Biology subjects

Meng, Q.

Publications and source records attributed to Meng, Q..

59 records · Page 4Linked to original sources

bioRxiv2019

Stromal ISLR promotes intestinal regeneration and cancer by suppressing epithelial Hippo signaling

The YAP signaling activation in epithelial cells is essential for intestinal regeneration and tumorigenesis. However, the molecular mechanism linking stromal signals to YAP-mediated intestinal regeneration and tumorigenesis is poorly defined. Here we report a stroma-epithelia YAP signaling axis essential for stromal cells to modulate epithelial cell growth during intestinal regeneration and tumorigenesis. Specifically, upon inflammation and in cancer, an oncogenic transcription factor ETS1 in stromal cells induces expression of a secreted protein ISLR that can directly binds to a transmembrane protocadherin FAT1 on the surface of epithelial cells. This binding suppressed the Hippo signaling by disrupting MST1-FAT1 association, resulting in YAP signaling activation. Deletion of Islr in stromal cells in mice markedly impaired intestinal regeneration, and suppressed tumorigenesis in the colon. Moreover, the expression of stromal cell-specific ISLR and ETS1 significantly increased in inflamed mucosa of human IBD patients and in human colorectal adenocarcinoma, accounting for the epithelial YAP hyperactivation. Collectively, our findings uncovered a molecular mechanism governing signals for communication between stroma and epithelium during tissue regeneration and tumorigenesis.

cancer biology↗

bioRxiv2018

A novel computational complete deconvolution method using RNA-seq data

The cell type composition of many biological tissues varies widely across samples. Such sample heterogeneity hampers efforts to probe the role of each cell type in the tissue microenvironment. Current approaches that address this issue have drawbacks. Cell sorting or single-cell based experimental techniques disrupt in situ interactions and alter physiological status of cells in tissues. Computational methods are flexible and promising; but they often estimate either sample-specific proportions of each cell type or cell-type-specific gene expression profiles, not both, by requiring the other as input. We introduce a computational Complete Deconvolution method that can estimate both sample-specific proportions of each cell type and cell-type-specific gene expression profiles simultaneously using bulk RNA-Seq data only (CDSeq). We assessed our methods performance using several synthetic and experimental mixtures of varied but known cell type composition and compared its performance to the performance of two state-of-the art deconvolution methods on the same mixtures. The results showed CDSeq can estimate both sample-specific proportions of each component cell type and cell-typespecificgene expression profiles with high accuracy. CDSeq holds promise for computationally deciphering complex mixtures of cell types, each with differing expression profiles, using RNA-seq data measured in bulk tissue (MATLAB code is available at https://github.com/kkang7/CDSeq_011).

bioinformatics↗

bioRxiv2018

Comprehensive proteomic and metabolomic profiling of mcr-1 mediated colistin resistance in Escherichia coli

The spread of mcr-1 in human and veterinary medicine has jeopardized the use of polymyxins, the last-resort antibiotics against life-threatening multidrug-resistant Gram-negative bacteria. As a lipid-modified gene, whether mcr-1 brings proteomic and metabolomic changes in the bacteria and affects the corresponding metabolic pathway is largely unknown. Herein, we used label-free quantitative proteomics and untargeted metabolomics to profile comprehensive proteome and metabolome characteristics of mcr-1-mediated colistin-resistant and -sensitive Escherichia coli and further insight the resistant mechanism of colistin. We identified large sets of differential expression proteins and metabolites that contributed to mcr-1-mediated antibiotic resistance predominantly in the different growth conditions with and without colistin. mcr-1 could cause the down-regulated expression of most proteins to adapt drug pressure. Pathway analysis showed that metabolic process was significantly affected, mainly related to glycerophospholipid metabolism, thiamine metabolism, and lipopolysaccharide biosynthesis. The substrate phosphatidylethanolamine for mcr-1 to mediate colistin resistance is accumulated in colistin-resistant E. coli. Notably, mcr-1 can not only cause the phosphoethanolamine modification of bacterial cell membrane lipid A, but also affect the biosynthesis and transport of lipoprotein in colistin resistance through disturbing the expression of efflux pump proteins involved in cationic antibacterial peptide resistance pathway. Overall, the disturbed glycerophospholipid metabolism, lipopolysaccharide biosynthesis and the accumulation of the substrate phosphatidylethanolamine is closely related with mcr-1-mediated colistin resistance and these findings can further provide valuable information to inhibit colistin resistance by blocking this metabolic process.

pharmacology and toxicology↗

bioRxiv2018

Prenatal Bisphenol A Exposure in Mice Induces Multi-tissue Multi-omics Disruptions Linking to Cardiometabolic Disorders

The health impacts of endocrine disrupting chemicals (EDCs) remain debated and their tissue and molecular targets are poorly understood. Here we leveraged systems biology approaches to assess the target tissues, molecular pathways, and gene regulatory networks associated with prenatal exposure to the model EDC Bisphenol A (BPA). Prenatal BPA exposure led to scores of transcriptomic and methylomic alterations in the adipose, hypothalamus, and liver tissues in mouse offspring, with cross-tissue perturbations in lipid metabolism as well as tissue-specific alterations in histone subunits, glucose metabolism and extracellular matrix. Network modeling prioritized main molecular targets of BPA, including Pparg, Hnf4a, Esr1, and Fasn. Lastly, integrative analyses identified the association of BPA molecular signatures with cardiometabolic phenotypes in mouse and human. Our multi-tissue, multi-omics investigation provides strong evidence that BPA perturbs diverse molecular networks in central and peripheral tissues, and offers insights into the molecular targets that link BPA to human cardiometabolic disorders.\n\nAuthor summaryThe inability to pinpoint the mechanistic underpinnings of environmentally-induced diseases likely stems from the pleiotropic effects of chemicals such as BPA on diverse tissues and molecular space (transcriptome, epigenome, etc.). This makes it challenging to fully dissect their health impact and merits a call for modern big data approaches to examine environmental factors. Our data-driven study is the first unbiased, multi-tissue multiomic systems biology investigation of the molecular circuitry and mechanisms underlying offspring response to prenatal BPA exposure. Importantly, the incorporation of network-based modeling allows us to capture novel players in the regulation of BPA activities in vivo, and the integration with human disease association datasets helps bridge the molecular pathways affected by BPA with diverse human diseases. In doing so, our study provides compelling molecular evidence that developmental BPA exposure significantly perturbs metabolic and endocrine systems in the offspring, and supports BPA as one of the environmental factors involved in the developmental origins of health and disease (DOHaD).

systems biology↗

bioRxiv2018

Inhibition of norepinephrine signaling during a sensitive period disrupts locus coeruleus circuitry and emotional behaviors in adulthood

Deficits in arousal and stress responsiveness span numerous psychiatric developmental disorders including depression and anxiety. Arousal is supported by norepinephrine (NE) released from locus coeruleus (LC) neurons onto cortical and limbic areas. During development, the NE system matures in concert with increased exploration of the animals environment. While several psychiatric medications target the LC-NE system, the possibility that its modulation during discreet developmental periods can have long-lasting consequences for mental health has not been explored. We used a pharmacogenetic strategy in mice to reversibly inhibit NE signaling during brief developmental periods to determine the long-lasting impact on adult circuits mediating emotional behavior. We also examine whether disruption of NE signaling during development results in permanent changes within the adult LC-NE system. Finally, we test whether developmental exposure to the -2 receptor agonist guanfacine recapitulates the effect seen with our pharmacogenetic strategy. Our results reveal a sensitive period (postnatal days 10-21) during which alterations in NE signaling result in long-term changes in adult emotional behavior. Changes in NE signaling during this sensitive period results in changes in stress-related LC neuron activity, alterations in -2 autoreceptor function, and circuit-specific molecular changes in LC-NE target regions in adulthood. Treating animals with guanfacine during the sensitive period produced similar results. Our findings indicate an early critical role for NE in sculpting brain circuits that support adult emotional function.

neuroscience↗