Biology subjects

Yue, Z.

Publications and source records attributed to Yue, Z..

69 records · Page 4Linked to original sources

bioRxiv2021

The First High-Quality Reference Genome of Sika Deer Provides Insights for High-Tannin Adaptation

Sika deer are known to prefer oak leaves, which are rich in tannins and toxic to most mammals; however, the genetic mechanisms underlying their unique ability to adapt to living in the jungle are still unclear. In identifying the mechanism responsible for the tolerance of a highly toxic diet, we have made a major advancement in the elucidation of the genomics of sika deer. We generated the first high-quality, chromosome-level genome assembly of sika deer and measured the correlation between tannin intake and RNA expression in 15 tissues through 180 experiments. Comparative genome analyses showed that the UGT and CYP gene families are functionally involved in the adaptation of sika deer to high-tannin food, especially the expansion of UGT genes in a subfamily. The first chromosome-level assembly and genetic characterization of the tolerance toa highly toxic diet suggest that the sika deer genome will serve as an essential resource for understanding evolutionary events and tannin adaptation. Our study provides a paradigm of comparative expressive genomics that can be applied to the study of unique biological features in non-model animals.

genomics↗

bioRxiv2021

A Non-redundant Role for T cell-derived IL-22 in Antibacterial Defense of Colonic Crypts

IL-22 is a key cytokine in immune defense against pathogens at barrier sites. In response to enteric attaching and effacing bacteria, IL-22 produced by type 3 innate lymphoid cells (ILC3s) is thought to be important early for induction of antimicrobial peptides (AMPs) that protect intestinal epithelial cells (IECs) in advance of T cell-derived IL-22 that arises later. Yet, the basis for a requirement for both innate and adaptive IL-22-producing immune cells in protecting the intestinal mucosa is unknown. Here, using novel mice that both report IL-22 expression and can be targeted for its lineage-specific deletion, we show that mice with deficiency of IL-22 targeted to innate immune cells, including ILC3s, have impaired STAT3 activation of surface colonic IECs colonized by bacteria early in infection. In contrast, mice with IL-22 deficiency limited to T cells have complete loss of STAT3 activation in IECs lining colonic crypts and fail to protect the crypts from bacterial invasion late despite ongoing production of IL-22 from ILC3s. T cell-derived IL-22 is required for upregulation of many host-protective genes by crypt IECs, including those encoding AMPs, neutrophil-recruiting chemokines, and mucins and mucin-related molecules, while also restricting pro-inflammatory genes downstream of IFN{gamma} and TNF signals. Thus, T cell-derived IL-22 is indispensable for antibacterial defense and damage control of intestinal crypts.

immunology↗

bioRxiv2021

Recurrent chromosome reshuffling and the evolution of neo-sex chromosomes in parrots

The karyotype of most birds has remained considerably stable during more than 100 million years evolution, except for some groups, such as parrots. The evolutionary processes and underlying genetic mechanism of chromosomal rearrangements in parrots, however, are poorly understood. Here, using chromosome-level assemblies of three parrot genomes (monk parakeet, blue-fronted amazon, budgerigar), we uncovered frequent chromosome fusions and fissions among parrots, with most of them being lineage-specific. In particular, at least 12 chromosomes recurrently experienced inter-chromosomal fusions in different parrot lineages. Two conserved vertebrate genes, ALC1 and PARP3, with known functions in the repair of double-strand breaks and maintenance of genome stability, were specifically lost in parrots. The loss of ALC1 was associated with multiple deletions and an accumulation of CR1-psi, a novel subfamily of transposable elements (TEs) that recently amplified in parrots, while the loss of PARP3 was associated with an inversion. Additionally, the fusion of the ZW sex chromosomes and chromosome 11 has created a pair of neo-sex chromosomes in the ancestor of parrots, and the chromosome 25 has been further added to the sex chromosomes in monk parakeet. The newly formed neo-sex chromosomes were validated by our chromosomal painting, genomic and phylogenetic analyses. Transcriptome profiling for multiple tissues of males and females did not reveal signals of female-specific selection driving the formation of neo-sex chromosomes. Finally, we identified one W-specific satellite repeat that contributed to the unusual enlargement of the W chromosome in monk parakeet. Together, the combination of our genomic and cytogenetic analyses highlight the role of TEs and genetic drift in promoting chromosome rearrangements, gene loss and the evolution of neo-sex chromosome in parrots.

evolutionary biology↗

bioRxiv2020

Multiscale Simulation Reveals Passive Proton Transport Through SERCA on the Microsecond Timescale

The sarcoplasmic reticulum Ca2+-ATPase (SERCA) transports two Ca2+ ions from the cytoplasm to the reticulum lumen at the expense of ATP hydrolysis. In addition to transporting Ca2+, SERCA facilitates bidirectional proton transport across the sarcoplasmic reticulum to maintain the charge balance of the transport sites and to balance the charge deficit generated by the exchange of Ca2+. Previous studies have shown the existence of a transient water-filled pore in SERCA that connects the Ca2+-binding sites with the lumen, but the capacity of this pathway to sustain passive proton transport has remained unknown. In this study, we used the multiscale reactive molecular dynamics (MS-RMD) method and free energy sampling to quantify the free energy profile and timescale of the proton transport across this pathway while also explicitly accounting for the dynamically coupled hydration changes of the pore. We find that proton transport from the central binding site to the lumen has a microsecond timescale, revealing a novel passive cytoplasm-to-lumen proton flow beside the well-known inverse proton countertransport occurring in active Ca2+ transport. We propose that this proton transport mechanism is operational and serves as a functional conduit for passive proton transport across the sarcoplasmic reticulum. SIGNIFICANCEMultiscale reactive molecular dynamics combined with free energy sampling was applied to study proton transport through a transient water pore connecting the Ca2+-binding site to the lumen in SERCA. This is the first computational study of this large biomolecular system that treats the hydrated excess proton and its transport through water structures and amino acids explicitly. When also correctly accounting for the hydration fluctuations of the pore, it is found that a transiently hydrated channel can transport protons on a microsecond timescale. These results quantitatively support the hypothesis of the proton intake into the sarcoplasm via SERCA, in addition to the well-known proton pumping by SERCA to the cytoplasm along with Ca2+ transport.

biophysics↗

bioRxiv2020

Effects of Sodium tanshinone IIA sulfonate on H9C2 cardiomyocyte injury induced by sodium arsenite

Arsenic is a grade I human carcinogen that can cause kinds of damage to the body. The heart is one of the main target organs of arsenic damage, but the preventive and curative measures underlying arsenic poisoning are not clear. To investigate the effect of tanshinone IIA sulfonate (STS) on the injury of H9C2 cardiomyocytes induced by NaAsO2,H9C2 cardiomyocyteswere divided into four groups where control group with general medium, arsenic (As) group received sodium arsenite (NaAsO2)-containing general medium, STS pretreatment+As group and finally the STS alone group. Compared with the control group, different concentrations of STS had no significant effect on the cell viability (n = 6, P > 0.05); Compared with the control group, there was no significant change in the viability of cells treated with arsenic for 12 h after STS pretreatment for 6 h (n = 6, P > 0.05),the viability of cells treated with NaAsO2 alone was decreased(n = 6, P < 0.05);Compared with the control group, the cell viability was decreased after STS pretreatment for 12h and arsenic for 24h, the cell viability of NaAsO2 group was also decreased, the viability of NaAsO2 cells was lower than that of STS pretreated for 12h with NaAsO2 for 24h(n=6,p<0.05).The content of Caspase 3/7 in the NaAsO2 group was higher than that in the STS and NaAsO2 group and the Control group and STS group after 12h, the differences were statistically significant(n=6,p<0.05).After STS pretreatment for 12h and NaAsO2 for 24 h, there was no significant difference in Caspase 8 content between NaAsO2 group and other groups(n=6,P>0.05) As a result, Sodium tanshinone IIA sulfonate can attenuate the injury of H9C2 cardiomyocytes induced by sodium arsenite.

cell biology↗

bioRxiv2020

Causal dynamical modelling predicts novel regulatory genes of FOXP3 in human regulatory T cells

Regulatory T cells (Tregs), characterized as a CD4+CD25+FOXP3+ subset of T cells, are vital to the induction of immune tolerance and the maintenance of immune homeostasis. While target genes of Treg master regulator FOXP3 have been identified, the upstream regulatory machinery of FOXP3 still remains largely unknown. Here we dynamically model causal relationships among genes from available time-series genome-scale datasets, to predict direct or indirect regulatory genes of FOXP3 in human primary Tregs. From the whole genome, we selected five top ranked candidates for further experimental validation. Following knockdown, three out of the five candidates indeed showed significant effects on the mRNA expression of FOXP3. Further experiments showed that one out of these three predicted candidates, namely nuclear receptor binding factor 2 (NRBF2), also affected FOXP3 protein expression. These results open new doors to identify potential new mechanisms of immune related diseases.

systems biology↗

bioRxiv2019

Microglia Clear Neuron-released α-Synuclein via Selective Autophagy and Prevent Neurodegeneration

Microglia maintain brain homeostasis by removing neuron-derived components such as myelin and cell debris. The evidence linking microglia to neurodegenerative diseases is growing, however, the precise mechanisms remain poorly understood. Herein we report a neuroprotective role for microglia in the clearance of neuron-released -synuclein. Neuronal -synuclein activates microglia, which in turn engulf -synuclein into autophagosomes for degradation via selective autophagy (termed Synucleinphagy). Synucleinphagy is initiated by the interaction of -synuclein with Toll-like receptor 4 (TLR4), which induces transcriptional upregulation of p62/SQSTM1 through the NF-{kappa}B signaling pathway without causing TLR4 endocytosis. Induction of p62, an autophagy receptor, is necessary for the formation of -synuclein/ubiquitin-positive puncta that are degraded by autophagy. Finally, disruption of microglial autophagy in mice expressing human -synuclein promotes the accumulation of misfolded -synuclein and causes midbrain dopaminergic neuron degeneration. Our study thus identifies a novel neuroprotective function of microglia in the clearance of -synuclein via TLR4-NF-{kappa}B-p62 mediated Synucleinphagy.

neuroscience↗

bioRxiv2019

Molecular Networks and Key Regulators of the Dysregulated Neuronal System in Alzheimer’s Disease

To study the molecular mechanisms driving the pathogenesis and identify novel therapeutic targets of late onset Alzheimers Disease (LOAD), we performed an integrative network analysis of whole-genome DNA and RNA sequencing profiling of four cortical areas, including the parahippocampal gyrus, across 364 donors spanning the full spectrum of LOAD-related cognitive and neuropathological disease severities. Our analyses revealed thousands of molecular changes and uncovered for the first-time multiple neuron specific gene subnetworks most dysregulated in LOAD. ATP6V1A, a critical subunit of vacuolar-type H+-ATPase (v-ATPase), was predicted to be a key regulator of one neuronal subnetwork and its role in disease-related processes was evaluated through CRISPR-based manipulation of human induced pluripotent stem cell derived neurons and RNAi-based knockdown in transgenic Drosophila models. This study advances our understanding of LOAD pathogenesis by providing the global landscape and detailed circuits of complex molecular interactions and regulations in several key brain regions affected by LOAD and the resulting network models provide a blueprint for developing next generation therapeutics against LOAD.

neuroscience↗

bioRxiv2019

Disruption of the CSF-1-CSF-1R axis alters cerebellar microglia and is associated with motor and social interaction defects

Microglia, the brain resident macrophages, critically shape forebrain neuronal circuits. However, their precise function in the cerebellum is unknown. Here we show that human and mouse cerebellar microglia express a unique molecular program distinct from forebrain microglia. Cerebellar microglial identity was driven by the CSF-1R ligand CSF-1, independently of the alternate CSF-1R ligand, IL-34. Accordingly, CSF-1 depletion from Nestin+ cells led to severe depletion and transcriptional alterations of cerebellar microglia, while microglia in the forebrain remained intact. Strikingly, CSF-1 deficiency and alteration of cerebellar microglia were associated with reduced Purkinje cells, altered neuronal function, and defects in motor learning and social novelty interactions. These findings reveal a novel CSF-1-CSF-1R signaling-mediated mechanism that contributes to motor function and social behavior.\n\nSummaryMicroglia are a heterogeneous population whose identity and function are dictated by signals from their microenvironment. Kana et al. show that CSF-1 signaling is critical for maintaining cerebellar microglial transcriptional identity and homeostasis, and that altering the CSF-1 - CSF-1R axis leads to motor and behavioral defects.

neuroscience↗

bioRxiv2019

Spread of pathological α-synuclein from urogenital nerves initiates multiple system atrophy-like symptoms

Multiple system atrophy (MSA) is a fatal adult-onset movement disorder with autonomic failures, especially urogenital dysfunction. The neuropathological feature of MSA is the accumulation of misfolded -synuclein (-Syn) in the nervous system. Here, we show that misfolded -Syn exist in nerve terminals in detrusor (DET) and external urethral sphincter (EUS) of patients with MSA. Moreover, -Syn preformed fibrils inoculated into the EUS or DET in TgM83+/- mice initiated the transmission of misfolded -Syn from the lower urinary tract to brain, and these mice developed -Syn inclusion pathology through micturition reflex pathways along with urinary dysfunction and motor impairments. These findings indicate that spreading of misfolded -Syn from the autonomic control of the lower urinary tract to the brain via micturition reflex pathways induces autonomic failure and motor impairments. These results provide important new insights into the pathogenesis of MSA as well as highlight potential targets for early detection and therapeutics.

neuroscience↗

bioRxiv2018

Contractile actomyosin network on nuclear envelope remnants positions chromosomes for mitosis

To ensure proper segregation during mitosis, chromosomes must be efficiently captured by kinetochore microtubules and subsequently aligned on the mitotic spindle. The efficacy of chromosome capture by the mitotic spindle can be influenced by how widely chromosomes are scattered in space. Here, we quantify chromosome-scattering volume (CSV) and find that it is reduced immediately after nuclear envelope breakdown (NEBD) in human cells. The reduction of CSV occurs independently of microtubules and is therefore not an outcome of interactions between chromosomes and the spindle. We find that, prior to NEBD, an acto-myosin network is assembled in a LINC complex-dependent manner on the cytoplasmic surface of the nuclear envelope. This acto-myosin network remains around chromosomes soon after NEBD, and its myosin-II-mediated contraction reduces CSV and facilitates chromosome interaction with spindle microtubules.

cell biology↗

bioRxiv2018

Live-cell imaging of marked chromosome regions reveals dynamics of mitotic chromosome resolution and compaction

When human cells enter mitosis, chromosomes undergo substantial changes in their organisation to resolve sister chromatids and compact chromosomes. Despite the fundamental importance of this phenomenon to genome stability, we still do not fully comprehend the timing and coordination of these events. To address these questions, we need to evaluate the progression of both sister chromatid resolution and chromosome compaction in one assay. We achieved this by analysing changes in configuration of marked chromosome regions over time, with high spatial and temporal resolution. This assay showed that sister chromatid resolution is an iterative process that begins in late G2 phase and completes in prophase. Cohesins and WAPL antagonistically regulate sister chromatid resolution in late G2 and prophase whilst local enrichment of cohesin on chromosomes prevents precocious sister chromatid resolution. Moreover, our assay allowed quantitative evaluation of the timing and efficiency of condensin II and I activities in promoting sister chromatid resolution and chromosome compaction, respectively. Thus, our real-time assay sheds new light on the dynamics of mitotic chromosome resolution and compaction.

cell biology↗

bioRxiv2018

A new approach to design artificial 3D micro-niches with combined chemical, topographical and rheological cues

The in vitro methods to recapitulate environmental cues around cells are usually optimized to test a specific property of the environment (biochemical nature or the stiffness of the extra cellular matrix (ECM), or nanotopography) for its capability to induce defined cell behaviors (lineage commitment, migration). Approaches that combine different environmental cues in 3D to assess the biological response of cells to the spatial organization of different biophysical and biochemical cues are growingly being developed. We demonstrate how the lamination of through-hole polymeric bio-functionalized membranes can be implemented to create complex bona fide micro-niches with differential 3D environmental properties using photoactive materials. Our approach enables to create micro-niches ranging in size from single cells to cell aggregates. They are bio-functionalized in 3D simultaneously with topographical featured, protein patterns and structured ECM surrogate with 1 micrometer resolution. We demonstrate how these niches extend in 3D the ability to pattern cells. We exemplify how they can be used to standardize cells shapes in 3D and to trigger the apico-basal polarization of single epithelial cells.

bioengineering↗

bioRxiv2017

Haploinsufficiency of Parkinsonism Gene SYNJ1 Contributes to Dopamine neuron Vulnerability in Aged Mice

Parkinsons disease (PD) is an age-dependent neurodegenerative disorder characterized by the loss of substantia nigra dopaminergic (DAergic) neurons in ventral midbrain (MB). Identification of interactions between aging and the known risk variants is crucial to understanding the etiology of PD. Recessive mutations in SYNJ1 have recently been linked to familial early-onset atypical Parkinsonism. We now show an age-dependent decline of SYNJ1 expression in the striatum as well as in striatal DAergic terminals of aged mice. Heterozygous deletion of SYNJ1 in mice causes selective elevation of PIP2 in the MB, and manipulation of PIP2 levels also impairs synaptic vesicle recycling preferentially in MB neurons. SYNJ1+/- mice display progressive PD-like behavioral alterations and DAergic terminal degeneration. Furthermore, we found down-regulation of human SYNJ1 transcripts in a subset of sporadic PD brains, corroborating the role of an age-dependent decrease in SYNJ1 in predisposing DAergic neuron vulnerability and PD pathogenesis.

neuroscience↗

bioRxiv2017

A circadian clock in the blood-brain barrier regulates xenobiotic efflux from the brain

HighlightsO_LIThe Drosophila BBB displays a circadian rhythm of permeability\nC_LIO_LICyclic efflux driven by a clock in the BBB underlies the permeability rhythm\nC_LIO_LICircadian control is non-cell-autonomous via gap junction regulation of [Mg2+]i\nC_LIO_LIAn anti-seizure drug is more effective when administered at night\nC_LI\n\nSummaryEndogenous circadian rhythms are thought to modulate responses to external factors, but mechanisms that confer time-of-day differences in organismal responses to environmental insults / therapeutic treatments are poorly understood. Using a xenobiotic, we find that permeability of the Drosophila \"blood\"-brain barrier (BBB) is higher at night. The permeability rhythm is driven by circadian regulation of efflux and depends upon a molecular clock in the perineurial glia of the BBB, although efflux transporters are restricted to subperineurial glia (SPG). We show that transmission of circadian signals across the layers requires gap junctions, which are expressed cyclically. Specifically, during nighttime gap junctions reduce intracellular magnesium ([Mg2+]i), a positive regulator of efflux, in SPG. Consistent with lower nighttime efflux, nighttime administration of the anti-epileptic phenytoin is more effective at treating a Drosophila seizure model. These findings identify a novel mechanism of circadian regulation and have therapeutic implications for drugs targeted to the central nervous system.

neuroscience↗