins, and some of the most advanced candidates are the fully synthetic peroxide antimalarials, OZ277 (arterolane) and OZ439 (artefenomel). The mechanism of action of peroxide antimalarials involves the reductive activation of the peroxide bond by intra-parasitic haem, but there is no consensus regarding the specific protein targets of the resulting radical species for artemisinins and/or the ozonides. This study provides a comprehensive and unbiased chemoproteomic profile of over 400 target proteins, and confirms the specific impact of peroxide antimalarials on redox metabolism. The key role of redox targets is particularly relevant considering that the mechanism of artemisinin resistance appears to involve modulation of peroxide activation and redox homeostasis.

pharmacology and toxicology↗

bioRxiv2021

TET1 controls Cxcl1 induction by DNA demethylation and promotes neutrophil recruitment during acute lung injury

Neutrophils are rapidly recruited from the peripheral blood to the inflammatory site to initiate inflammatory response against pathogenic infections. The process to recruit neutrophils must be properly regulated since the abnormal accumulation of neutrophils can cause organ damage and dysfunction. The acute respiratory distress syndrome (ARDS)/acute lung injury (ALI) is a common cause of respiratory failure that is characterized by the infiltration of neutrophils and epithelial integrity disruption. Indeed, recent studies suggest a pathogenic role of neutrophils in the clinic severity of the coronavirus disease 2019 (COVID-19) ARDS. The chemokine CXCL1, which is rapidly induced by inflammatory stimuli, plays a key role in neutrophil influx during lung inflammation. The molecular basis of Cxcl1 induction is not fully understood. Here we report that TET1, a member of the ten eleven translocation (TET) methylcytosine dioxygenase protein family, displays a striking specificity in the regulation of gene expression in macrophages. RNA sequencing (RNA-seq) analysis showed that Tet1 disruption significantly altered the expression of only 48 genes that include Cxcl1 and several other genes known to be important for cell migration and trafficking in bone marrow derived macrophages (BMDMs) in response to LPS stimulation. TET1 regulates the induction of Cxcl1 by facilitating the DNA demethylation of the Cxcl1 promoter. In Tet1-/- mice, the induction of Cxcl1 was suppressed, resulting in defective neutrophil recruitment to the lung during LPS-induced acute lung injury. Our results identify a novel epigenetic mechanism that selectively controls Cxcl1 induction and neutrophil recruitment during acute lung injury. Key PointsO_LITET1 has a striking specificity in macrophage gene regulation and controls Cxcl1 induction by inflammatory stimuli via DNA demethylation C_LIO_LINeutrophil recruitment is defective in Tet1 deficient mice during acute lung injury C_LI

immunology↗