bioRxiv : the preprint server for biology最新文献

{"title":"Impaired hippocampal functions underlying memory encoding and consolidation precede robust Aβ deposition in a mouse model of Alzheimer's disease.","authors":"Hanyan Li, Zhuoyang Zhao, Aline Fassini, Han K Lee, Reese J Green, Stephen N Gomperts","doi":"10.1101/2024.05.26.595168","DOIUrl":"10.1101/2024.05.26.595168","url":null,"abstract":"<p><p>Current therapeutic strategies for Alzheimer's disease (AD) target amyloid-beta (Aβ) fibrils and high molecular weight protofibrils associated with plaques, but molecular cascades associated with AD may drive neural systems failure before Aβ plaque deposition in AD. Employing hippocampal electrophysiological recordings and dynamic calcium imaging across the sleep-wake cycle in the APP/PS1 mouse model of AD before Aβ plaques accumulated, we detected marked impairments of hippocampal systems function: In a spatial behavioral task, but not REM sleep, phase-amplitude coupling (PAC) of the hippocampal theta and gamma oscillations was impaired and place cell calcium fluctuations were hyper-synchronized with the theta oscillation. In subsequent slow wave sleep (SWS), place cell reactivation was reduced. These degraded neural functions underlying memory encoding and consolidation support targeting pathological processes of the pre-plaque phase of AD to treat and prevent hippocampal impairments.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11160633/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141297436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predicting Affinity Through Homology (PATH): Interpretable Binding Affinity Prediction with Persistent Homology.","authors":"Yuxi Long, Bruce R Donald","doi":"10.1101/2023.11.16.567384","DOIUrl":"10.1101/2023.11.16.567384","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Accurate binding affinity prediction is crucial to structure-based drug design. Recent work used computational topology to obtain an effective representation of protein-ligand interactions. While algorithms using algebraic topology have proven useful in predicting properties of biomolecules, previous algorithms employed uninterpretable machine learning models which failed to explain the underlying geometric and topological features that drive accurate binding affinity prediction. Moreover, they had high computational complexity which made them intractable for large proteins. We present the fastest known algorithm to compute persistent homology features for protein-ligand complexes using opposition distance, with a runtime that is independent of the protein size. Then, we exploit these features in a novel, interpretable algorithm to predict protein-ligand binding affinity. Our algorithm achieves interpretability through an effective embedding of distances across bipartite matchings of the protein and ligand atoms into real-valued functions by summing Gaussians centered at features constructed by persistent homology. We name these functions &lt;i&gt;internuclear persistent contours (IPCs)&lt;/i&gt; . Next, we introduce &lt;i&gt;persistence fingerprints&lt;/i&gt; , a vector with 10 components that sketches the distances of different bipartite matching between protein and ligand atoms, refined from IPCs. Let the number of protein atoms in the protein-ligand complex be &lt;i&gt;n&lt;/i&gt; , number of ligand atoms be &lt;i&gt;m&lt;/i&gt; , and &lt;i&gt;ω&lt;/i&gt; ≈ 2.4 be the matrix multiplication exponent. We show that for any 0 &lt;i&gt;&lt; ε &lt;&lt;/i&gt; 1, after an 𝒪 ( &lt;i&gt;mn&lt;/i&gt; log( &lt;i&gt;mn&lt;/i&gt; )) preprocessing procedure, we can compute an &lt;i&gt;ε&lt;/i&gt; -accurate approximation to the persistence fingerprint in 𝒪 ( &lt;i&gt;m&lt;/i&gt; log &lt;sup&gt;6 &lt;i&gt;ω&lt;/i&gt;&lt;/sup&gt; ( &lt;i&gt;m/ε&lt;/i&gt; )) time, independent of protein size. This is an improvement in time complexity by a factor of 𝒪 (( &lt;i&gt;m&lt;/i&gt; + &lt;i&gt;n&lt;/i&gt; ) &lt;sup&gt;3&lt;/sup&gt; ) over any previous binding affinity prediction that uses persistent homology. We show that the representational power of persistence fingerprint generalizes to protein-ligand binding datasets beyond the training dataset. Then, we introduce &lt;i&gt;PATH&lt;/i&gt; , Predicting Affinity Through Homology, a two-part algorithm consisting of PATH &lt;sup&gt;+&lt;/sup&gt; and PATH &lt;sup&gt;-&lt;/sup&gt; . PATH &lt;sup&gt;+&lt;/sup&gt; is an interpretable, small ensemble of shallow regression trees for binding affinity prediction from persistence fingerprints. We show that despite using 1,400-fold fewer features, PATH &lt;sup&gt;+&lt;/sup&gt; has comparable performance to a previous state-of-the-art binding affinity prediction algorithm that uses persistent homology. Moreover, PATH &lt;sup&gt;+&lt;/sup&gt; has the advantage of being interpretable. We visualize the features captured by persistence fingerprint for variant HIV-1 protease complexes and show that persistence fingerprint captures binding-relevant structural mutations. PATH &lt;sup&gt;-&lt;/sup&gt; , in turn, uses regression trees over IPCs to differenti","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10680814/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138447341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"YAP-Driven Oral Epithelial Stem Cell Malignant Reprogramming at Single Cell Resolution.","authors":"Farhoud Faraji, Sydney I Ramirez, Lauren Clubb, Kuniaki Sato, Valeria Burghi, Thomas S Hoang, Adam Officer, Paola Y Anguiano Quiroz, William Mg Galloway, Zbigniew Mikulski, Kate Medetgul-Ernar, Pauline Marangoni, Kyle B Jones, Alfredo A Molinolo, Kenneth Kim, Kanako Sakaguchi, Joseph A Califano, Quinton Smith, Alon Goren, Ophir D Klein, Pablo Tamayo, J Silvio Gutkind","doi":"10.1101/2023.07.24.550427","DOIUrl":"10.1101/2023.07.24.550427","url":null,"abstract":"<p><p>Tumor initiation represents the first step in tumorigenesis during which normal progenitor cells undergo cell fate transition to cancer. Capturing this process as it occurs in vivo, however, remains elusive. Here we employ spatiotemporally controlled oncogene activation and tumor suppressor inhibition together with multiomics to unveil the processes underlying oral epithelial progenitor cell reprogramming into tumor initiating cells (TIC) at single cell resolution. TIC displayed a distinct stem-like state, defined by aberrant proliferative, hypoxic, squamous differentiation, and partial epithelial to mesenchymal (pEMT) invasive gene programs. YAP-mediated TIC programs included the activation of oncogenic transcriptional networks and mTOR signaling, and the recruitment of myeloid cells to the invasive front contributing to tumor infiltration. TIC transcriptional programs are conserved in human head and neck cancer and associated with poor patient survival. These findings illuminate processes underlying cancer initiation at single cell resolution, and identify candidate targets for early cancer detection and prevention.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10402053/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10319328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Localized synthesis of molecular chaperones sustains neuronal proteostasis.","authors":"Celia Alecki, Javeria Rizwan, Phuong Le, Suleima Jacob-Tomas, Mario Fernandez-Comaduran, Morgane Verbrugghe, Jia Stella M Xu, Sandra Minotti, James Lynch, Jeetayu Biswas, Tad Wu, Heather Durham, Gene W Yeo, Maria Vera","doi":"10.1101/2023.10.03.560761","DOIUrl":"10.1101/2023.10.03.560761","url":null,"abstract":"<p><p>Neurons are challenged to maintain proteostasis in neuronal projections, particularly with the physiological stress at synapses to support intercellular communication underlying important functions such as memory and movement control. Proteostasis is maintained through regulated protein synthesis and degradation and chaperone-assisted protein folding. Using high-resolution fluorescent microscopy, we discovered that neurons localize a subset of chaperone mRNAs to their dendrites, particularly more proximal regions, and increase this asymmetric localization following proteotoxic stress through microtubule-based transport from the soma. The most abundant chaperone mRNA in dendrites encodes the constitutive heat shock protein 70, HSPA8. Proteotoxic stress in cultured neurons, induced by inhibiting proteasome activity or inducing oxidative stress, enhanced transport of Hspa8 mRNAs to dendrites and the percentage of mRNAs engaged in translation on mono and polyribosomes. Knocking down the ALS-related protein Fused in Sarcoma (FUS) and a dominant mutation in the heterogenous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1) impaired stress-mediated localization of Hspa8 mRNA to dendrites in cultured murine motor neurons and human iPSC-derived neurons, respectively, revealing the importance of these RNA-binding proteins in maintaining proteostasis. These results reveal the increased dendritic localization and translation of the constitutive HSP70 Hspa8 mRNA as a crucial neuronal stress response to uphold proteostasis and prevent neurodegeneration.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10592939/pdf/nihpp-2023.10.03.560761v1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49694600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional Localization of the Human Auditory and Visual Thalamus Using a Thalamic Localizer Functional Magnetic Resonance Imaging Task.","authors":"John C Williams, Philip N Tubiolo, Zu Jie Zheng, Eilon B Silver-Frankel, Dathy T Pham, Natalka K Haubold, Sameera K Abeykoon, Anissa Abi-Dargham, Guillermo Horga, Jared X Van Snellenberg","doi":"10.1101/2024.04.28.591516","DOIUrl":"10.1101/2024.04.28.591516","url":null,"abstract":"<p><p>Functional magnetic resonance imaging (fMRI) of the auditory and visual sensory systems of the human brain is an active area of investigation in the study of human health and disease. The medial geniculate nucleus (MGN) and lateral geniculate nucleus (LGN) are key thalamic nuclei involved in the processing and relay of auditory and visual information, respectively, and are the subject of blood-oxygen-level-dependent (BOLD) fMRI studies of neural activation and functional connectivity in human participants. However, localization of BOLD fMRI signal originating from neural activity in MGN and LGN remains a technical challenge, due in part to the poor definition of boundaries of these thalamic nuclei in standard T1-weighted and T2-weighted magnetic resonance imaging sequences. Here, we report the development and evaluation of an auditory and visual sensory thalamic localizer (TL) fMRI task that produces participant-specific functionally-defined regions of interest (fROIs) of both MGN and LGN, using 3 Tesla multiband fMRI and a clustered-sparse temporal acquisition sequence, in less than 16 minutes of scan time. We demonstrate the use of MGN and LGN fROIs obtained from the TL fMRI task in standard resting-state functional connectivity (RSFC) fMRI analyses in the same participants. In RSFC analyses, we validated the specificity of MGN and LGN fROIs for signals obtained from primary auditory and visual cortex, respectively, and benchmark their performance against alternative atlas- and segmentation-based localization methods. The TL fMRI task and analysis code (written in Presentation and MATLAB, respectively) have been made freely available to the wider research community.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11092475/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140923918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hierarchical motion perception as causal inference.","authors":"Sabyasachi Shivkumar, Gregory C DeAngelis, Ralf M Haefner","doi":"10.1101/2023.11.18.567582","DOIUrl":"10.1101/2023.11.18.567582","url":null,"abstract":"<p><p>Since motion can only be defined relative to a reference frame, which reference frame guides perception? A century of psychophysical studies has produced conflicting evidence: retinotopic, egocentric, world-centric, or even object-centric. We introduce a hierarchical Bayesian model mapping retinal velocities to perceived velocities. Our model mirrors the structure in the world, in which visual elements move within causally connected reference frames. Friction renders velocities in these reference frames mostly stationary, formalized by an additional delta component (at zero) in the prior. Inverting this model automatically segments visual inputs into groups, groups into supergroups, etc. and \"perceives\" motion in the appropriate reference frame. Critical model predictions are supported by two new experiments, and fitting our model to the data allows us to infer the subjective set of reference frames used by individual observers. Our model provides a quantitative normative justification for key Gestalt principles providing inspiration for building better models of visual processing in general.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10680834/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138447355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BIBSNet: A Deep Learning Baby Image Brain Segmentation Network for MRI Scans.","authors":"Timothy J Hendrickson, Paul Reiners, Lucille A Moore, Jacob T Lundquist, Begim Fayzullobekova, Anders J Perrone, Erik G Lee, Julia Moser, Trevor K M Day, Dimitrios Alexopoulos, Martin Styner, Omid Kardan, Taylor A Chamberlain, Anurima Mummaneni, Henrique A Caldas, Brad Bower, Sally Stoyell, Tabitha Martin, Sooyeon Sung, Ermias Fair, Kenevan Carter, Jonathan Uriarte-Lopez, Amanda R Rueter, Essa Yacoub, Monica D Rosenberg, Christopher D Smyser, Jed T Elison, Alice Graham, Damien A Fair, Eric Feczko","doi":"10.1101/2023.03.22.533696","DOIUrl":"10.1101/2023.03.22.533696","url":null,"abstract":"<p><strong>Objectives: </strong>Brain segmentation of infant magnetic resonance (MR) images is vitally important in studying developmental mental health and disease. The infant brain undergoes many changes throughout the first years of postnatal life, making tissue segmentation difficult for most existing algorithms. Here, we introduce a deep neural network BIBSNet (<b>B</b>aby and <b>I</b>nfant <b>B</b>rain <b>S</b>egmentation Neural <b>Net</b>work), an open-source, community-driven model that relies on data augmentation and a large sample size of manually annotated images to facilitate the production of robust and generalizable brain segmentations.</p><p><strong>Experimental design: </strong>Included in model training and testing were MR brain images on 84 participants with an age range of 0-8 months (median postmenstrual ages of 13.57 months). Using manually annotated real and synthetic segmentation images, the model was trained using a 10-fold cross-validation procedure. Testing occurred on MRI data processed with the DCAN labs infant-ABCD-BIDS processing pipeline using segmentations produced from gold standard manual annotation, joint-label fusion (JLF), and BIBSNet to assess model performance.</p><p><strong>Principal observations: </strong>Using group analyses, results suggest that cortical metrics produced using BIBSNet segmentations outperforms JLF segmentations. Additionally, when analyzing individual differences, BIBSNet segmentations perform even better.</p><p><strong>Conclusions: </strong>BIBSNet segmentation shows marked improvement over JLF segmentations across all age groups analyzed. The BIBSNet model is 600x faster compared to JLF and can be easily included in other processing pipelines.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10055337/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9465054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Desmosome mutations impact the tumor microenvironment to promote melanoma proliferation.","authors":"Maayan Baron, Mohita Tagore, Patrick Wall, Fan Zheng, Dalia Barkley, Itai Yanai, Jing Yang, Maija Kiuru, Richard M White, Trey Ideker","doi":"10.1101/2023.09.19.558457","DOIUrl":"10.1101/2023.09.19.558457","url":null,"abstract":"<p><p>Desmosomes are transmembrane protein complexes that contribute to cell-cell adhesion in epithelia and other tissues. Here, we report the discovery of frequent genetic alterations in the desmosome in human cancers, with the strongest signal seen in cutaneous melanoma where desmosomes are mutated in >70% of cases. In primary but not metastatic melanoma biopsies, the burden of coding mutations in desmosome genes associates with a strong reduction in desmosome gene expression. Analysis by spatial transcriptomics and protein immunofluorescence suggests that these expression decreases occur in keratinocytes in the microenvironment rather than in primary melanoma cells. In further support of a microenvironmental origin, we find that desmosome gene knockdown in keratinocytes yields markedly increased proliferation of adjacent melanoma cells in keratinocyte/melanoma co-cultures. Similar increases in melanoma proliferation are observed in media preconditioned by desmosome-deficient keratinocytes. Thus, gradual accumulation of desmosome mutations in neighboring cells may prime melanoma cells for neoplastic transformation.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/c3/ff/nihpp-2023.09.19.558457v1.PMC10541613.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41153104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predicting the effect of CRISPR-Cas9-based epigenome editing.","authors":"Sanjit Singh Batra, Alan Cabrera, Jeffrey P Spence, Jacob Goell, Selvalakshmi S Anand, Isaac B Hilton, Yun S Song","doi":"10.1101/2023.10.03.560674","DOIUrl":"10.1101/2023.10.03.560674","url":null,"abstract":"<p><p>Epigenetic regulation orchestrates mammalian transcription, but functional links between them remain elusive. To tackle this problem, we use epigenomic and transcriptomic data from 13 ENCODE cell types to train machine learning models to predict gene expression from histone post-translational modifications (PTMs), achieving transcriptome-wide correlations of ~ 0.70 - 0.79 for most cell types. Our models recapitulate known associations between histone PTMs and expression patterns, including predicting that acetylation of histone subunit H3 lysine residue 27 (H3K27ac) near the transcription start site (TSS) significantly increases expression levels. To validate this prediction experimentally and investigate how natural vs. engineered deposition of H3K27ac might differentially affect expression, we apply the synthetic dCas9-p300 histone acetyltransferase system to 8 genes in the HEK293T cell line and to 5 genes in the K562 cell line. Further, to facilitate model building, we perform MNase-seq to map genome-wide nucleosome occupancy levels in HEK293T. We observe that our models perform well in accurately ranking relative fold-changes among genes in response to the dCas9-p300 system; however, their ability to rank fold-changes within individual genes is noticeably diminished compared to predicting expression across cell types from their native epigenetic signatures. Our findings highlight the need for more comprehensive genome-scale epigenome editing datasets, better understanding of the actual modifications made by epigenome editing tools, and improved causal models that transfer better from endogenous cellular measurements to perturbation experiments. Together these improvements would facilitate the ability to understand and predictably control the dynamic human epigenome with consequences for human health.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10592942/pdf/nihpp-2023.10.03.560674v1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49694644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Suppression of epithelial proliferation and tumourigenesis by immunoglobulin A.","authors":"Gregory P Donaldson, Gabriella L Reis, Marwa Saad, Christopher Wichmann, Izabela Mamede, Guo Chen, Nicole L DelGaudio, Dayu Zhang, Begüm Aydin, Caroline E Harrer, Tiago B R Castro, Sergei Grivennikov, Bernardo S Reis, Beth M Stadtmueller, Gabriel D Victora, Daniel Mucida","doi":"10.1101/2023.10.06.561290","DOIUrl":"10.1101/2023.10.06.561290","url":null,"abstract":"<p><p>Immunoglobulin A (IgA) is the most abundant antibody isotype produced across mammals and plays a specialized role in mucosal homeostasis ¹ . Constantly secreted into the lumen of the intestine, IgA binds commensal microbiota to regulate their colonization and function ^2,3 with unclear implications for health. IgA deficiency is common in humans but is difficult to study due to its complex aetiology and comorbidities ^4-8 . Using genetically and environmentally controlled mice, here we show that IgA-deficient animals have increased susceptibility to endogenous colorectal tumours. Cellular and molecular analyses revealed that, in the absence of IgA, colonic epithelial cells induce antibacterial factors and accelerate cell cycling in response to the microbiota. Oral treatment with IgA was sufficient to both reduce steady-state proliferation and protect mice from tumours, but this function was due to antibody structure rather than binding specificity. In both organoid and monolayer culture systems, IgA directly suppressed epithelial growth. Co-immunoprecipitation mass spectrometry and a targeted CRISPR screen identified DMBT1 as an IgA-binding epithelial surface protein required for IgA-mediated suppression of proliferation. Together, IgA and DMBT1 regulate Notch signalling and tune the normal cycling of absorptive colonocyte progenitors. In mice, deleting the transmembrane and cytoplasmic signalling portions of DMBT1 or blocking Notch signalling was sufficient to reverse both the increased proliferation and tumour susceptibility of IgA knockouts. These experiments establish a homeostatic function for IgA in tempering physiological epithelial responses to microbiota to maintain mucosal health.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10592636/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49694708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}