Biology subjects

Ma, Y.

Publications and source records attributed to Ma, Y..

At least 217 records · Page 12Linked to original sources

bioRxiv2024

Embryo spatial 3D genomics

The 3D architecture of the genome is crucial for controlling gene expression and organ development. Here, we introduce a spatial 3D genomics approach for assessing chromatin conformation in-situ in tissue sections, by integrating microfluidic deterministic barcoding and SPRITE procedures. This method was applied to mouse embryo sections, revealing a hierarchical model of chromatin interactions within and between compartments in various organs. The intra-compartment interactions vary among organs to orchestrate gene expressions, while the inter-compartment interactions remain identical in the most organs. Beyond this, the liver exhibits overwhelmingly packed chromatin with enhanced adjacent-compartment interactions, possibly related to its physiology. These findings highlight the importance of tissue-spatial information in understanding embryonic chromatin organization. The approach presents a powerful tool for investigating these processes in tissues with high heterogeneity. One Sentence SummaryA spatial 3D genomics approach was developed that accesses hierarchical chromatin conformation in-situ in tissue sections.

genetics↗

bioRxiv2024

Transcriptional repression and enhancer decommissioning silence cell cycle genes in postmitotic tissues.

The mechanisms that maintain a non-cycling status in postmitotic tissues are not well understood. Many cell cycle genes have promoters and enhancers that remain accessible even when cells are terminally differentiated and in a non-cycling state, suggesting their repression must be maintained long term. In contrast, enhancer decommissioning has been observed for rate-limiting cell cycle genes in the Drosophila wing, a tissue where the cells die soon after eclosion, but it has been unclear if this also occurs in other contexts of terminal differentiation. In this study, we show that enhancer decommissioning also occurs at specific, rate-limiting cell cycle genes in the long-lived tissues of the Drosophila eye and brain, and we propose this loss of chromatin accessibility may help maintain a robust postmitotic state. We examined the decommissioned enhancers at specific rate-limiting cell cycle genes and show that they encode dynamic temporal and spatial expression patterns that include shared, as well as tissue-specific elements, resulting in broad gene expression with developmentally controlled temporal regulation. We extend our analysis to cell cycle gene expression and chromatin accessibility in the mammalian retina using a published dataset, and find that the principles of cell cycle gene regulation identified in terminally differentiating Drosophila tissues are conserved in the differentiating mammalian retina. We propose a robust, non-cycling status is maintained in long-lived postmitotic tissues through a combination of stable repression at most cell cycle gens, alongside enhancer decommissioning at specific rate-limiting cell cycle genes. HighlightsIn long-lived postmitotic Drosophila tissues, most cell cycle genes retain accessible chromatin despite persistent transcriptional downregulation. Cell cycle genes with accessible enhancers remain activatable during terminal differentiation, suggesting their repression must be continuously maintained in the postmitotic state. Long-lived postmitotic tissues decommission enhancers at specific, rate-limiting cell cycle genes in a developmentally regulated manner. Genome-wide enhancer identification performed in cell culture misses many developmentally dynamic enhancers in vivo. Decommissioned enhancers at cell cycle genes include shared and tissue-specific elements that in combination, result in broad gene expression with temporal regulation. The principles of cell cycle gene regulation identified in Drosophila are conserved in the mammalian retina.

developmental biology↗

bioRxiv2024

pNet: A toolbox for personalized functional networks modeling

Personalized functional networks (FNs) derived from functional magnetic resonance imaging (fMRI) data are useful for characterizing individual variations in the brain functional topography associated with the brain development, aging, and disorders. To facilitate applications of the personalized FNs with enhanced reliability and reproducibility, we develop an open-source toolbox that is user-friendly, extendable, and includes rigorous quality control (QC), featuring multiple user interfaces (graphics, command line, and a step-by-step guideline) and job-scheduling for high performance computing (HPC) clusters. Particularly, the toolbox, named personalized functional network modeling (pNet), takes fMRI inputs in either volumetric or surface type, ensuring compatibility with multiple fMRI data formats, and computes personalized FNs using two distinct modeling methods: one method optimizes the functional coherence of FNs, while the other enhances their independence. Additionally, the toolbox provides HTML-based reports for QC and visualization of personalized FNs. The toolbox is developed in both MATLAB and Python platforms with a modular design to facilitate extension and modification by users familiar with either programming language. We have evaluated the toolbox on two fMRI datasets and demonstrated its effectiveness and user-friendliness with interactive and scripting examples. pNet is publicly available at https://github.com/MLDataAnalytics/pNet.

neuroscience↗

bioRxiv2024

Potent neutralization by a receptor binding domain monoclonal antibody with broad specificity for SARS-CoV-2 JN.1 and other variants

SARS-CoV-2 continues to be a public health burden, driven in-part by its continued antigenic diversification and resulting emergence of new variants. While increasing herd immunity, current vaccines, and therapeutics have improved outcomes for some; prophylactic and treatment interventions that are not compromised by viral evolution of the Spike protein are still needed. Using a rationally designed SARS-CoV-2 Receptor Binding Domain (RBD) - ACE2 fusion protein and differential selection process with native Omicron RBD protein, we developed a recombinant human monoclonal antibody (hmAb) from a convalescent individual following SARS-CoV-2 Omicron infection. The resulting hmAb, 1301B7 potently neutralized a wide range of SARS-CoV-2 variants including the original Wuhan and more recent Omicron JN.1 strain, as well as SARS-CoV. Structure determination of the SARS-CoV-2 EG5.1 Spike/1301B7 Fab complex by cryo-electron microscopy at 3.1[A] resolution demonstrates 1301B7 contacts the ACE2 binding site of RBD exclusively through its VH1-69 heavy chain, making contacts using CDRs1-3, as well as framework region 3 (FR3). Broad specificity is achieved through 1301B7 binding to many conserved residues of Omicron variants including Y501 and H505. Consistent with its extensive binding epitope, 1301B7 is able to potently diminish viral burden in the upper and lower respiratory tract and protect mice from challenge with Omicron XBB1.5 and Omicron JN.1 viruses. These results suggest 1301B7 has broad potential to prevent or treat clinical SARS-CoV-2 infections and to guide development of RBD-based universal SARS-CoV-2 prophylactic vaccines and therapeutic approaches.

immunology↗

bioRxiv2024

Towards anchoring evolutionary fitness for protein stability with virtual chemical environment recovery

Predicting the protein stability changes upon mutations is one of the effective ways to improve the efficiency of protein engineering. Here, we propose a dual-view ensemble learning-based framework, DVE-stability, for mutation-induced protein stability change prediction from single sequence. DVE-stability integrates the global and local dependencies of mutations to capture the intramolecular interactions from two views through ensemble learning, in which a structural microenvironment simulation module is designed to indirectly introduce the information of structural microenvironment at the sequence level. DVE-stability achieved state-of-the-art prediction performance on 7 single-point mutation benchmark datasets, and comprehensively surpassed other methods on 5 of them. Furthermore, DVE-stability outperformed other methods comprehensively through zero-shot inference on multiple-point mutation prediction task, demonstrating superior model generalizability to capture the epistasis of multiple-point mutations. More importantly, DVE-stability exhibited superior generalization performance in predicting rare beneficial mutations that are crucial for practical protein directed evolution scenarios. In addition, DVE-stability identified important intramolecular interactions via attention scores, demonstrating interpretable. Overall, DVE-stability provides a flexible and efficient tool for mutation-induced protein stability change prediction in an interpretable ensemble learning manner.

bioinformatics↗

bioRxiv2024

Bridging the Gap: Multi-Omics Profiling of Brain Tissue in Alzheimer's Disease and Older Controls in Multi-Ethnic Populations

INTRODUCTIONMulti-omics studies in Alzheimers disease (AD) revealed many potential disease pathways and therapeutic targets. Despite their promise of precision medicine, these studies lacked African Americans (AA) and Latin Americans (LA), who are disproportionately affected by AD. METHODSTo bridge this gap, Accelerating Medicines Partnership in AD (AMP-AD) expanded brain multi-omics profiling to multi-ethnic donors. RESULTSWe generated multi-omics data and curated and harmonized phenotypic data from AA (n=306), LA (n=326), or AA and LA (n=4) brain donors plus Non-Hispanic White (n=252) and other (n=20) ethnic groups, to establish a foundational dataset enriched for AA and LA participants. This study describes the data available to the research community, including transcriptome from three brain regions, whole genome sequence, and proteome measures. DISCUSSIONInclusion of traditionally underrepresented groups in multi-omics studies is essential to discover the full spectrum of precision medicine targets that will be pertinent to all populations affected with AD.

neuroscience↗

bioRxiv2024

CRISPR/Cas-based genome editing for cyanophage of Anabeana sp.

Efforts have been directed towards genome editing in cyanobacteria, yet achieving genome reduction in cyanophages remains a challenging task. In this study, we utilized the CRISPR-Cas12a system to successfully delete multiple genes within A-1(L) and A-4(L) cyanophages. Through careful manipulation, we generated a deletion mutant cyanophage with a 2,778 bp reduction in genome size, representing a 6.6% decrease compared to the wild type (WT). In summary, our research has introduced a robust method for gene editing in cyanophages, facilitating the identification of nonessential genes essential for cyanophage propagation. This advancement holds promise in addressing the widespread issue of water blooms and the associated environmental hazards.

bioengineering↗

bioRxiv2024

CCDC113 stabilizes sperm axoneme and head-tail coupling apparatus to ensure male fertility

The structural integrity of the sperm is crucial for male fertility, defects in sperm head-tail linkage and flagellar axoneme are associated with acephalic spermatozoa syndrome (ASS) and the multiple morphological abnormalities of the sperm flagella (MMAF). Notably, impaired head-tail coupling apparatus (HTCA) often accompanies defects in the flagellum structure, however, the molecular mechanisms underlying this phenomenon remain elusive. Here, we identified an evolutionarily conserved coiled-coil domain-containing (CCDC) protein, CCDC113, and found the disruption of CCDC113 produced spermatozoa with disorganized sperm flagella and HTCA, which caused male infertility. Further analysis revealed that CCDC113 could bind to CFAP57 and CFAP91, and function as an adaptor protein for the connection of radial spokes, nexin-dynein regulatory complex (N-DRC) and doublet microtubules (DMTs) in the sperm axoneme. Moreover, CCDC113 was identified as a structural component of HTCA, collaborating with SUN5 and CENTLEIN to connect sperm head to tail during spermiogenesis. Together, our studies reveal that CCDC113 serve as a critical hub for sperm axoneme and HTCA stabilization, providing insights into the potential pathogenesis of infertility associated with human CCDC113 mutations.

developmental biology↗

bioRxiv2024

FLASH Irradiation Regulates IFN-β induction by mtDNA via Cytochrome c Leakage

Ultrahigh dose rate radiotherapy (FLASH-RT) is under intensive investigation for its biological benefits. The mechanisms underlying its ability to spare normal tissues while suppress tumor growth still remain controversial. Here we reveal that compared to the low dose rate electron irradiation (0.36 Gy/s), FLASH electron irradiation at 61 or 610 Gy/s enhances the cytochrome c leakage from mitochondria in human breast cells MCF-10A, which elicits substantial caspase activation, suppresses both the cytosolic mitochondrial DNA (mtDNA) accumulation and IFN-{beta} secretion. Besides, the deletion of mtDNA severely decreases the radiation-induced cGAS-STING activation. Conversely, the cytochrome c leakage in carcinoma cells MDA-MB-231 post electron irradiation is limited, especially for the case of FLASH irradiation, resulting in less cytosolic cytochrome c but stronger cGAS-STING activation than those in MCF-10A cells. The enhanced difference of cytochrome c leakage between cancer cells and normal cells post FLASH irradiation indicates a potential mechanism of FLASH effect by regulating the apoptotic and inflammatory pathway.

biophysics↗

bioRxiv2024

The lipid droplet protein DHRS3 is a regulator of melanoma cell state

Lipid droplets are fat storage organelles composed of a protein envelope and lipid rich core. Regulation of this protein envelope underlies differential lipid droplet formation and function. In melanoma, lipid droplet formation has been linked to tumor progression and metastasis, but it is unknown whether lipid droplet proteins play a role. To address this, we performed proteomic analysis of the lipid droplet envelope in melanoma. We found that lipid droplet proteins were differentially enriched in distinct melanoma states; from melanocytic to undifferentiated. DHRS3, which converts all-trans-retinal to all-trans-retinol, is upregulated in the MITFLO/undifferentiated/neural crest-like melanoma cell state and reduced in the MITFHI/melanocytic state. Increased DHRS3 expression is sufficient to drive MITFHI/melanocytic cells to a more undifferentiated/invasive state. These changes are due to retinoic acid mediated regulation of melanocytic genes. Our data demonstrate that melanoma cell state can be regulated by expression of lipid droplet proteins which affect downstream retinoid signaling.

cancer biology↗

bioRxiv2024

A zebrafish system for identifying genetic dependencies in melanocytes and melanoma

The advent of large-scale sequencing in both development and disease has identified large numbers of candidate genes that may be linked to important phenotypes. We have developed a rapid, scalable system for assessing the role of candidate genes using zebrafish. We generated transgenic zebrafish in which Cas9 was knocked-in to the endogenous mitfa locus, a master transcription factor of the melanocyte lineage. The main advantage of this system compared to existing techniques is maintenance of endogenous regulatory elements. We used this system to identify both cell-autonomous and non-cell autonomous regulators of normal melanocyte development. We then applied this to the melanoma setting to demonstrate that loss of genes required for melanocyte survival can paradoxically promote more aggressive phenotypes, highlighting that in vitro screens can mask in vivo phenotypes. Our genetic approach offers a versatile tool for exploring developmental processes and disease mechanisms that can readily be applied to other cell lineages.

genetics↗

bioRxiv2024

Phase Contrast Tomography (PCT)

Phase contrast microscopy has been employed for 2D imaging of thin samples since its invention. Herein, we propose and demonstrate phase contrast tomography (PCT) that incorporates the scanning of LED illumination with quantitative phase contrast microscopy (QPCM) to realize 3D phase imaging of a sample. The proposed PCT is demonstrated 3D imaging of 200-nm polystyrene microspheres (PMs) and sub-organelles inside COS7 cells. The results reveal that the proposed PCT has high spatial resolution and stability without speckle noise, and thence, it has a great potential to be applied to industrial testing and life science research.

biophysics↗

bioRxiv2024

Cancer Stemness Online: A resource for investigating cancer stemness and associations with immune response

Cancer progression involves the gradual loss of a differentiated phenotype and acquisition of progenitor and stem-cell-like features, which are potential culprit in immunotherapy resistance. Although the state-of-art predictive computational methods have facilitated predicting the cancer stemness, currently there is no efficient resource that can meet various requirements of usage. Here, we presented the Cancer Stemness Online, an integrated resource for efficiently scoring cancer stemness potential at bulk and single-cell level. The resource integrates 8 robust predictive algorithms as well as 27 signature gene sets associated with cancer stemness for predicting the stemness scores. Downstream analyses were performed from five different aspects, including identifying the signature genes of cancer stemness, exploring the association with cancer hallmarks, cellular states, immune response and communication with immune cells, investigating the contributions for patient survival and the robustness analysis of cancer stemness among different methods. Moreover, the pre-calculated cancer stemness atlas for more than 40 cancer types can be accessed by users. Both the tables and diverse visualization for the analytical results are available for download. Together, Cancer Stemness Online is a powerful resource for scoring cancer stemness and going deeper and wider in the downstream functional interpretation, including immune response as well as cancer hallmark. Cancer Stemness Online is freely accessible at http://bio-bigdata.hrbmu.edu.cn/CancerStemnessOnline.

bioinformatics↗

bioRxiv2024

DiDBiT-TMT: A novel method to quantify changes in the proteomic landscape induced by neural plasticity

Withdrawal StatementThe authors have withdrawn this manuscript because during the peer review process in the journal, it was discovered that one of the processed proteomic data groups (the chemical LTP group) was mistakenly processed from the raw data for the norepinephrine group, resulting in an apparent complete overlap between the two conditions. For a correct analysis, please refer to the currently published peer-reviewed publication through the following DOI: https://doi.org/10.1021/acs.jproteome.4c00180 Therefore, the authors do not wish this preprint to be cited as reference for the project. If you have any questions, please contact the corresponding author.

neuroscience↗

bioRxiv2024

Increased dosage of wild-type KRAS protein drives KRAS-mutant lung tumorigenesis and drug resistance

Almost 30% of lung adenocarcinomas are driven by activating KRAS mutations. The heterogeneous clinical behavior observed in these cancers could be due to the imbalance of wild-type and oncogenic KRAS alleles. However, the role of RAS dysregulation at the protein level needs to be further explored. A genome-wide global protein stability screen identified the CUL3 ubiquitin ligase adaptor LZTR1, as a major proteostatic regulator of wild-type but not mutant KRAS. In KRAS-mutant lung adenocarcinoma, shallow deletion of LZTR1 is observed in up to 50% of patients and is associated with hypoxic signatures and poorer progression-free disease survival. In a Kras-mutant lung cancer mouse model, heterozygous loss of Lztr1 promoted tumor growth, led to peritumoral vascular remodeling, and limited the response to the KRAS-G12D inhibitor MRTX1133. The vascular alteration in LZTR1-depleted lung cancer was mediated by increased wild-type KRAS protein dosage, which promoted mTOR pathway activation and a subsequent increase in VEGFA secretion. The inhibition of the PI3K/mTOR pathway using dactolisib normalized tumor vasculature, improved drug delivery, and overcame resistance to KRAS-G12D inhibitors. In summary, the dysregulation of RAS proteostasis contributes to lung tumorigenesis, and targeting wild-type KRAS signaling is crucial to overcome intrinsic resistance to inhibitors of mutant KRAS. SignificanceOur study highlights the impact of RAS proteostasis on lung cancer development and progression. Vascular normalization achieved by suppressing wild-type KRAS signaling improved the delivery and response to MRTX1133 in KRAS-mutant lung cancer with shallow LZTR1 deletion.

cancer biology↗

bioRxiv2024

MU-BRAIN: MUltiethnic Brain Rna-seq for Alzheimer INitiative

Alzheimers Disease (AD) exhibits a complex molecular and phenotypic profile. Investigating gene expression plays a crucial role in unraveling the diseases etiology and progression. Transcriptome data across ethnic groups lack, negatively impacting equity in intervention and research. We employed 565 brains across six U.S. brain banks (n=399 non-Hispanic Whites, n=113 Hispanics, n=12 African Americans) to generated bulk RNA sequencing from prefrontal cortex. We sought to identify cross-ancestry and ancestry-specific differentially expressed genes (DEG) across Braak stages, adjusting for sex, age at death, and RNA quality metrics. We further validated our findings using the Religious Orders Study/Memory Aging Project brains (ROS/MAP; n=1,095) and performed metanalysis (n=1,660). We conducted Gene Set and Variation and Enrichment analysis (GSVA; GSEA). We employed a machine-learning approach for phenotype prediction and gene prioritization to construct a polytranscriptomics risk score (PTRS) splitting our sample into training and testing sub-samples, either randomly or by ethnicity ("ancestry-agnostic" and "ancestry-aware", respectively). Lastly, we validated top DEG using single-nucleus RNA sequencing (snRNAseq) data. We identified several DEG associated with Braak staging: AD-known genes VGF (Padj =3.78E- 07) and ADAMTS2 (Pad j=1.21E-04) were consistently differentially expressed across statistical models, ethnicities, and replicated in ROS/MAP. Genes from the heat shock protein (HSP) family, e.g. HSPB7 (Padj =3.78E-07), were the top differentially expressed genes and replicated in ROS/MAP. Ethnic-stratified analyses prioritized TNFSF14 and SPOCD1 as top Hispanics DEG. GSEA highlighted "Alzheimer disease" (Padj =4.24E-06) and "TYROBP causal network in microglia" (Padj =1.68E-08) pathways. Up- and down-regulated genes were enriched in several pathways (e.g. "Immune response activation signal pathways", "Vesicle-mediated transport in synapse", "cognition"). Ancestry-agnostic and ancestry-aware PTRS effectively classified brains (AUC=0.77 and 0.73 respectively) and replicated in ROS/MAP. snRNAseq validated prioritized genes, including VGF (downregulated in neurons; Padj=1.1 E-07). This is the largest diverse AD transcriptome in post-mortem brain tissue, to our knowledge. We identified perturbated genes, pathways and network expressions in AD brains resulting in cross- ethnic and ethnic-specific findings, ultimately highlighting the diversity within AD pathogenesis. The latter underscores the need for an integrative and personalized approach in AD studies.

genetics↗

bioRxiv2024

Mechanical confinement governs phenotypic plasticity in melanoma

Phenotype switching is a form of cellular plasticity in which cancer cells reversibly move between two opposite extremes - proliferative versus invasive states. While it has long been hypothesised that such switching is triggered by external cues, the identity of these cues has remained elusive. Here, we demonstrate that mechanical confinement mediates phenotype switching through chromatin remodelling. Using a zebrafish model of melanoma coupled with human samples, we profiled tumor cells at the interface between the tumor and surrounding microenvironment. Morphological analysis of these rare cells showed flattened, elliptical nuclei suggestive of mechanical confinement by adjacent tissue. Spatial and single-cell transcriptomics demonstrated that the interface cells adopted a gene program of neuronal invasion, including acquisition of an acetylated tubulin cage that protects the nucleus during migration. We identified the DNA-bending protein HMGB2 as a confinement-induced mediator of the neuronal state. HMGB2 is upregulated in confined cells, and quantitative modelling revealed that confinement prolongs contact time between HMGB2 and chromatin, leading to changes in chromatin configuration that favor the neuronal phenotype. Genetic disruption of HMGB2 showed that it regulates the trade-off between proliferative and invasive states, in which confined HMGB2high tumor cells are less proliferative but more drug resistant. Our results implicate the mechanical microenvironment as a mechanism driving phenotype switching in melanoma.

cancer biology↗

bioRxiv2024

LncRNA-CIR6 Mediates Repair of Infarcted Hearts by Inducing MSCs Differentiation into Cardiogenic Cells through CDK1

PurposeThis study aims to investigate the induction effect of LncRNA-CIR6 on MSCs differentiation into Cardiogenic Cells in vitro and in vivo. MethodsIn addition to pretreatment with the Ro-3306 (CDK1 inhibitor), LncRNA-CIR6 was transfected into BMSCs and hUCMSCs using jetPRIME. LncRNA-CIR6 was transfected into C57BL/6 mice heart by 100 L of AAV9-cTnT-LncRNA-CIR6-ZsGreen i.v. After 3 weeks of transfection followed by AMI surgery, hUCMSCs (5x105/100 L) were injected by i.v 1 week later. Cardiac function was evaluated using VEVO 2100 and electric mapping 9 days after cell injection. IF, Evans blue-TTC, Masson staining, FACS, and WB were used to determine relevant indicators. ResultsLncRNA-CIR6 induced a significant percentage of differentiation in BMSCs (83.00{+/-}0.58)% and hUCMSCs (95.43{+/-}2.13)% into cardiogenic cells, as determined by the expression of cTnT. Compared with MI group, cardiac contraction and conduction function in MI heart treated by LncRNA-CIR6 or combined with MSCs injection groups were significantly increased as well as the area of MI and fibrosis were significantly lower. The transcriptional expression region of LncRNA-CIR6 was in Chr17 from 80209290 to 80209536. The functional region of LncRNA-CIR6 was located at nucleotides 0-50/190-255 in the sequence. CDK1 is a protein found to be related to the proliferation and differentiation of cardiomyocytes is which located in the functional region of LncRNA-CIR6 secondary structure (from 0 to 17). Ro-3306 impeded the differentiation of MSCs into cardiogenic cells, while MSCs transfected with LncRNA-CIR6 showed high expression of CDK1. LncRNA-CIR6 mediates repair of infarcted hearts by inducing MSCs differentiation into cardiogenic cells through CDK1. ConclusionsLncRNA-CIR6 mediates repair of infarcted hearts by inducing MSCs differentiation into cardiogenic cells through CDK1.

molecular biology↗