Biology subjects

Ye, Z.

Publications and source records attributed to Ye, Z..

159 records · Page 9Linked to original sources

bioRxiv2019

MECP2 duplication causes aberrant GABA pathways, circuits and behaviors in transgenic monkeys: neural mappings to patients with autism

MECP2 gain- and loss-of-function in genetically-engineered monkeys demonstrably recapitulate typical phenotypes in patients, yet where MECP2 mutation affects the monkey brain and whether/how it relates to autism pathology remains unknown. Using expression profiles of 13,888 genes in 182 macaque neocortical samples, we first show that MECP2 coexpressed genes are enriched in GABA-related signaling pathways. We then perform analyses on multiple phenotypic levels including locomotive and cognitive behavior, resting-state electroencephalography and fMRI in MECP2 overexpressed and wild-type macaque monkeys. Behaviorally, transgenic monkeys exhibit hyperactive and repetitive locomotion, greater separation anxiety response, and less flexibility in rule switching. Moreover, decreased neural synchronization at beta frequency (12-30 Hz) is associated with greater locomotion after peer separation. Further analysis of fMRI-derived connectomics reveals widespread hyper- and hypo-connectivity, where hyper-connectivity prominently involving prefrontal and cingulate networks accounts for deficits in cognitive flexibility. To map MECP2-related aberrant circuits of monkeys to the pathological circuits of autistic patients, individuals in a large public neuroimaging database of autism were clustered using community detection on functional connectivity patterns. In a stratified cohort of 49 autisms and 72 controls, the dysfunctional connectivity profile particularly in prefrontal and temporal networks is highly correlated with that of transgenic monkeys, as is further responsible for the severity of social communicative deficits in patients. Through establishing a circuit-based construct link between transgenic animal models and stratified clinical patients, the present findings with explicable biological causes are potentially amenable to translation for accurate diagnosis and evaluation of future treatments in autism-related disorders.\n\nOne sentence summaryWe identify shared circuit-level abnormalities between MECP2 transgenic monkeys and a stratified subgroup of human autism, and demonstrate the translational need of a multimodal approach to capture multifaceted effects triggered by a single genetic event in a genetically-engineered primate model.

neuroscience↗

bioRxiv2019

jULIEs: extracellular probes for recordings and stimulation in the structurally and functionally intact mouse brain

High signal-to-noise, scalable and minimally invasive recording and stimulation of the nervous system in intact animals is of fundamental importance to advance the understanding of brain function. Extracellular electrodes are among the most powerful tools capable of interfacing with large neuronal populations1-3. Neuronal tissue damage remains a major limiting factor in scaling electrode arrays, and has been found to correlate with electrode diameter across different electrode materials, such as microfabricated Michigan and Utah-style arrays4, MEMS and microsystems5, soft polymer or tungsten electrodes6 and Parylene C probes7. Small diameter ultramicroelectrodes (UMEs), while highly desirable, pose significant technical challenges such as reaching sufficient electrolyte-electrode coupling and limiting stray signal loss. To overcome these challenges, we have designed juxtacellular Ultra-Low Impedance Electrodes (jULIEs), a scalable technique for achieving high signal-to-noise electrical recordings as well as stimulation with UMEs. jULIEs are metal-glass composite UMEs thermally drawn to outer diameters (OD) of <25 {micro}m, with metal core diameters (ID) of as little as 1 {micro}m. We introduce a two-step electrochemical modification strategy that reduces UME coupling impedances by two orders of magnitude. Modifications enabled high signal-to-noise neural recordings in vivo through wires with micrometer scale core diameters. Histological and imaging experiments indicated that local vascular damage is minimal. Spikes reached amplitudes over 1 mV in vivo, indicating that recordings are possible in close proximity to intact neurons. Recording sites can be arranged in arbitrary patterns tailored to various neuroanatomical target structures and allowing parallel penetrations. jULIEs thus represent a versatile platform that allows for reliable recording and manipulation of neural activity in any areas of the functionally intact mammalian brain.

neuroscience↗

bioRxiv2019

Pro-inflammatory cytokines disrupt β-cell circadian clocks in diabetes

Intrinsic {beta}-cell circadian clocks are a prerequisite for the control of glucose homeostasis through regulation of {beta}-cell function and turnover. However, little is known about the contributions of circadian clock disruption to the natural progression of {beta}-cell failure in diabetes. To address this, we examined the effects of cytokine-mediated inflammation, common to the pathophysiology of Type 1 and Type 2 diabetes, on the physiological, molecular, and epigenetic regulation of circadian clocks in {beta}-cells. Specifically, we provide evidence that the key diabetogenic cytokine IL-1{beta} disrupts functionality of the {beta}-cell circadian clock and circadian regulation of insulin secretion through impaired expression of the key transcription factor Bmal1, evident at the level of promoter activation, mRNA, and protein expression. Additionally, IL-1{beta}-mediated inflammation was shown to augment genome-wide DNA-binding patterns of Bmal1 (and its heterodimer, Clock) in {beta}-cells towards binding sites in the proximity of genes annotated to pathways regulating {beta}-cell apoptosis, inflammation, and dedifferentiation. Finally, we identified that the development of hyperglycemia in humans is associated with compromised {beta}-cell BMAL1 expression suggestive of a causative link between circadian clock disruption and {beta}-cell failure in diabetes.

cell biology↗

bioRxiv2019

Analysis of task-based functional MRI data preprocessed with fMRIPrep

Functional magnetic resonance imaging (fMRI) is a standard tool to investigate the neural correlates of cognition. fMRI noninvasively measures brain activity, allowing identification of patterns evoked by tasks performed during scanning. Despite the long history of this technique, the idiosyncrasies of each dataset have led to the use of ad-hoc preprocessing protocols customized for nearly every different study. This approach is time-consuming, error-prone, and unsuitable for combining datasets from many sources. Here we showcase fMRIPrep (http://fmriprep.org), a robust tool to prepare human fMRI data for statistical analysis. This software instrument addresses the reproducibility concerns of the established protocols for fMRI preprocessing. By leveraging the Brain Imaging Data Structure (BIDS) to standardize both the input datasets --MRI data as stored by the scanner-- and the outputs --data ready for modeling and analysis--, fMRIPrep is capable of preprocessing a diversity of datasets without manual intervention. In support of the growing popularity of fMRIPrep, this protocol describes how to integrate the tool in a task-based fMRI investigation workflow.

bioinformatics↗

bioRxiv2018

3D Chromatin Architecture Remodeling during Human Cardiomyocyte Differentiation Reveals A Novel Role of HERV-H In Demarcating Chromatin Domains

Dynamic restructuring of chromatin architecture has been implicated in cell-type specific gene regulatory programs; yet, how chromatin remodels during lineage specification remains to be elucidated. Through interrogating chromatin reorganization during human cardiomyocyte differentiation, we uncover dynamic chromatin interactions between genes and distal regulatory elements harboring noncoding variants associated with adult and congenital heart diseases. Unexpectedly, we also discover a new class of human pluripotent stem cell (PSC)-specific topologically associating domains (TAD) that are created by the actively transcribed endogenous retrotransposon HERV-H. Deletion or silencing of specific HERV-H elements eliminates corresponding TAD boundaries, while de novo insertion of HERV-H can introduce new chromatin domain boundaries in human PSCs. Furthermore, comparative analysis of chromatin architecture in other species that lack HERV-H sequences supports a role for actively transcribed HERV-H in demarcating human PSC-specific TADs. The biological role of HERV-H is further underscored by the observation that deletion of a specific HERV-H reduces transcription of genes upstream and facilitates cell differentiation. Overall, our results highlight a previously unrecognized role for retrotransposons in restructuring genome architecture in the human genome and delineate dynamic gene regulatory networks during cardiomyocyte development that inform how non-coding genetic variants contribute to human heart diseases.

genomics↗

bioRxiv2018

Comparative analysis of PknB inhibitors for reactivity and toxicity

Bacterial serine/threonine kinases are increasingly sought after as drug targets for new antibiotics. PknB, an essential kinase in Mycobacteria tuberculosis, is intensely targeted, and many inhibitors are in the developmental pipeline. These inhibitors typically are derived from screens of known kinase inhibitors and most share similar chemical properties as their parent compounds were all designed for optimal pharmacokinetic properties in the human body. Here, we investigate the reactivity and toxicity of a proposed PknB inhibitor, YH-8, which does not follow traditional drug design rules. We found that the compound is highly reactive with thiolating agents and has appreciable toxicity in a zebrafish animal model. Furthermore, we find minimal anti-mycobacterial activity with non-tubercular mycobacteria strains. These data suggest that further investigation is needed into its efficacy and physiochemical properties if it is to be further developed as an effective antibiotic.

microbiology↗

bioRxiv2018

Cellular acidosis triggers MondoA transcriptional activity by driving mitochondrial ATP production

MondoA and its transcriptional target thioredoxin-interacting protein (TXNIP) constitute a regulatory loop that senses glycolytic flux and controls glucose availability. Cellular stress also triggers MondoA activity and TXNIP expression. To understand how MondoA integrates glucose and stress signals, we studied its activation by acidosis. We found that acidosis drives mitochondrial ATP (mtATP) synthesis. The subsequent export of mtATP from mitochondria via adenine-nucleotide transporter and voltage-dependent anion channel, and the enzymatic activity of mitochondria-bound hexokinase results in the production of glucose-6-phosphate (G6P), a known activator of MondoA transcriptional activity. MondoA localizes to the outer-mitochondrial membrane (OMM), and in response to G6P, shuttles to the nucleus and activates transcription. Our data suggests that MondoA is a required feature of a glucose- and mtATP-dependent, OMM-localized signaling center. We propose MondoA functions as a coincidence detector and its ability to sense glucose and cellular stress is coupled to the concerted production of G6P.

cancer biology↗

bioRxiv2018

Ras Suppresses TXNIP Expression by Restricting Ribosome Translocation

Oncogenic Ras upregulates aerobic glycolysis to meet the bioenergetic and biosynthetic demands of rapidly growing cells. In contrast, Thioredoxin interacting protein (TXNIP) is a potent inhibitor of glucose uptake and is frequently downregulated in human cancers. Our lab previously discovered that Ras activation suppresses TXNIP transcription and translation. In this report, we developed a system to study how Ras affects TXNIP translation in the absence of transcriptional affects. We show that whereas Ras drives a global increase in protein translation, it suppresses TXNIP protein synthesis by reducing the rate at which ribosomes transit the coding region of TXNIP mRNA. To investigate the underlying mechanism(s), we randomized or optimized the codons in the TXNIP message without altering the TXNIP primary amino acid sequence. Translation from these mRNA variants is still repressed by Ras, intimating that mRNA secondary structure, miRNAs, RNA binding proteins, or codon usage do not contribute to the blockade of TXNIP synthesis. Rather, we show that the N-terminus of the growing TXNIP polypeptide is the target for Ras-dependent translational repression. Our work demonstrates how Ras suppresses TXNIP translation elongation in the face of a global upregulation of protein synthesis and provides new insight into Ras-dependent metabolic reprogramming.

cancer biology↗

bioRxiv2018

EZH2 co-opts gain-of-function p53 mutants to promote cancer growth and metastasis

With the unfolding of more and more cancer-driven gain-of-function (GOF) mutants of p53, it is important to define a common mechanism to systematically target different mutants rather than develop strategies tailored to inhibit each mutant individually. Here, using RNA immunoprecipitation sequencing (RIP-seq) we identified EZH2 as a p53 mRNA-binding protein. EZH2 bound to the internal ribosome entry site (IRES) in the 5 untranslated region (5UTR) of p53 mRNA and enhanced p53 protein translation in a methyltransferase-independent manner. EZH2 augmented p53 GOF mutant-mediated cancer growth and metastasis by increasing p53 GOF mutant protein level. EZH2 overexpression associated with the worse outcome only in patients with p53-mutated cancer. Depletion of EZH2 by antisense oligonucleotides inhibited p53 GOF mutant-mediated cancer growth. Our findings reveal a non-methyltransferase function of EZH2 that controls protein translation of p53 GOF mutants, inhibition of which causes synthetic lethality in cancer cells expressing p53 GOF mutants.

cancer biology↗

bioRxiv2018

Proteome-scale detection of drug-target interactions using correlations in transcriptomic perturbations

The development of an expanded chemical space for screening is an essential step in the challenge of identifying chemical probes for new, genomic-era protein targets. However, the difficulty of identifying targets for novel compounds leads to the prioritization of synthesis linked to known active scaffolds that bind familiar protein families, slowing the exploration of available chemical space. To change this paradigm, we validated a new pipeline capable of identifying compound-protein interactions even for compounds with no similarity to known drugs. Based on differential mRNA profiles from drug treatments and gene knockdowns across multiple cell types, we show that drugs cause gene regulatory network effects that correlate with those produced by silencing their target protein-coding gene. Applying supervised machine learning to exploit compound-knockdown signature correlations and enriching our predictions using an orthogonal structure-based screen, we achieved top-10/top-100 target prediction accuracies of 26%/41%, respectively, on a validation set 152 FDA-approved drugs and 3104 potential targets. We further predicted targets for 1680 compounds and validated a total of seven novel interactions with four difficult targets, including non-covalent modulators of HRAS and KRAS. We found that drug-target interactions manifest as gene expression correlations between drug treatment and both target gene knockdown and up/down-stream knockdowns. These correlations provide biologically relevant insight on the cell-level impact of disrupting protein interactions, highlighting the complex genetic phenotypes of drug treatments. Our pipeline can accelerate the identification and development of novel chemistries with potential to become drugs by screening for compound-target interactions in the full human interactome.

genomics↗

bioRxiv2017

Whole exome sequencing study of colorectal cancer in Chinese population reveals novel prevalently mutated genes and decreased mutation frequency of APC and Wnt signaling in lymph node positive cancer

Colorectal cancer is the fifth prevalent cancer in China. Nevertheless, a large-scale characterization of Chinese colorectal cancer mutation spectrum has not been carried out. In this study, we have performed whole exome-sequencing analysis of 98 patients tumor samples with matched pairs of normal colon tissues using Illumina and Complete Genomics high-throughput sequencing platforms. Canonical CRC somatic gene mutations with high prevalence (>10%) have been verified, including TP53, APC, KRAS, SMAD4, FBXW7 and PIK3CA. PEG3 is identified as a novel frequently mutated gene (10.6%). APC and Wnt signaling exhibit significantly lower mutation frequencies than those in TCGA data. Analysis with clinical characteristics indicates that APC gene and Wnt signaling display lower mutation rate in lymph node positive cancer than negative ones, which are not observed in TCGA data. APC gene and Wnt signaling are considered as the key molecule and pathway for colorectal cancer initiation, and these findings greatly undermine their importance in tumor progression for Chinese patients. Taken together, the application of next-generation sequencing has led to the determination of novel somatic mutations and alternative disease mechanisms in colorectal cancer progression, which may be useful for understanding disease mechanism and personalizing treatment for Chinese patients.

genomics↗

bioRxiv2017

Preservation of Chromatin Organization after Acute Loss of CTCF in Mouse Embryonic Stem Cells

The CCCTC-binding factor (CTCF) is widely regarded as a key player in chromosome organization in mammalian cells, yet direct assessment of the impact of loss of CTCF on genome architecture has been difficult due to its essential role in cell proliferation and early embryogenesis. Here, using auxin-inducible degron techniques to acutely deplete CTCF in mouse embryonic stem cells, we show that cell growth is severely slowed yet chromatin organization remains largely intact after loss of CTCF. Depletion of CTCF reduces interactions between chromatin loop anchors, diminishes occupancy of cohesin complex genome-wide, and slightly weakens topologically associating domain (TAD) structure, but the active and inactive chromatin compartments are maintained and the vast majority of TAD boundaries persist. Furthermore, transcriptional regulation and histone marks associated with enhancers are broadly unchanged upon CTCF depletion. Our results suggest CTCF-independent mechanisms in maintenance of chromatin organization.

genomics↗

bioRxiv2017

Histone H3 Lysine 4 methyltransferases MLL3 and MLL4 Modulate Long-range Chromatin Interactions at Enhancers

Regulation of gene expression in mammalian cells depends on long-range chromatin interactions between enhancers and promoters. Currently, the exact mechanisms that connect distal enhancers to their specific target promoters remain to be fully elucidated. Here we show that the histone H3 Lysine 4 monomethylation (H3K4me1) writer proteins MLL3 and MLL4 (MLL3/4) play an active role in this process. We demonstrate that in differentiating mouse embryonic stem cells, MLL3/4-dependent deposition of H3K4me1 at enhancers correlates with increased levels of chromatin interactions, whereas loss of MLL3/4 leads to greatly reduced frequencies of chromatin interactions and failure of lineage-specific gene expression programs. We further show that H3K4me1 facilitates recruitment of the Cohesin complex to chromatin in vitro and in vivo, providing a potential mechanism for MLL3/4 to promote chromatin looping. Taken together, our results support an active role for MLL3/4 in modulating chromatin organization at enhancers in mammalian cells.

genomics↗

bioRxiv2017

Prevailing homozygous deletion of interferon and defensin genes in human cancers

Interferons and defensins are antimicrobial peptides that can also induce anti-tumor immunity. By analyzing the copy number profiles of 10,759 patients across 31 cancer types, we found the homozygous deletions of interferon and defensin genes are prevailing in most human cancers, and that patients with these homozygous deletions exhibited significant reduced overall survival or disease-free survival. We further demonstrated that the homozygous deletion of interferon and defensin genes significantly impacted the expression of genes regulated by tumor necrosis factor (TNF) and IFN{gamma}. Our findings suggested a novel immune escape mechanism that disrupts the tumor cells ability to be recognized, and have implications for personalized immunotherapy.

immunology↗

bioRxiv2017

CircularLogo: A light weighted web application to visualize intra-motif dependencies

BackgroundThe sequence logo has been widely used to represent DNA or RNA motifs for more than three decades. Despite its intelligibility and intuitiveness, the traditional sequence logo is unable to display the intra-motif dependencies and therefore is insufficient to fully characterize nucleotide motifs. Many methods have been developed to quantify the intra-motif dependencies, but fewer tools are available for visualization.\n\nResultWe developed CircularLogo, a web-based interactive application, which is able to not only visualize the position-specific nucleotide consensus and diversity but also display the intra-motif dependencies. Applying CircularLogo to HNF6 binding sites and tRNA sequences demonstrated its ability to show intra-motif dependencies and intuitively reveal biomolecular structure. CircularLogo is implemented in JavaScript and Python based on the Django web framework. The programs source code and users manual are freely available at http://circularlogo.sourceforge.net. CircularLogo web server can be accessed from http://bioinformaticstools.mayo.edu/circularlogo/index.html.\n\nConclusionCircularLogo is an innovative web application that is specifically designed to visualize and interactively explore intra-motif dependencies.

bioinformatics↗