Biology subjects

Chang, Y.

Publications and source records attributed to Chang, Y..

At least 73 records · Page 4Linked to original sources

bioRxiv2024

Development of an orally bioavailable mSWI/SNF ATPase degrader and acquired mechanisms of resistance in prostate cancer

Mammalian switch/sucrose non-fermentable (mSWI/SNF) ATPase degraders have been shown to be effective in enhancer-driven cancers by functioning to impede oncogenic transcription factor chromatin accessibility. Here, we developed AU-24118, a first-in-class, orally bioavailable proteolysis targeting chimera (PROTAC) degrader of mSWI/SNF ATPases (SMARCA2 and SMARCA4) and PBRM1. AU-24118 demonstrated tumor regression in a model of castration-resistant prostate cancer (CRPC) which was further enhanced with combination enzalutamide treatment, a standard of care androgen receptor (AR) antagonist used in CRPC patients. Importantly, AU-24118 exhibited favorable pharmacokinetic profiles in preclinical analyses in mice and rats, and further toxicity testing in mice showed a favorable safety profile. As acquired resistance is common with targeted cancer therapeutics, experiments were designed to explore potential mechanisms of resistance that may arise with long-term mSWI/SNF ATPase PROTAC treatment. Prostate cancer cell lines exposed to long-term treatment with high doses of a mSWI/SNF ATPase degrader developed SMARCA4 bromodomain mutations and ABCB1 overexpression as acquired mechanisms of resistance. Intriguingly, while SMARCA4 mutations provided specific resistance to mSWI/SNF degraders, ABCB1 overexpression provided broader resistance to other potent PROTAC degraders targeting bromodomain-containing protein 4 (BRD4) and AR. The ABCB1 inhibitor, zosuquidar, reversed resistance to all three PROTAC degraders tested. Combined, these findings position mSWI/SNF degraders for clinical translation for patients with enhancer-driven cancers and define strategies to overcome resistance mechanisms that may arise. Significance StatementThe mSWI/SNF complex is a promising therapeutic target for enhancer-driven cancers. PROTACs, which enable the targeting of "undruggable" proteins, often face the challenge of achieving oral bioavailability. Here, we present AU-24118, a first-in-class, orally bioavailable mSWI/SNF ATPase dual degrader with remarkable efficacy in in vitro and in vivo models. Additionally, our study describes two distinct mechanisms of resistance to PROTAC degraders, providing crucial insights into potential challenges facing their clinical application. These findings are critical for advancing PROTAC-based therapies to clinical settings as targeted therapies for cancers.

cancer biology↗

bioRxiv2024

Lipid membrane topographies are regulators for the spatial distribution of liquid protein condensates

Liquid protein condensates play important roles in orchestrating subcellular organization and in serving as hubs for biochemical reactions. Recent studies have established associations between lipid membranes and proteins capable of forming liquid condensates, and shown that liquid protein condensates can remodel lipid membranes. However, little is known about how the topography of membranes affects liquid condensates. Here, we devised a cell-free system to reconstitute liquid condensates on lipid membranes with microstructured topographies and demonstrated an important role of lipid membranes topography as a biophysical regulator. By employing membrane surfaces designed with microwells, we found that liquid condensates assemble into orderly patterns. Furthermore, we demonstrated that membrane topographies influence the shape of liquid condensates. Finally, we showed that capillary forces, mediated by membrane topographies, led to the directed fusion of liquid condensates. Our results demonstrate that membrane topography is a potent biophysical regulator for the localization and shape of mesoscale liquid protein condensates.

biophysics↗

bioRxiv2024

Architecture of intact mammalian pyruvate dehydrogenase complex revealed by in-situ structural analysis

The multi-enzyme pyruvate dehydrogenase complex (PDC) links glycolysis to the citric acid cycle by converting pyruvate into acetyl-coenzyme A and is essential for cellular energy metabolism. Although individual components have been characterized, the structure of intact PDC remains unclear, hampering our understanding of its composition and multi-step catalytic reactions. Here, we report the in-situ architecture of intact PDC within mammalian mitochondria by cryo-electron tomography. The organization of peripheral E1 and E3 multimers varies substantially among PDCs. We discovered 1-46 E1 heterotetramers surrounding each PDC core, and up to 12 E3 dimers locating primarily along the pentagonal openings. Furthermore, we observed dynamic interactions of the substrate translocating lipoyl domains (LDs) with both E1 and E2, implicating the mechanism of substrate channeling. Our findings reveal the intrinsic dynamics of PDC peripheral compositions, suggesting an additional model in which the number of assembled E1 heterotetramer, E3 dimer, and functional LDs of PDC may be regulated to further control its catalytic activity.

cell biology↗

bioRxiv2023

Unveiling Elevated Spontaneous Mutation Rates in Phyllostachys edulis (Moso Bamboo) through Whole Genome Sequencing (WGS) and Investigating the Impact of Atmospheric and Room Temperature Plasma (ARTP) Induced Mutagenesis

Moso bamboo, recognized for its wide distribution and economic importance, encounters challenges in varietal enhancement due to its protracted sexual reproduction cycle. This study employed whole-genome resequencing to uncover spontaneous mutations in Moso bamboo and investigated mutagenesis using atmospheric and room temperature plasma (ARTP). Through the sequencing results, we identified the population of flowering bamboo as an asexual breeding line. Notably, the flowering Moso bamboo population, exclusively derived from asexual reproduction, exhibited a high spontaneous mutation rate (4.54 x 10-4 to 1.15 x 10-3/bp) during sexual reproduction, considering parental and cross-pollination effects. Genetic disparities between offspring and parents exhibited a bimodal distribution, indicating a substantial cross-pollination rate. ARTP mutagenesis increased structural variations in offspring, while changes in SNPs and INDELs were less pronounced. Sanger sequencing validated a gene subset, providing a foundation for spontaneous mutation rate investigation via whole-genome sequencing. These insights, particularly from mutagenized offspring sequencing, contribute to Moso bamboo breeding strategies. HighlightMoso bamboo breeding revolutionized--high spontaneous mutations in asexually derived flowering population. ARTP mutagenesis boosts structural variations, shaping innovative breeding approaches.

genetics↗

bioRxiv2023

AVM: a manually curated database of aerosol-transmitted virus mutations, human diseases, and drugs

Aerosol-transmitted viruses, with aerosol particles floating in the air to long distances, have the characteristics of strong infectivity and wide spread that is difficult to control. They cause various human diseases, posing a huge threat to human health. Some mutations can increase the transmissibility and virulence of the strain, which can reduce the protection of vaccines and weaken efficacy of antiviral drugs. Here, we established a manually curated database, AVM, to store this information. The current version of the AVM contains a total of 42,041 virus mutations, including 2613 immune escape mutations, 45 clinical information datasets, and 407 drugs, antibodies, or vaccines. In addition, we recorded 88 human diseases associated with viruses, and we found that the same virus can attack multiple target organs in the body and lead to diversified diseases. Further, the AVM database offers a straightforward user interface to expediently browse, retrieve, and download details. The AVM database is a comprehensive resource that provides timely and valuable assistance regarding the transmission, treatment, and related diseases of aerosol-transmitted viruses (http://bio-bigdata.hrbmu.edu.cn/AVM or http://www.bio-bigdata.center/AVM).

bioinformatics↗

bioRxiv2023

MEM-GAN: A Pseudo Membrane Generator for Single-cell Imaging in Fluorescent Microscopy

Fluorescent microscopy imaging is vital to capturing single-cell spatial data, characterizing tissue organization and facilitating comprehensive analysis of cellular state. Advancements in fluorescent microscopy imaging technologies have enabled precise downstream cellular analysis, particularly in cell segmentation. Accurate segmentation of individual cells allows better profiling and understanding of cell properties and behaviors. The majority of existing segmentation methods predominantly concentrate on enhancing segmentation algorithms, and their effectiveness strongly relies on the input stained image quality. Factors such as high cellular density, indistinct cell boundaries, and staining artifacts can result in uneven and low-quality staining, particularly causing missing or unclear membrane staining. These artifacts adversely impact the efficacy of the subsequent cell segmentation methods. To tackle this insufficient membrane staining, we propose a novel approach, MO_SCPLOWEMC_SCPLOW-GAN, to generate high-quality membranes for cells with missing or weak membranes. Inspired by advanced style transfer techniques in computer vision, MO_SCPLOWEMC_SCPLOW-GAN styles the content of the cells with missing or weak membranes into cells with integrated membrane staining. Considering the differences in membrane morphology between epithelial/tumor cells and immune cells, MO_SCPLOWEMC_SCPLOW-GAN deals with tumor and immune cells separately, not only enhancing membrane staining for cells with partially weak membrane signals but also generating membranes for cells with only nuclear channels. The proposed MO_SCPLOWEMC_SCPLOW-GAN is evaluated using the publicly available CosMx dataset. Experimental results demonstrate significant improvements in image staining quality, more accurate representation of membrane morphology characteristics, and better performance in downstream segmentation tasks. MO_SCPLOWEMC_SCPLOW-GAN is flexibly adapted and applied to other spatially resolved transcriptomics datasets, such as MERFISH and FISHseq. Our work provides a new perspective on tackling the challenges in cell segmentation from fluorescent microscopy image restoration. The implementation of MO_SCPLOWEMC_SCPLOW-GAN is open-source and available at the github repository https://github.com/OmicsML/Mem-GAN. The interactive webserver-based demo of MO_SCPLOWEMC_SCPLOW-GAN can be accessed at http://omicsml.ai/memgan.

bioinformatics↗

bioRxiv2023

CAG repeat expansions create splicing acceptor sites and produce aberrant repeat-containing RNAs

Expansions of CAG trinucleotide repeats cause several rare neurodegenerative diseases. The disease-causing repeats are translated in multiple reading frames, without an identifiable initiation codon. The molecular mechanism of this repeat-associated non-AUG (RAN) translation is not known. We find that expanded CAG repeats create new splice acceptor sites. Splicing of proximal donors to the repeats produces unexpected repeat-containing transcripts. Upon splicing, depending on the sequences surrounding the donor, CAG repeats may become embedded in AUG-initiated open reading frames. Canonical AUG-initiated translation of these aberrant RNAs accounts for proteins that are attributed to RAN translation. Disruption of the relevant splice donors or the in-frame AUG initiation codons is sufficient to abrogate RAN translation. Our findings provide a molecular explanation for the abnormal translation products observed in CAG trinucleotide repeat expansion disorders and add to the repertoire of mechanisms by which repeat expansion mutations disrupt cellular functions.

molecular biology↗

bioRxiv2023

A brain circuit and neuronal mechanism for decoding and adapting to change in daylength

Changes in daylight amount (photoperiod) drive pronounced alterations in physiology and behaviour1,2. Adaptive responses to seasonal photoperiods are vital to all organisms - dysregulation is associated with disease, from affective disorders3 to metabolic syndromes4. Circadian rhythm circuitry has been implicated5,6 yet little is known about the precise neural and cellular substrates that underlie phase synchronization to photoperiod change. Here we present a previously unknown brain circuit and novel system of axon branch-specific and reversible neurotransmitter deployment that together prove critical for behavioural and sleep adaptation to photoperiod change. We found that the recently defined neuron type called mrEn1-Pet17 located in the mouse brainstem Median Raphe Nucleus (MRN) segregates serotonin versus VGLUT3 (here proxy for the neurotransmitter glutamate) to different axonal branches innervating specific brain regions involved in circadian rhythm and sleep/wake timing8,9. We found that whether measured during the light or dark phase of the day this branch-specific neurotransmitter deployment in mrEn1-Pet1 neurons was indistinguishable; however, it strikingly reorganizes on photoperiod change. Specifically, axonal boutons but not cell soma show a shift in neurochemical phenotype upon change away from equinox light/dark conditions that reverses upon return to equinox. When we genetically disabled the deployment of VGLUT3 in mrEn1-Pet1 neurons, we found that sleep/wake periods and voluntary activity failed to synchronize to the new photoperiod or was significantly delayed. Combining intersectional rabies virus tracing and projection-specific neuronal silencing in vivo, we delineated a Preoptic Area-to-mrEn1Pet1 connection responsible for decoding the photoperiodic inputs, driving the neurochemical shift and promoting behavioural synchronization. Our results reveal a previously unrecognized brain circuit along with a novel form of periodic, branch-specific neurotransmitter deployment that together regulate organismal adaptation to photoperiod changes.

neuroscience↗

bioRxiv2023

Structural Basis for Hyperpolarization-dependent Opening of the Human HCN1 Channel

Hyperpolarization and cyclic-nucleotide (HCN) activated ion channels play a critical role in generating self-propagating action potentials in pacemaking and rhythmic electrical circuits in the human body. Unlike most voltage-gated ion channels, the HCN channels activate upon membrane hyperpolarization, but the structural mechanisms underlying this gating behavior remain unclear. Here, we present cryo-electron microscopy structures of human HCN1 in Closed, Intermediate, and Open states. Our structures reveal that the inward motion of two gating charges past the charge transfer center (CTC) and concomitant tilting of the S5 helix drives the opening of the central pore. In the intermediate state structure, a single gating charge is positioned below the CTC and the pore appears closed, whereas in the open state structure, both charges move past CTC and the pore is fully open. Remarkably, the downward motion of the voltage sensor is accompanied by progressive unwinding of the inner end of S4 and S5 helices disrupting the tight gating interface that stabilizes the Closed state structure. This "melting" transition at the intracellular gating interface leads to a concerted iris-like displacement of S5 and S6 helices, resulting in pore opening. These findings reveal key structural features that are likely to underlie reversed voltage-dependence of HCN channels.

biochemistry↗

bioRxiv2023

PSite: inference of read-specific P-site offsets for ribosomal footprints

SummaryRibosome profiling is a powerful method for global survey of ribosomal footprints. Inferring the offsets of footprint 5 ends to the ribosomal P-site is essential to pinpoint codons translated by ribosomes. By convention, global or read length-specific P-site offsets are estimated by inspecting the distribution of ribosome footprints around the annotated start or stop codons. However, actual offsets might be different even for footprints of the same length due to the influence of sequence context and the cutting bias of endoribonucleases. To address this issue, we present PSite, a python package for inferring read-specific P-site offsets using a gradient boosting trees model. PSite assigned more reads to the correct reading frame than conventional methods and improved the prediction of translated ORFs by existing software. Besides, PSite is robust to ribosome profiling datasets of varying quality or using endonucleases with cutting bias for digestion. Availability and implementationhttps://github.com/gxelab/psite. Contacthong_zhang@lzu.edu.cn.

bioinformatics↗

bioRxiv2023

Predicting the impact of rare variants on RNA splicing in CAGI6

BackgroundVariants which disrupt splicing are a frequent cause of rare disease that have been under-ascertained clinically. Accurate and efficient methods to predict a variants impact on splicing are needed to interpret the growing number of variants of unknown significance (VUS) identified by exome and genome sequencing. Here we present the results of the CAGI6 Splicing VUS challenge, which invited predictions of the splicing impact of 56 variants ascertained clinically and functionally validated to determine splicing impact. ResultsThe performance of 12 prediction methods, along with SpliceAI and CADD, was compared on the 56 functionally validated variants. The maximum overall accuracy achieved was 82% from two different approaches, one weighting SpliceAI scores by minor allele frequency, and one applying the recently published Splicing Prediction Pipeline (SPiP). SPiP performed optimally in terms of sensitivity, while an ensemble method combining multiple prediction tools and information from databases exceeded all others for specificity. ConclusionsSeveral challenge methods equalled or exceeded the performance of SpliceAI, with ultimate choice of prediction method likely to depend on experimental or clinical aims. One quarter of the variants were incorrectly predicted by at least 50% of the methods, highlighting the need for further improvements to splicing prediction methods for successful clinical application.

bioinformatics↗

bioRxiv2023

mTOR Inhibition Suppresses Salinomycin-Induced Ferroptosis in Breast Cancer Stem Cells by Ironing Out Mitochondrial Dysfunctions

Ferroptosis constitutes a promising therapeutic strategy against cancer by efficiently targeting the highly tumorigenic and treatment-resistant cancer stem cells (CSCs). We previously showed that the lysosomal iron-targeting drug Salinomycin (Sal) was able to eliminate CSCs by triggering ferroptosis. Here, in a well-established breast CSCs model (human mammary epithelial HMLER CD24low/CD44high), we identified that pharmacological inhibition of mechanistic target of rapamycin (mTOR), suppresses Sal-induced ferroptosis. Mechanistically, mTOR inhibition modulates iron cellular flux and prevents the iron and ROS bursts induced by Sal. Besides, integration of multi-omics data identified mitochondria as a key target of Sal action. We demonstrated that mTOR inhibition prevents Sal-induced mitochondrial functional and structural alteration, and that Sal-induced metabolic plasticity is mainly dependent on the mTOR pathway. Overall, our findings provide experimental evidences on the detailed mechanisms of mTOR as a crucial effector of Sal-induced ferroptosis, and gives proof-of-concept that careful evaluation of such combination therapy (here mTOR and ferroptosis co-targeting) is required for effective treatment. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/539040v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@8b8772org.highwire.dtl.DTLVardef@695e0forg.highwire.dtl.DTLVardef@19e3f83org.highwire.dtl.DTLVardef@5bc0a6_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2023

Vglut2-based glutamatergic signaling in central noradrenergic neurons is dispensable for normal breathing and chemosensory reflexes

Central noradrenergic (NA) neurons are key constituents of the respiratory homeostatic network. NA dysfunction is implicated in several developmental respiratory disorders including Congenital Central Hyperventilation Syndrome (CCHS), Sudden Infant Death Syndrome (SIDS) and Rett Syndrome. The current unchallenged paradigm in the field, supported by multiple studies, is that glutamate co-transmission in subsets of central NA neurons plays a role in breathing control. If true, NA-glutamate co-transmission may also be mechanistically important in respiratory disorders. However, the requirement of NA-derived glutamate in breathing has not been directly tested and the extent of glutamate co-transmission in the central NA system remains uncharacterized. Therefore, we fully characterized the cumulative fate maps and acute adult expression patterns of all three Vesicular Glutamate Transporters (Slc17a7 (Vglut1), Slc17a6 (Vglut2), and Slc17a8 (Vglut3)) in NA neurons, identifying a novel, dynamic expression pattern for Vglut2 and an undescribed co-expression domain for Vglut3 in the NA system. In contrast to our initial hypothesis that NA derived glutamate is required to breathing, our functional studies showed that loss of Vglut2 throughout the NA system failed to alter breathing or metabolism under room air, hypercapnia, or hypoxia in unrestrained and unanesthetized mice. These data demonstrate that Vglut2-based glutamatergic signaling within the central NA system is not required for normal baseline breathing and hypercapnic, hypoxic chemosensory reflexes. These outcomes challenge the current understanding of central NA neurons in the control of breathing and suggests that glutamate may not be a critical target to understand NA neuron dysfunction in respiratory diseases.

neuroscience↗

bioRxiv2023

SpatialCTD: a large-scale TME spatial transcriptomic dataset to evaluate cell type deconvolution for immuno-oncology

Recent technological advancements have enabled spatially resolved transcriptomic profiling but at multi-cellular resolution. The task of cell type deconvolution has been introduced to disentangle discrete cell types from such multi-cellular spots. However, existing datasets for cell type deconvolution are limited in scale, predominantly encompassing data on mice, and are not designed for human immuno-oncology. In order to overcome these limitations and promote comprehensive investigation of cell type deconvolution for human immuno-oncology, we introduce a large-scale spatial transcriptomic dataset named SO_SCPLOWPATIALC_SCPLOWCTD, encompassing 1.8 million cells from the human tumor microenvironment across the lung, kidney, and liver. Distinct from existing approaches that primarily depend on single-cell RNA sequencing data as a reference without incorporating spatial information, we introduce Graph Neural Network-based method (i.e., GNNDO_SCPLOWECONVOLVERC_SCPLOW) that effectively utilize the spatial information from reference samples, and extensive experiments show that GNNDO_SCPLOWECONVOLVERC_SCPLOW often outperforms existing state-of-the-art methods by a substantial margin, without requiring single-cell RNA-seq data. To enable comprehensive evaluations on spatial transcriptomics data from flexible protocols, we provide an online tool capable of converting spatial transcriptomic data from other platforms (e.g., 10x Visium, MERFISH and sci-Space) into pseudo spots, featuring adjustable spot size. The SO_SCPLOWPATIALC_SCPLOWCTD dataset and GNNDO_SCPLOWECONVOLVERC_SCPLOW implementation are available at https://github.com/OmicsML/SpatialCTD, and the online converter tool can be accessed at https://omicsml.github.io/SpatialCTD/.

bioinformatics↗

bioRxiv2023

TREM2 mediates MHCII-associated CD4+ T cell response against gliomas

Triggering receptor expressed on myeloid cells 2 (TREM2) was recently highlighted as a novel immune suppressive marker in peripheral tumors. The aim of this study was to characterize TREM2 expression in gliomas and investigate its contribution in glioma progression by using Trem2-/-mouse line. Our results showed that higher TREM2 expression was correlated with poor prognosis in glioma patients. Unexpectedly, TREM2 deficiency did not have a beneficial effect in a pre-clinical model of glioma. The increased TREM2 expression in glioma was likely due to increased myeloid cell infiltration, as evidenced by our single-cell analysis showing that almost all microglia and macrophages in gliomas were TREM2+. Furthermore, we found that deficiency of TREM2 impaired tumor-myeloid phagocytosis and MHCII presentation, and significantly reduced CD4+ T cells in tumor hemispheres. Our results revealed a previously unrecognized protective role of tumor-myeloid TREM2 in promoting MHCII-associated CD4+ T cell response against gliomas. SUMMARYAuthors found that although higher TREM2 expression is correlated with poor prognosis in glioma patients, its absence has no beneficial effect in a pre-clinical model of glioma. Deficiency of TREM2 impairs myeloid cell phagocytosis of tumor debris, leading to a reduction in MHCII-dependent CD4+ anti-glioma immunity.

neuroscience↗

bioRxiv2023

Dimension-agnostic and granularity-based spatially variable gene identification

Identifying spatially variable genes (SVGs) is critical in linking molecular cell functions with tissue phenotypes. Spatially resolved transcriptomics captures cellular-level gene expression with corresponding spatial coordinates in two or three dimensions and can be used to infer SVGs effectively. However, current computational methods may not achieve reliable results and often cannot handle three-dimensional spatial transcriptomic data. Here we introduce BSP (big-small patch), a spatial granularity-guided and non-parametric model to identify SVGs from two or three-dimensional spatial transcriptomics data in a fast and robust manner. This new method has been extensively tested in simulations, demonstrating superior accuracy, robustness, and high efficiency. BSP is further validated by substantiated biological discoveries in cancer, neural science, rheumatoid arthritis, and kidney studies with various types of spatial transcriptomics technologies.

bioinformatics↗

bioRxiv2023

Phenelzine-based probes reveal Secernin-3 is involved in thermal nociception

Chemical platforms that facilitate both the identification and elucidation of new areas for therapeutic development are necessary but lacking. Activity-based protein profiling (ABPP) leverages active site-directed chemical probes as target discovery tools that resolve activity from expression and immediately marry the targets identified with lead compounds for drug design. However, this approach has traditionally focused on predictable and intrinsic enzyme functionality. Here, we applied our activity-based proteomics discovery platform to map non-encoded and post-translationally acquired enzyme functionalities (e.g. cofactors) in vivo using chemical probes that exploit the nucleophilic hydrazine pharmacophores found in a classic antidepressant drug (e.g. phenelzine, Nardil (R)). We show the probes are in vivo active and can map proteome-wide tissue-specific target engagement of the drug. In addition to engaging targets (flavoenzymes monoamine oxidase A/B) that are associated with the known therapeutic mechanism as well as several other members of the flavoenzyme family, the probes captured the previously discovered N-terminal glyoxylyl (Glox) group of Secernin-3 (SCRN3) in vivo through a divergent mechanism, indicating this functional feature has biochemical activity in the brain. SCRN3 protein is ubiquitously expressed in the brain, yet gene expression is regulated by inflammatory stimuli. In an inflammatory pain mouse model, behavioral assessment of nociception showed Scrn3 male knockout mice selectively exhibited impaired thermal nociceptive sensitivity. Our study provides a guided workflow to entangle molecular (off)targets and pharmacological mechanisms for therapeutic development.

neuroscience↗

bioRxiv2022

The HP1γ epigenetic silencer dampens IFN-γ response at the gut epithelial barrier

Interferon gamma (IFN-{gamma}) plays central roles in the pathophysiology of inflammatory bowel disease (IBD), both activating inflammatory responses and immunosuppressive functions. However, the epigenetic mechanisms controlling the expression of IFN-{gamma} responsive genes at the gut epithelial barrier are not well understood. In this study, we identified the epigenetic regulator HP1{gamma} as a transcriptional repressor of the IFN-{gamma}-responsive genes STAT1 (signal transducer and activator of transcription 1) and PD-L1 (Programmed Cell Death Ligand 1). Accordingly, HP1{gamma} gene inactivation in the mouse gut epithelium resulted in an immunopathology with a long-lasting up-regulation of STAT1 and PD-L1. Colon organoids models and in vitro cell lines showed that HP1{gamma} deficiency primed STAT1 and PD-L1 expressions, ultimately sensitizing epithelial cells to IFN-{gamma} stimulation. Chromatin immunoprecipitation experiments suggest that HP1 promoter tethering is involved in the silencing of gene expression. Overall, these results identify HP1{gamma} as an epigenetic silencing pathway controlling the IFN-{gamma} response at the epithelial barrier.

immunology↗