Biology subjects

Guo, M.

Publications and source records attributed to Guo, M..

At least 73 records · Page 4Linked to original sources

bioRxiv2024

High efficient chromatin conformation capture without pre-enrichment (HiChew) in single cells

This study presents HiChew, a cutting-edge technique for high-efficiency chromatin conformation capture in single cells, without the need for pre-enrichment. This unique approach minimizes the risk of cell or DNA loss. When compared to Dip-C, HiChew captures valid pairs with 4-8 times more efficiency, reducing wastage and saving significant sequencing budget. Furthermore, HiChew delivers a lower false positive ratio, ensuring data accuracy. It also achieves more contacts per cell, enhancing resolution in single cell. HiChews superior performance not only enhances single-cell Hi-C but also streamlines conventional Hi-C, making it more robust than conventional HiC methods. This study also unveils a fascinating mechanism of gene activation in the B compartment of chromatin, providing insight into the elusive aspect of gene expression within this region.

genomics↗

bioRxiv2024

Exploring DNA movement through the application of droplet based high efficient chromatin conformation capture (DropHiChew) and loop velocity

This study presents a novel approach to understanding DNA movement dynamics through the development of a droplet-based, high-efficient chromatin conformation capture method, known as DropHiChew, and a new algorithm, loop velocity. DropHiChew, a user-friendly and cost-effective technique, employs the 10X single-cell systems allowing for easy experimental implementation. The loop velocity algorithm, on the other hand, enables the estimation of the speed and direction of cell development, providing a dynamic perspective on chromatin movement. Even with shallow sequencing, our loop velocity algorithm accurately gauges the trajectory of DNA motion and cellular states. The combined use of DropHiChew and loop velocity offers potential for a wide array of applications in future chromatin capture studies, including disease modeling, cellular differentiation studies, and developmental biology.

genomics↗

bioRxiv2024

Chromosome-level genome assembly of autotetraploid Selenicereus megalanthus and gaining genomic insights into the evolution of trait patterning in diploid and polyploid pitaya species

Yellow pitaya (Selenicereus megalanthus, 2n=4x=44) breeding remains severely hindered due to lacking a reference genome. Here we report yellow pitayas high-quality chromosome-level genome assembly and link the phenotypic trait with genomic data, based on Hi-C, ATAC, and RNA-seq data of specific tissues. We declared yellow pitaya as an autotetraploid with a 7.16 Gb genome size (harboring 27,246 high confidence genes) and majorly evolved from diploid ancestors, which remains unknown. Beyond generating the genome assembly, we explored the 3D chromatin organization which revealed insights into the genome, compartments A (648 and 519), compartments B (728 and 1064), topologically associated domains-TADs (3376 and 2031), and varying numbers of structural variations (SVs) in diploid and polyploid pitaya species, respectively. Overall, TAD boundaries were enriched with the motifs of AP2, WRKY18/60/75, MYB63/116, PHL2, and GATA8 in both pitaya species. By linking the open chromatin genomic structure to function, we identified the major changes in betalains biosynthesis pathway in diploid and polyploid pitaya. Moreover, the higher genetic expression of SmeADH1 [Chr11, Compartment A (135400000 - 135500000), genes inside the TAD region (135480000 - 135520000)], and lower expression of HuDOPA [Chr11, Compartment A (87100000 - 87200000), genes inside the TAD region (87160000-87200000)] acts as a key regulator of yellow and red color on the pericarp of polyploid and diploid pitaya, respectively. In addition, higher expression of HuCYP76AD1 genes in diploid pitaya and lower expression of SmeCYP76AD1 in polyploid pitaya potentially created the difference in the oxidase process that led to the production of betacyanin and betaxanthin, respectively. Furthermore, our results revealed not only the type of motifs that play a potential role in trait patterning but we also further uncovered that motif count in TAD-boundaries may impact the gene expression within the TAD regions of diploid and polyploid pitaya. Our valuable genomic resource and comparison of 3D euchromatin architecture of diploid and polyploid pitaya species will not only aid in the advancement of molecular breeding efforts but also offer insights into the organization of genomes, SVs, compartmentalization (A and B), and TADs, which have the potential to strengthen the idea of TADs-based trait improvement to achieve global food security.

plant biology↗

bioRxiv2024

Patho-transcriptomic analysis of invasive mucinous adenocarcinoma of the lung (IMA): comparison with lung adenocarcinoma with signet ring cell features (SRCC)

BackgroundInvasive mucinous adenocarcinoma (IMA) comprises [~]5% of lung adenocarcinoma. There is no effective therapy for IMA when surgical resection is not possible. IMA is sometimes confused with adenocarcinoma with signet ring cell features (SRCC) pathologically since both adenocarcinomas feature tumor cells with abundant intracellular mucin. The molecular mechanisms by which such mucin-producing lung adenocarcinomas develop remain unknown. MethodsUsing a Visium spatial transcriptomics approach, we analyzed IMA and compared it with SRCC patho-transcriptomically. Combining spatial transcriptomics data with in vitro studies using RNA-seq and ChIP-seq, we assessed downstream targets of transcription factors HNF4A and SPDEF that are highly expressed in IMA and/or SRCC. ResultsSpatial transcriptomics analysis indicated that there are 6 distinct cell clusters in IMA and SRCC. Notably, two clusters (C1 and C3) of mucinous tumor cells exist in both adenocarcinomas albeit at a different ratio. Importantly, a portion of genes (e.g., NKX2-1, GKN1, HNF4A and FOXA3) are distinctly expressed while some mucous-related genes (e.g., SPDEF and FOXA2) are expressed in both adenocarcinomas. We determined that HNF4A induces MUC3A/B and TM4SF4 and that BI 6015, an HNF4A antagonist, suppressed the growth of IMA cells. Using mutant SPDEF that is associated with COVID-19, we also determined that an intact DNA-binding domain of SPDEF is required for SPDEF-mediated induction of mucin genes (MUC5AC, MUC5B and AGR2). Additionally, we found that XMU-MP-1, a SPDEF inhibitor, suppressed the growth of IMA cells. ConclusionThese results revealed that IMA and SRCC contain heterogenous tumor cell types, some of which are targetable.

cancer biology↗

bioRxiv2024

Brain-derived exosomal hemoglobin transfer contributes to neuronal mitochondrial homeostasis under hypoxia

Hypoxia is an important physiological stress causing nerve injuries and several brain diseases. However, the mechanism of brain response to hypoxia remains unclear, thus limiting the development of interventional strategies. This study conducted combined analyses of single-nucleus transcriptome sequencing and extracellular vesicle transcriptome sequencing on hypoxic mouse brains, described cell-cell communication in the brain under hypoxia from intercellular and extracellular dimensions, confirmed that hemoglobin mRNA was transferred from non-neuronal cells to neurons, and eventually expressed. Then we further explored the role of exosomal hemoglobin transfer in vitro, clarified that hypoxia promoted the transfer and expression of exosomal hemoglobin between endothelial cells and neurons. And we found the vital function of exosomal hemoglobin to protect against neurological injury by maintaining mitochondrial homeostasis in neurons. In conclusion, this study identified a novel mechanism of mutual aid in hypoxia responses in the brain, involving exosomal hemoglobin transfer, clarified the important role of exosomal communication in the process of brain stress response, and provided a novel interventional perspective for hypoxia-related brain diseases.

cell biology↗

bioRxiv2024

TRAPT: A multi-stage fused deep learning framework for transcriptional regulators prediction via integrating large-scale epigenomic data

It is a challenging task to identify functional transcriptional regulators, which control expression of gene sets via regulatory elements and epigenomic signals, involving context-specific studies such as development and diseases. Integrating large-scale multi-omics epigenomic data enables the elucidation of the complex epigenomic control patterns of regulatory elements and regulators. Here, we propose TRAPT, a multi-modality deep learning framework that predicts functional transcriptional regulators from a queried gene set by integrating large-scale multi-omics epigenomic data, including histone modifications, ATAC-seq and TR-ChIP-seq. We design two-stage self-knowledge distillation model to learn nonlinear embedded representation of upstream and downstream regulatory element activity, and merge multi-modality epigenomic features from TR and the queried gene sets for inferring regulator activity. Experimental results on 1072 TR-related datasets demonstrate that TRAPT outperforms current state-of-the-art methods in predicting transcriptional regulators, especially in the prediction of transcription co-factors and chromatin regulators. Additionally, we have successfully identified key transcriptional regulators associated with the disease, genetic variation, cell fate decisions, and tissues. Our method provides an innovative perspective for integrating epigenomic data and has the potential to significantly assist researchers in deepening their understanding of gene expression regulation mechanisms.

bioinformatics↗

bioRxiv2024

Adapting C4 photosynthesis to atmospheric change and increasing productivity by elevating Rubisco content in Sorghum and Sugarcane

Meta-analyses and theory show that with rising atmospheric [CO2], Rubisco has become the greatest limitation to light-saturated leaf CO2 assimilation rates (Asat) in C4 crops. So would transgenically increasing Rubisco increase Asat and result in increased productivity in the field? Here, we successfully overexpressed the Rubisco small subunit (RbcS) with Rubisco accumulation factor 1 (Raf1) in both sorghum and sugarcane, resulting in significant increases in Rubisco content of 13-25% and up to 90% respectively. Asat increased 12-15% and Rubisco enzyme activity [~]40% in three independent transgenic events of both species. Sorghum plants also showed increased speeds of photosynthetic induction and decreased bundle sheath leakiness. These improvements translated into average increases of 15.5% in biomass in field-grown sorghum and a 37-81% increase in greenhouse-grown sugarcane. This suggests a potential opportunity to achieve substantial increases in productivity of this key economically important clade of C4 crops, future proofing their value under global atmospheric change. Significance StatementThe world is projected to need a 60% increase in food supply by 2050 (UN), and this must be achieved under conditions of global change without expanding onto yet more land. C4 crops, while few in number, account for a large proportion of agricultural productivity. We reason that rising atmospheric [CO2] has very recently made Rubisco, the enzyme used for all carbon fixation in plants, the greatest limitation to light saturated photosynthesis in C4 crops. We demonstrate that transgenically increasing Rubisco content in sorghum and sugarcane, increases their photosynthetic efficiency and productivity, including in a field trial of sorghum. This shows a means to sustainably increase the productivity of this key group of crops.

plant biology↗

bioRxiv2024

Nuclear size-regulated emergence of topological packing order on growing human lung alveolospheres

Within multicellular living systems, cells coordinate their positions with spatiotemporal accuracy to form various structures, setting the clock to control developmental processes and trigger maturation. These arrangements can be regulated by tissue topology, biochemical cues, as well as mechanical perturbations. However, the fundamental rules of how local cell packing order is regulated in forming three-dimensional (3D) multicellular architectures remain unclear. Furthermore, how cellular coordination evolves during developmental processes, and whether this cell patterning behavior is indicative of more complex biological functions, is largely unknown. Here, using human lung alveolospheres as a model system, by combining experiments and numerical simulations, we find that, surprisingly, cell packing behavior on alveolospheres resembles hard-disk packing but with increased randomness; the stiffer cell nuclei act as the hard disks surrounded by deformable cell bodies. Interestingly, we observe the emergence of topological packing order during alveolosphere growth, as a result of increasing nucleus-to-cell size ratio. Specifically, we find more hexagon-concentrated cellular packing with increasing bond orientational order, indicating a topological gas-to-liquid transition. Additionally, by osmotically changing the compactness of cells on alveolospheres, we observe that the variations in packing order align with the change of nucleus-to-cell size ratio. Together, our findings reveal the underlying rules of cell coordination and topological phases during human lung alveolosphere growth. These static packing characteristics are consistent with cell dynamics, together suggesting that better cellular packing stabilizes local cell neighborhoods and may regulate more complex biological functions such as organ development and cellular maturation.

biophysics↗

bioRxiv2024

Dynamic Gamma Modulation of Hippocampal Place Cells Predominates Development of Theta Sequences

The experience-dependent spatial cognitive process requires sequential organization of hippocampal neural activities by theta rhythm, which develops to represent highly compressed information for rapid learning. However, how the theta sequences were developed in a finer time scale within theta cycles remains unclear. In this study, we found that sweep-ahead structure of theta sequences developing with exploration was predominantly dependent on a relatively large proportion of FG-cells, i.e. a subset of place cells dominantly phase-locked to fast gamma rhythms. These ensembles integrated compressed spatial information by cells consistently firing at precessing slow gamma phases within the theta cycle. Accordingly, the sweep-ahead structure of FG-cell sequences was positively correlated with the intensity of slow gamma phase precession, in particular during early development of theta sequences. These findings highlight the dynamic network-modulation by fast and slow gamma in the development of theta sequences which may further facilitate memory encoding and retrieval.

neuroscience↗

bioRxiv2024

Three-dimensional spatio-angular fluorescence microscopy with a polarized dual-view inverted selective-plane illumination microscope (pol-diSPIM)

Polarized fluorescence microscopy is a valuable tool for measuring molecular orientations, but techniques for recovering three-dimensional orientations and positions of fluorescent ensembles are limited. We report a polarized dual-view light-sheet system for determining the three-dimensional orientations and diffraction-limited positions of ensembles of fluorescent dipoles that label biological structures, and we share a set of visualization, histogram, and profiling tools for interpreting these positions and orientations. We model our samples, their excitation, and their detection using coarse-grained representations we call orientation distribution functions (ODFs). We apply ODFs to create physics-informed models of image formation with spatio-angular point-spread and transfer functions. We use theory and experiment to conclude that light-sheet tilting is a necessary part of our design for recovering all three-dimensional orientations. We use our system to extend known two-dimensional results to three dimensions in FM1-43-labelled giant unilamellar vesicles, fast-scarlet-labelled cellulose in xylem cells, and phalloidin-labelled actin in U2OS cells. Additionally, we observe phalloidin-labelled actin in mouse fibroblasts grown on grids of labelled nanowires and identify correlations between local actin alignment and global cell-scale orientation, indicating cellular coordination across length scales.

biophysics↗

bioRxiv2024

Discovering CRISPR-Cas system with self-processing pre-crRNA capability by foundation models

The discovery and functional annotation of CRISPR-Cas systems laid the groundwork for the development of novel CRISPR-based gene editing tools. Traditional similarity- search-based Cas discovery strategies, which rely heavily on local sequence alignment and reference Cas homologs, may overlook a significant number of remote homologs with limited sequence similarity; and it can not be applied directly for functional recognition. With the rapid development of protein large language models (LLMs), protein foundation models are expected to help model Cas systems with limited Cas homologs without extensive task-specific training data; however, the full potential of these models for Cas discovery and functional annotation has yet to be determined. To this end, we present a novel, effective and unified AI framework, CHOOSER (Cas HOmlog Observing and SElf-processing scReening), for alignment-free discovery of novel CRISPR-Cas systems with self-processing precursor CRISPR RNA (pre-crRNA) capability utilizing protein foundation models. CHOOSER successfully retrieved 11 novel homologs of Cas{lambda}, the majority of which are predicted to be able to self-process pre-crRNA, nearly doubling the current catalog. One of the candidates, EphcCas{lambda}, was subsequently experimentally validated for its ability to self-process pre-crRNA, target DNA cleavage, and trans-cleavage and was shown to be a promising candidate for use as a CRISPR-Cas-based pathogen detection system. Overall, our study provides an unprecedented perspective and methodology for discovering novel CRISPR-Cas systems with specific functions using foundation models, underscoring the potential for transforming newly identified Cas homologs into genetic editing tools.

bioinformatics↗

bioRxiv2024

Engineering customized viral receptors for various coronaviruses

Coronaviruses display versatile receptor usage, yet in-depth characterization of coronaviruses lacking known receptor identities has been impeded by the absence of feasible infection models1,2. Here, we developed an innovative strategy to engineer functional customized viral receptors (CVRs). The modular design relies on building receptor frameworks comprising various function modules and generating specific epitope-targeting viral binding domains. We showed the key factors for CVRs to efficiently facilitate spike cleavage, membrane fusion, pseudovirus entry, and authentic virus propagation for various coronaviruses, resembling their native receptors. Applying this strategy, we delineated the accessible receptor binding epitopes for functional SARS-CoV-2 CVR design and elucidated the mechanism of entry supported by an amino-terminus domain (NTD) targeting S2L20-CVR. Furthermore, we created CVR-expressing cells for assessing antibodies and inhibitors against 12 representative coronaviruses from six subgenera, most of which lacking known receptors. Notably, a pan-sarbecovirus CVR supported entry of various sarbecoviruses, as well as propagation of a replicable HKU3 pseudovirus and the authentic strain RsHuB2019A3. Through combining an HKU5-specific CVR with reverse genetics, we successfully rescued and cultured wild-type and fluorescence protein-incorporated HKU5, a receptor-unidentified merbecovirus. Our study demonstrated the great potential of CVR strategy in establishing native receptor-independent infection models, paving the way for studying various viruses that are challenging to culture due to the lack of susceptible cells. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=162 SRC="FIGDIR/small/583237v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@7cb9ccorg.highwire.dtl.DTLVardef@8a2855org.highwire.dtl.DTLVardef@5e14f0org.highwire.dtl.DTLVardef@b0b993_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphic abstractC_FLOATNO C_FIG

microbiology↗

bioRxiv2024

Deciphering Endothelial and Mesenchymal Organ Specification in Vascularized Lung and Intestinal Organoids

To investigate the co-development of vasculature, mesenchyme, and epithelium crucial for organogenesis and the acquisition of organ-specific characteristics, we constructed a human pluripotent stem cell-derived organoid system comprising lung or intestinal epithelium surrounded by organotypic mesenchyme and vasculature. We demonstrated the pivotal role of co-differentiating mesoderm and endoderm via precise BMP regulation in generating multilineage organoids and gut tube patterning. Single-cell RNA-seq analysis revealed organ specificity in endothelium and mesenchyme, and uncovered key ligands driving endothelial specification in the lung (e.g., WNT2B and Semaphorins) or intestine (e.g., GDF15). Upon transplantation under the kidney capsule in mice, these organoids further matured and developed perfusable human-specific sub-epithelial capillaries. Additionally, our model recapitulated the abnormal endothelial-epithelial crosstalk in patients with FOXF1 deletion or mutations. Multilineage organoids provide a unique platform to study developmental cues guiding endothelial and mesenchymal cell fate determination, and investigate intricate cell-cell communications in human organogenesis and disease. HighlightsO_LIBMP signaling fine-tunes the co-differentiation of mesoderm and endoderm. C_LIO_LIThe cellular composition in multilineage organoids resembles that of human fetal organs. C_LIO_LIMesenchyme and endothelium co-developed within the organoids adopt organ-specific characteristics. C_LIO_LIMultilineage organoids recapitulate abnormal endothelial-epithelial crosstalk in FOXF1-associated disorders. C_LI

developmental biology↗

bioRxiv2023

PRDM3/16 Regulate Chromatin Accessibility Required for NKX2-1 Mediated Alveolar Epithelial Differentiation and Function

Differential chromatin accessibility accompanies and mediates transcriptional control of diverse cell fates and their differentiation during embryogenesis. While the critical role of NKX2-1 and its transcriptional targets in lung morphogenesis and pulmonary epithelial cell differentiation is increasingly known, mechanisms by which chromatin accessibility alters the epigenetic landscape and how NKX2-1 interacts with other co-activators required for alveolar epithelial cell differentiation and function are not well understood. Here, we demonstrate that the paired domain zinc finger transcriptional regulators PRDM3 and PRDM16 regulate chromatin accessibility to mediate cell differentiation decisions during lung morphogenesis. Combined deletion of Prdm3 and Prdm16 in early lung endoderm caused perinatal lethality due to respiratory failure from loss of AT2 cell function. Prdm3/16 deletion led to the accumulation of partially differentiated AT1 cells and loss of AT2 cells. Combination of single cell RNA-seq, bulk ATAC-seq, and CUT&RUN demonstrated that PRDM3 and PRDM16 enhanced chromatin accessibility at NKX2-1 transcriptional targets in peripheral epithelial cells, all three factors binding together at a multitude of cell-type specific cis-active DNA elements. Network analysis demonstrated that PRDM3/16 regulated genes critical for perinatal AT2 cell differentiation, surfactant homeostasis, and innate host defense. Lineage specific deletion of PRDM3/16 in AT2 cells led to lineage infidelity, with PRDM3/16 null cells acquiring partial AT1 fate. Together, these data demonstrate that NKX2-1-dependent regulation of alveolar epithelial cell differentiation is mediated by epigenomic modulation via PRDM3/16. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=130 HEIGHT=200 SRC="FIGDIR/small/570481v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@500f6org.highwire.dtl.DTLVardef@821daaorg.highwire.dtl.DTLVardef@69ba87org.highwire.dtl.DTLVardef@154f754_HPS_FORMAT_FIGEXP M_FIG C_FIG Model of the role of PRMD3/16 in alveolar developmentPRMD3/16 participate in cell fate specification in the lung by modulating chromatin accessibility (top row) and by partnering with NKX2-1 and partner transcription factors to drive gene expression (second row) via a gene regulatory network required for terminal cell differentiation and surfactant expression in AT2 cells (third row). Loss of PRDM3/16 activity in lung endoderm leads to reduced AT2 quorum, failure of AT2 surfactant function, and transition to an immature AT1 phenotype (bottom panel).

developmental biology↗

bioRxiv2023

Phase diversity-based wavefront sensing for fluorescence microscopy

Fluorescence microscopy is an invaluable tool in biology, yet its performance is compromised when the wavefront of light is distorted due to optical imperfections or the refractile nature of the sample. Such optical aberrations can dramatically lower the information content of images by degrading image contrast, resolution, and signal. Adaptive optics (AO) methods can sense and subsequently cancel the aberrated wavefront, but are too complex, inefficient, slow, or expensive for routine adoption by most labs. Here we introduce a rapid, sensitive, and robust wavefront sensing scheme based on phase diversity, a method successfully deployed in astronomy but underused in microscopy. Our method enables accurate wavefront sensing to less than {lambda}/35 root mean square (RMS) error with few measurements, and AO with no additional hardware besides a corrective element. After validating the method with simulations, we demonstrate calibration of a deformable mirror > 100-fold faster than comparable methods (corresponding to wavefront sensing on the ~100 ms scale), and sensing and subsequent correction of severe aberrations (RMS wavefront distortion exceeding {lambda}/2), restoring diffraction-limited imaging on extended biological samples.

bioengineering↗

bioRxiv2023

Deep learning-based aberration compensation improves contrast and resolution in fluorescence microscopy

Optical aberrations hinder fluorescence microscopy of thick samples, reducing image signal, contrast, and resolution. Here we introduce a deep learning-based strategy for aberration compensation, improving image quality without slowing image acquisition, applying additional dose, or introducing more optics into the imaging path. Our method (i) introduces synthetic aberrations to images acquired on the shallow side of image stacks, making them resemble those acquired deeper into the volume and (ii) trains neural networks to reverse the effect of these aberrations. We use simulations and experiments to show that applying the trained de-aberration networks outperforms alternative methods, providing restoration on par with adaptive optics techniques; and subsequently apply the networks to diverse datasets captured with confocal, light-sheet, multi-photon, and super-resolution microscopy. In all cases, the improved quality of the restored data facilitates qualitative image inspection and improves downstream image quantitation, including orientational analysis of blood vessels in mouse tissue and improved membrane and nuclear segmentation in C. elegans embryos.

bioengineering↗

bioRxiv2023

Determining how MAFA and MAFB transcription factors activity is influenced by structural differences predicted by AlphaFold2

MAFA and MAFB are related basic-leucine-zipper domain containing transcription factors which have important overlapping and distinct regulatory roles in a variety of cellular contexts, including hormone production in pancreatic islet and {beta} cells. Here we first examined how mutating conserved MAF protein-DNA contacts obtained from X-ray crystal structure analysis impacted their DNA-binding and Insulin enhancer-driven activity. While most of these interactions were essential and their disruption severely compromised activity, we identified that regions outside of the contact areas also contributed to activity. AlphaFold 2, an artificial intelligence-based structural prediction program, was next used to determine if there were also differences in the three-dimensional organization of the non-DNA binding/dimerization sequences of MAFA and MAFB. This analysis was conducted on the wildtype (WT) proteins as well as the pathogenic MAFASer64Phe and MAFBSer70Ala trans-activation domain mutants, with differences revealed between MAFAWT and MAFBWT as well as between MAFASer64Phe and MAFAWT, but not between MAFBSer70Ala and MAFBWT. Moreover, dissimilarities between these proteins were also observed in their ability to cooperatively stimulate Insulin enhancer-driven activity in the presence of other islet-enriched transcription factors. Analysis of MAFA and MAFB chimeras disclosed that these properties were greatly influenced by unique C-terminal region structural differences predicted by AlphaFold 2. Importantly, these results have revealed features of these closely related proteins that are functionally significant in islet biology.

molecular biology↗

bioRxiv2023

Oxytocin alleviated colitis and colitis-associated colorectal tumorigenesis by targeting fucosylated MUC2

Colon cancer is commonly regarded as hormone-independent. However, there have been reports suggesting the involvement of sex hormones in colon cancer development. Nevertheless, the role of hormones from the hypothalamus-hypophysis axis in colitis-associated colorectal cancer (CAC) remains uncertain. In this study, we observed a significant reduction in the expression of the oxytocin receptor (OXTR) in colon samples from both colitis and CAC patients. To investigate further, we generated mice with an intestinal epithelium cell (IEC)-specific knockout of OXTR. These mice exhibited markedly increased susceptibility to dextran sulfate sodium (DSS)-induced colitis and DSS/Azoxymethane (AOM)-induced CAC compared to wild-type mice. Our findings indicate that OXTR depletion impaired the inner mucus of the colon epithelium. Mechanistically, oxytocin was found to regulate MUC2 maturation through B3GNT7-mediated fucosylation. Interestingly, we observed a positive correlation between B3GNT7 expression and OXTR expression in human colitis and CAC colon samples. Moreover, the administration of oxytocin significantly alleviated tumor burden. Hence, our study unveils oxytocins promising potential as an affordable and effective therapeutic intervention for individuals affected by colitis and CAC.

physiology↗