Biology subjects

Hu, T.

Publications and source records attributed to Hu, T..

9 recordsLinked to original sources

bioRxiv2026

Soils from different landscape elements diverge in response to multiple global change factors

Global change factors (GCFs) are known to affect terrestrial ecosystems across a range of land-use types, including farmlands, grasslands, and forests. However, it remains unclear whether different landscape elements within the same region respond differently to the same global change pressures. Here, we investigated this question using four soils collected from co-located farmland, grassland, pine forest, and oak forest, representing distinct landscape elements under the same regional climatic conditions. Each soil was exposed to one of six individual GCFs, warming, drought, nitrogen deposition, salinity, microplastics, and antibiotics, as well as to all six factors combined. We found that landscape elements exhibited strongly divergent responses to the same GCFs. The effects on soil functions also varied among soils under combined stress, with responses diverging from different null-model predictions depending on soils and response variable. Moreover, landscape-element specific response patterns became more pronounced under multiple concurrent stressors. Overall, our findings show that landscape heterogeneity represents a mosaic of different capacities to resist and respond to global change, even under shared climatic and geographic conditions. Global change assessments and ecosystem models should therefore better account for landscape-level heterogeneity, and management strategies aimed at enhancing ecosystem resilience should be tailored to individual landscape elements.

ecology↗

bioRxiv2018

Measuring the importance of vertices in the weighted human disease network

Many human genetic disorders and diseases are known to be related to each other through frequently observed co-occurrences. Studying the correlations among multiple diseases provides an important avenue to better understand the common genetic background of diseases and to help develop new drugs that can treat multiple diseases. Meanwhile, network science has seen increasing applications on modeling complex biological systems, and can be a powerful tool to elucidate the correlations of multiple human diseases. In this article, known disease-gene associations were represented using a weighted bipartite network. We extracted a weighted human diseases network from such a bipartite network to show the correlations of diseases. Subsequently, we proposed a new centrality measurement for the weighted human disease network in order to quantify the importance of diseases. Using our centrality measurement to quantify the importance of vertices in the weighted human disease network, we were able to find a set of most central diseases. By investigating the 30 top diseases and their most correlated neighbors in the network, we identified disease linkages including known disease pairs and novel findings. Our research helps better understand the common genetic origin of human diseases and suggests top diseases that likely induce other related diseases.

bioinformatics↗

bioRxiv2018

Trio deep-sequencing does not reveal unexpected mutations in Cas9-edited monkeys

CRISPR-Cas9 is a widely-used genome editing tool, but its off-target effect remains a concern, especially in view of future clinical applications. Non-human primates (NHPs) share close genetic and physiological similarities with humans, making them an ideal preclinical model for developing Cas9-based therapies. However, no comprehensive in vivo off-target assessment has been conducted in NHPs. Here we performed whole genome trio sequencing of Cas9-treated monkeys. We found they only carried a small number of de novo mutations that can be explained by expected spontaneous mutations, and no unexpected mutations were detected.

bioengineering↗

bioRxiv2018

Decoupling the impact of microRNAs on translational repression versus RNA degradation in embryonic stem cells

Translation and mRNA degradation are intimately connected, yet the mechanisms that regulate them are not fully understood. Here we studied the link between translation and mRNA stability in embryonic stem cells (ESCs). Transcripts showed a wide range of stabilities, which correlated with their translation levels. The protein DHH1 links translation to mRNA stability in yeast; however loss of the mammalian homolog, DDX6, in ESCs did not disrupt the correlation across transcripts. Instead, the loss of DDX6 led to upregulated translation of microRNA targets, without concurrent changes in mRNA stability. The Ddx6 knockout cells were phenotypically and molecularly similar to cells lacking all microRNAs (Dgcr8 knockout ESCs). These data show that the loss of DDX6 can separate the two canonical functions of microRNAs: translational repression and transcript destabilization. Furthermore, these data uncover a central role for translational repression independent of transcript destabilization in defining the downstream consequences of microRNA loss.

genetics↗

bioRxiv2018

HDAC11 Suppresses the Thermogenic Program of Adipose Tissue via BRD2

Little is known about the biological function of histone deacetylase 11 (HDAC11), which is the lone class IV HDAC. Here, we demonstrate that deletion of HDAC11 in mice stimulates brown adipose tissue (BAT) formation and beiging of white adipose tissue (WAT). Consequently, HDAC11-deficient mice exhibit dramatically enhanced thermogenic potential and, in response to high fat feeding, attenuated obesity, insulin resistance, and hepatic steatosis. Ex vivo and cell-based assays revealed that HDAC11 catalytic activity suppresses the BAT transcriptional program, in both the basal state and in response to {beta}-adrenergic receptor signaling, through a mechanism that is dependent on physical association with BRD2, a bromodomain and extraterminal (BET) acetyl-histone binding protein. These findings define a novel epigenetic pathway for the regulation of energy homeostasis, and suggest potential for HDAC11-selective inhibitors for the treatment of obesity and diabetes.

molecular biology↗

bioRxiv2018

Hemolysin liberates bacterial outer membrane vesicles for cytosolic lipopolysaccharide sensing

Inflammatory caspase-11/4/5 recognize cytosolic LPS from invading Gram-negative bacteria and induce pyroptosis and cytokine release, forming rapid innate antibacterial defenses. Since extracellular or vacuole-constrained bacteria are thought to rarely access the cytoplasm, how their LPS are exposed to the cytosolic sensors is a critical event for pathogen recognition. Hemolysin is a pore-forming bacterial toxin, which was generally accepted to rupture cell membrane, leading to cell lysis. Whether and how hemolysin participates in non-canonical inflammasome signaling remains uncovered. Here, we show that hemolysin-overexpressed enterobacteria triggered significantly increased caspase-4 activation in human intestinal epithelial cells (IECs). Hemolysin promoted LPS cytosolic delivery from extracellular bacteria through dynamin-dependent endocytosis. Further, we revealed that hemolysin was largely associated with bacterial outer membrane vesicles (OMVs) and induced rupture of OMV-containing vacuoles, subsequently increasing LPS exposure to the cytosolic sensor. Accordingly, overexpression of hemolysin promoted caspase-11 dependent IL-18 secretion, gut inflammation, and enterocyte pyroptosis in orally-infected mice, which was associated with restricting bacterial colonization in vivo. Together, our work reveals a concept that hemolysin promotes noncanonical inflammasome activation via liberating OMVs for cytosolic LPS sensing, which offers insights into innate immune surveillance of dysregulated hemolysin via caspase-11/4 in intestinal antibacterial defenses.\n\nSignificanceSensing of lipopolysaccharide (LPS) in the cytosol triggers non-canonical inflammasome-mediated innate responses. Recent work revealed that bacterial outer membrane vesicles (OMVs) enables LPS to access the cytosol for extracellular bacteria. However, since intracellular OMVs are generally constrained in endosomes, how OMV-derived LPS gain access to the cytosol remains unknown. Here, we reported that hemolysin largely bound with OMVs and entered cells through dynamin-dependent endocytosis. Intracellular hemolysin significantly impaired OMVs-constrained vacuole integrity and increased OMV-derived LPS exposure to the cytosolic sensor, which promoted non-canonical inflammasome activation and restricted bacterial gut infections. This work reveals the role of hemolysin in promoting non-canonical inflammasome activation and alerting host immune recognition, which provides insights into the more sophisticated biological functions of hemolysin upon infection.

immunology↗

bioRxiv2018

Regulation by competition: a hidden layer of gene regulatory network

Molecular competition is ubiquitous, essential and multifunctional throughout diverse biological processes. Competition brings about trade-offs of shared limited resources among the cellular components, and it thus introduce a hidden layer of regulatory mechanism by connecting components even without direct physical interactions. By abstracting the analogous competition mechanism behind diverse molecular systems, we built a unified coarse-grained competition motif model to systematically compare experimental evidences in these processes and analyzed general properties shared behind them. We could predict in what molecular environments competition would reveal threshold behavior or display a negative linear dependence. We quantified how competition can shape regulator-target dose-response curve, modulate dynamic response speed, control target expression noise, and introduce correlated fluctuations between targets. This work uncovered the complexity and generality of molecular competition effect, which might act as a hidden regulatory mechanism with multiple functions throughout biological networks in both natural and synthetic systems.

systems biology↗

bioRxiv2018

iTAP, a novel iRhom interactor, controls TNF secretion by policing the stability of iRhom/TACE

The apical inflammatory cytokine TNF regulates numerous important biological processes including inflammation and cell death, and drives inflammatory diseases. TNF secretion requires ADAM17/TACE, which cleaves TNF from its transmembrane tether, releasing it for signalling. The trafficking of ADAM17/TACE to the cell surface, and stimulation of its proteolytic activity, depends on membrane proteins, called iRhoms. To delineate how the TNF/TACE/iRhom axis is regulated, we performed an immunoprecipitation/mass spectrometry screen to identify iRhom-binding proteins. Here we report a novel protein, that we name iTAP (iRhom tail-associated protein) that binds to iRhoms, enhancing the stability of iRhoms and TACE, preventing their degradation in lysosomes. iTAP-null primary human macrophages, or tissues from iTAP KO mice, are dramatically depleted in the levels of iRhom2 and active TACE, and are, consequently, profoundly impaired in TNF production. Our work illustrates iTAP as a physiological rheostat controlling TNF signalling and a novel target for the control of inflammation.

biochemistry↗

bioRxiv2017

Forward-reverse mutation cycles between stages of cancer development

Earlier, prominent occurrences of interstitial loss-of-heterozygosities (LOHs) were found in different cancers as a type of single-nucleotide-variations (SNVs), at rates far exceeding those of the commonly investigated gain-of-heterozygosities (GOHs) type of SNVs. Herein, such co-occurrences of LOHs and GOHs were confirmed in 102 cases of four cancer types analyzed with three different next-generation sequencing platforms, comparing non-tumor, paratumor, and tumor tissues with white-blood-cell controls; and in 246 pan-cancer cases of whole-genome tumor-control pairs. Unexpectedly, large numbers of SNVs enriched with CG>TG GOHs and copy-number-variations (CNVs) proximal to these GOHs were detected in the non-tumor tissues, which were extensively reversed in paratumors showing prominent TG>CG LOHs with proximal CNVs, and less so in tumors to form forward-reverse mutation cycles. Lineage effects in the reversions, likely resulting from directional selection, supported a sequential rather than parallel mode of evolution as described in a Stage Specific Populations model of cancer development.

cancer biology↗