Biology subjects

Wu, H.

Publications and source records attributed to Wu, H..

At least 487 records · Page 27Linked to original sources

bioRxiv2020

3D Genome Analysis Identifies Enhancer Hijacking Mechanism for High-Risk Factors in Human T-Lineage Acute Lymphoblastic Leukemia

Recent studies have demonstrated that 3D genome alterations play important roles in tumorigenesis1-3, including the development of hematological malignancies4-7. However, how such alterations may provide key insights into T-lineage acute lymphoblastic leukemia (T-ALL) patients is largely unknown. Here, we report integrated analyses of 3D genome alterations and differentially expressed genes (DEGs) in 18 newly diagnosed T-ALL patients and 4 healthy T cell controls. We found that 3D genome organization at the compartment, topologically associated domains (TAD) and loop levels as well as the gene expression profiles could hierarchically classify different subtypes of T-ALL according to the T cell differentiation trajectory. Alterations in the 3D genome were associated with nearly 45% of the upregulated genes in T-ALL. We also identified 34 previously unrecognized translocations in the noncoding regions of the genome and 44 new loops formed between translocated chromosomes, including translocation-mediated enhancer hijacking of the HOXA cluster. Our analysis demonstrated that T-ALLs with HOXA cluster overexpression were heterogeneous clinical entities, and ectopic expressions of the HOXA11-A13 genes, but not other genes in the HOXA cluster, were associated with immature phenotypes and poor outcomes. Our findings highlight the potentially important roles of 3D genome alterations in the etiology and prognosis of T-ALL.

genomics↗

bioRxiv2020

Harnessing Expressed Single Nucleotide Variation and Single Cell RNA Sequencing to Define Immune Cell Chimerism in the Rejecting Kidney Transplant

In solid organ transplantation, donor derived immune cells are assumed to decline with time after surgery. Whether donor leukocytes persist within kidney transplants or play any role in rejection is unknown, however, in part because of limited techniques for distinguishing recipient and donor cells. To address this question, we performed paired whole exome sequencing of donor and recipient DNA and single cell RNA sequencing (scRNA-seq) of 5 human kidney transplant biopsy cores. Exome sequences were used to define single nucleotide variations (SNV) across all samples. By analyzing expressed SNVs in the scRNA-seq dataset we could define recipient vs. donor cell origin for all 81,139 cells. The leukocyte donor to recipient ratio varied with rejection status for macrophages and with time post-transplant for lymphocytes. Recipient macrophages were characterized by inflammatory activation and donor macrophages by antigen presentation and complement signaling. Recipient origin T cells expressed cytotoxic and pro-inflammatory genes consistent with an effector cell phenotype whereas donor origin T cells are likely quiescent expressing oxidative phosphorylation genes relative to recipient T cells. Finally, both donor and recipient T cell clones were present within the rejecting kidney, suggesting lymphoid aggregation. Our results indicate that donor origin macrophages and T cells have distinct transcriptional profiles compared to their recipient counterparts and donor macrophages can persist for years post transplantation. This study demonstrates the power of this approach to accurately define leukocyte chimerism in a complex tissue such as the kidney transplant coupled with the ability to examine transcriptional profiles at single cell resolution.

genomics↗

bioRxiv2020

Single nucleus RNASeq profiling of mouse lung: reduced dissociation bias and improved detection of rare cell types compared with single cell RNASeq

RATIONALESingle cell RNA-sequencing (scRNASeq) has led to multiple recent advances in our understanding of lung biology and pathophysiology, but utility is limited by the need for fresh samples, loss of cell types due to death or inadequate dissociation, and the induction of transcriptional stress responses during tissue digestion. Single nucleus RNASeq (snRNASeq) has addressed these deficiencies in some other tissues, but no protocol exists for lung. We sought to develop such a protocol and compare its results with scRNA-seq. METHODSSingle nucleus suspensions were prepared rapidly (45 min) from two mouse lungs in lysis buffer on ice while a single cell suspension from an additional mouse lung was generated using a combination of enzymatic and mechanical dissociation (1.5 h). Cells and nuclei were processed using the 10x Genomics platform, and following sequencing of cDNA libraries single cell data was analyzed by Seurat. RESULTS16,656 single nucleus and 11,934 single cell transcriptomes were generated. Despite reduced mRNA levels in nuclei vs. cells, gene detection rates were equivalent in snRNASeq and scRNASeq ([~]1,750 genes and 3,000 UMI per cell) when mapping intronic and exonic reads. snRNASeq identified a much greater proportion of epithelial cells than scRNASeq (46% vs 2% of total), including basal and neuroendocrine cells, while reducing immune cells from 54% to 15%. snRNASeq transcripts are enriched for transcription factors and signaling proteins, with reduced detection of housekeeping genes, mitochondrial genes, and artifactual stress response genes. Both techniques improved mesenchymal cell detection over previous studies, and analysis of fibroblast diversity showed two transcriptionally distinct populations of Col13a1+ cells, termed Bmper+ and Brinp1+ fibroblasts. To define homeostatic signaling relationships among cell types, receptor-ligand mapping of was performed for alveolar compartment cells using snRNASeq data, revealing complex interplay among epithelial, mesenchymal, and capillary endothelial cells. CONCLUSIONSingle nucleus RNASeq can be readily applied to snap frozen, archival murine lung samples, improves dissociation bias, eliminates artifactual gene expression and provides similar gene detection compared to scRNASeq.

genomics↗

bioRxiv2020

Genome-wide identification of binding sites of GRHL2 in luminal-like and basal A subtypes of breast cancer

Grainyhead like 2 (GRHL2) is one of three mammalian homologues of the grainyhead (GRH) gene. It suppresses the oncogenic epithelial-mesenchymal transition (EMT), acting as a tumor suppressor. On the other hand, GHRL2 promotes cell proliferation by increasing human telomerase reverse transcriptase (hTERT) activity, serving as a tumor promoter. According to gene expression profiling, breast cancer can be divided into basal-like (basal A and basal B), luminal-like, HER2 enriched, claudin-low and normal-like subtypes. To identify common and subtype-specific genomic binding sites of GRHL2 in breast cancer, GRHL2 ChIP-seq was performed in three luminal-like and three basal A human breast cancer cell lines. Most binding sites of GRHL2 were found in intergenic and intron regions. 13,351 common binding sites were identified in basal A cells, which included 551 binding sites in gene promoter regions. For luminal-like cells, 6,527 common binding sites were identified, of which 208 binding sites were found in gene promoter regions. Basal A and luminal-like breast cancer cells shared 4711 GRHL2 binding sites, of which 171 binding sites were found in gene promoter regions. The identified GRHL2-binding motifs are all identical to a motif reported for human ovarian cancer, indicating conserved GRHL2 DNA-binding among human cancer cells. Notably, no binding sites of GRHL2 were detected in the promoter regions of several established EMT-related genes, including CDH1, ZEB1, ZEB2 and CDH2 genes. Collectively, this study provides a comprehensive overview of interactions of GRHL2 with DNA and lays the foundation for further understanding of common and subtype-specific signaling pathways regulated by GRHL2 in breast cancer.

cancer biology↗

bioRxiv2020

The Degradation-promoting Roles of Deubiquitinases Ubp6 and Ubp3 in Cytosolic and ER Protein Quality Control

The quality control of intracellular proteins is achieved by degrading misfolded proteins which cannot be refolded by molecular chaperones. In eukaryotes, such degradation is handled primarily by the ubiquitin-proteasome system. However, it remains unclear whether and how protein quality control deploys various deubiquitinases. To address this question, we screened deletions or mutation of the 20 deubiquitinase genes in Saccharomyces cerevisiae and discovered that almost half of the mutations slowed the removal of misfolded proteins whereas none of the remaining mutations accelerated this process significantly. Further characterization revealed that Ubp6 maintains the level of free ubiquitin to promote the elimination of misfolded cytosolic proteins, while Ubp3 supports the degradation of misfolded cytosolic and ER luminal proteins by different mechanisms.

cell biology↗

bioRxiv2020

Hesperetin inhibits foam cell formation in macrophages via activating LXRα signal in an AMPK dependent manner

Cholesterol efflux from macrophages is the first step of cholesterol reverse transport (RCT), whose increase inhibits cholesterol accumulation and foam cell formation to suppress atherogenesis. Liver X receptor alpha (LXR) and adenosine monophosphate activated protein kinases (AMPK) both have the pivotal role in cholesterol homeostasis. However the association between these two molecules in cell model of atherosclerosis is poorly understood. Hesperetin has been reported to possess several protective effects for cardiovascular diseases, while little is known about the role of hesperetin and its underlying mechanism on macrophage foam cell formation. In this study, we sought to investigate the potential effects of hesperetin in cholesterol efflux by using human macrophage derived foam cells, focusing on liver X receptor alpha (LXR) and adenosine monophosphate activated protein kinases (AMPK) implication. Hesperetin treatment concentration-dependently reduced foam cell formation, intracellular cholesterol level and cholesterol esterification rate, and enhanced cholesterol efflux in THP-1 macrophages. Hesperetin upregulated the protein levels of LXR and its targets including ABCA1, ABCG1 as well as SR-BI, and phosphorylated-AMPK. Meanwhile, hesperetin-induced upregulation of LXR expression was enhanced by AMPK agonist and inhibited by AMPK inhibitor. Furthermore, hesperetin increased mRNA level of LXR and its target genes, all which were depressed by AMPK1/2 small interfering RNA (siRNA) transfection. In conclusion, we founded for the first time that hesperetin could active AMPK. And this activation upregulated LXR and its targets including ABCA1, ABCG1 and SR-BI, which significantly inhibited foam cell formation and promoted cholesterol efflux in THP-1 macrophages. Our results highlight the therapeutic potential of hespretin for the possible reduction in foam cell formation. This new mechanism could contribute the anti-atherogenic effects of hesperetin.

pharmacology and toxicology↗

bioRxiv2020

Electron Microscopic Reconstruction of Neural Circuitry in the Cochlea

Recent studies have revealed great diversity in the structure, function and efferent innervation of afferent synaptic connections between the cochlear inner hair cells (IHCs) and spiral ganglion neurons (SGNs), which likely enables audition to process a wide range of sound pressures. By performing an extensive electron microscopic reconstruction of the neural circuitry in the mature mouse organ of Corti, we demonstrate that afferent SGN-dendrites differ in strength and composition of efferent innervation in a manner dependent on their afferent synaptic connectivity with IHCs. SGNs that sample glutamate release from several presynaptic ribbons receive more efferent innervation from lateral olivocochlear projections than those driven by a single ribbon. Next to the prevailing unbranched SGN-dendrites, we found branched SGN-dendrites that can contact several ribbons of 1-2 IHCs. Unexpectedly, medial olivocochlear neurons provide efferent innervation of SGN-dendrites, preferring those contacting single-ribbon, pillar-side synapses. We propose a fine-tuning of afferent and efferent SGN-innervation.

neuroscience↗

bioRxiv2020

A CSB-PAF1C axis restores processive transcription elongation after DNA damage repair

The coordinated transcription of genes involves the regulated release of RNA polymerase II (RNAPII) from promoter-proximal sites into active elongation. DNA lesions in transcribed strands block elongation and induce a strong transcriptional arrest. The transcription-coupled repair (TCR) pathway efficiently removes transcription-blocking DNA lesions, but this is not sufficient to resume transcription. Through proteomics screens, we find that the TCR-specific CSB protein loads the evolutionary conserved PAF1 complex (PAF1C) onto RNAPII in promoter-proximal regions in response to DNA damage. PAF1C is dispensable for TCR-mediated repair, but is essential for recovery of RNA synthesis after UV irradiation, suggesting an uncoupling between DNA repair and transcription recovery. Moreover, we find that PAF1C promotes RNAPII pause release in promoter-proximal regions and subsequently acts as a processivity factor that stimulates transcription elongation throughout genes. Our findings expose the molecular basis for a non-canonical PAF1C-dependent pathway that restores transcription throughout the human genome after genotoxic stress.

cell biology↗

bioRxiv2019

Massively parallel, time-resolved single-cell RNA sequencing with scNT-Seq

Single-cell RNA sequencing offers snapshots of whole transcriptomes but obscures the temporal dynamics of RNA biogenesis and decay. Here we present single-cell new transcript tagging sequencing (scNT-Seq), a method for massively parallel analysis of newly-transcribed and pre-existing RNAs from the same cell. This droplet microfluidics-based method enables high-throughput chemical conversion on barcoded beads, efficiently marking metabolically labeled newly-transcribed RNAs with T-to-C substitutions. By simultaneously measuring new and old transcriptomes, scNT-Seq reveals neuronal subtype-specific gene regulatory networks and time-resolved RNA trajectories in response to brief (minutes) versus sustained (hours) neuronal activation. Integrating scNT-Seq with genetic perturbation reveals that DNA methylcytosine dioxygenases may inhibit stepwise transition from pluripotent embryonic stem cell state to intermediate and totipotent two-cell-embryo-like (2C-like) states by promoting global RNA biogenesis. Furthermore, pulse-chase scNT-Seq enables transcriptome-wide measurements of RNA stability in rare 2C-like cells. Time-resolved single-cell transcriptomic analysis thus opens new lines of inquiry regarding cell-type-specific RNA regulatory mechanisms.

genomics↗

bioRxiv2019

Dissecting molecular regulatory mechanisms underlying noncoding susceptibility SNPs associated with 19 autoimmune diseases using multi-omics integrative analysis

The genome-wide association studies (GWAS) have identified hundreds of susceptibility loci associated with autoimmune diseases. However, over 90% of risk variants are located in the noncoding regions, leading to great challenges in deciphering the underlying causal functional variants/genes and biological mechanisms. Previous studies focused on developing new scoring method to prioritize functional/disease-relevant variants. However, they principally incorporated annotation data across all cells/tissues while omitted the cell-specific or context-specific regulation. Moreover, limited analyses were performed to dissect the detailed molecular regulatory circuits linking functional GWAS variants to disease etiology. Here we devised a new analysis frame that incorporate hundreds of immune cell-specific multi-omics data to prioritize functional noncoding susceptibility SNPs with gene targets and further dissect their downstream molecular mechanisms and clinical applications for 19 autoimmune diseases. Most prioritized SNPs have genetic associations with transcription factors (TFs) binding, histone modification or chromatin accessibility, indicating their allelic regulatory roles on target genes. Their target genes were significantly enriched in immunologically related pathways and other immunologically related functions. We also detected long-range regulation on 90.7% of target genes including 132 ones exclusively regulated by distal SNPs (eg, CD28, IL2RA), which involves several potential key TFs (eg, CTCF), suggesting the important roles of long-range chromatin interaction in autoimmune diseases. Moreover, we identified hundreds of known or predicted druggable genes, and predicted some new potential drug targets for several autoimmune diseases, including two genes (NFKB1, SH2B3) with known drug indications on other diseases, highlighting their potential drug repurposing opportunities. In summary, our analyses may provide unique resource for future functional follow-up and drug application on autoimmune diseases, which are freely available at http://fngwas.online/. Author SummaryAutoimmune diseases are groups of complex immune system disorders with high prevalence rates and high heritabilities. Previous studies have unraveled thousands of SNPs associated with different autoimmune diseases. However, it remains largely unknown on the molecular mechanisms underlying these genetic associations. Striking, over 90% of risk SNPs are located in the noncoding region. By leveraging multiple immune cell-specific multi-omics data across genomic, epigenetic, transcriptomic and 3D chromatin interaction information, we systematically analyzed the functional variants/genes and biological mechanisms underlying genetic association on 19 autoimmune diseases. We found that most functional SNPs may affect target gene expression through altering transcription factors (TFs) binding, histone modification or chromatin accessibility. Most target genes had known immunological functions. We detected prevailing long-range chromatin interaction linking distal functional SNPs to target genes. We also identified many known drug targets and predicted some new drug target genes for several autoimmune diseases, suggesting their potential clinical applications. All analysis results and tools are available online, which may provide unique resource for future functional follow-up and drug application. Our study may help reduce the gap between traditional genetic findings and biological mechanistically exploration of disease etiologies as well as clinical drug development.

immunology↗

bioRxiv2019

BTK operates a phospho-tyrosine switch to regulate NLRP3 inflammasome activity

Activity of the NLRP3 inflammasome, a critical mediator of inflammation (1), is controlled by accessory proteins (2, 3), post-translational modifications (4, 5), cellular localization (6, 7) and oligomerization (8). How these factors relate, is unclear. We show that the established drug target, Brutons Tyrosine Kinase (BTK) (2, 9), integrates several levels of NLRP3 regulation: BTK phosphorylation of four conserved tyrosine residues, by neutralizing the charge of a polybasic linker region, weakens the interaction of NLRP3 with Golgi phospholipids and may thus guide NLRP3 cytosolic localization. BTK activity also promotes NLRP3 oligomerization and subsequent formation of inflammasomes. As NLRP3 tyrosine modification ultimately also impacts on IL-1{beta} release, we propose BTK-mediated, charge-switch-based NLRP3 regulation as a novel and therapeutically tractable step in the control of inflammation. One Sentence SummaryMulti-phosphorylation of NLRP3 by Brutons tyrosine kinase modulates NLRP3 cellular localization, inflammasome assembly, and IL-1{beta} release.

immunology↗

bioRxiv2019

Zbtb24 binding protects promoter activity by antagonizing DNA methylation in mESCs

DNA methylation is a key epigenetic modification essential for normal development. How particular factors control DNA methylation patterns and activity of a given locus is incompletely understood. The zinc finger protein Zbtb24 has been implicated in transcriptional activation/repression and the DNA methylation maintenance pathway. Here, using whole genome bisulfite sequencing in mouse embryonic stem cells, we report that besides a general trend towards DNA hypomethylation, many genomic sites gain methylation in the absence of Zbtb24 and they include promoters of actively transcribed genes. DNA hypomethylation is not generally associated with gene expression changes, suggesting that additional epigenetic safeguards are in place that ensure silencing of the affected loci. Remarkably, we identify a set of genes that is particularly susceptible to Zbtb24 occupancy. At these sites, Zbtb24 binding is not only required for gene activity but also required for maintaining the unmethylated state of the promoter.

molecular biology↗

bioRxiv2019

Nick-seq for single-nucleotide resolution genomic maps of DNA modifications and damage

Here we present the Nick-seq platform for quantitative mapping of DNA modifications and damage at single-nucleotide resolution across genomes. Pre-existing breaks are blocked and DNA structures converted to strand-breaks for 3-extension by nick-translation to produce nuclease-resistant oligonucleotides, and 3-capture by terminal transferase tailing. Libraries from both products are subjected to next-generation sequencing. Nick-seq is a generally applicable method illustrated with quantitative profiling of single-strand-breaks, phosphorothioate modifications, and DNA oxidation.

molecular biology↗

bioRxiv2019

Effect of the divalent cations zinc and calcium on the structure and mechanics of reconstituted vimentin intermediate filaments

Divalent cations in a concentration-dependent manner behave as effective crosslinkers of intermediate filaments (IFs) such as vimentin IF (VIF). These interactions have been mostly attributed to their multivalency. However, ion-protein interactions often depend on the ion species, and these effects have not been widely studied in IFs. Here we investigate the effects of two biologically important divalent cations, Zn2+ and Ca2+, on VIF network structure and mechanics in vitro. We find that the network structure is unperturbed at micromolar Zn2+ concentrations, but strong bundle formation is observed at a concentration of 100 M. Microrheological measurements show that network stiffness increases with cation concentration. However, bundling of filaments softens the network. This trend also holds for VIF networks formed in the presence of Ca2+, but remarkably, a concentration of Ca2+ that is two orders higher is needed to achieve the same effect as with Zn2+, which suggests the importance of salt-protein interactions as described by the Hofmeister effect. Furthermore, we find evidence of competitive binding between the two divalent ion species. Hence, specific interactions between VIFs and divalent cations are likely to be an important mechanism by which cells can control their cytoplasmic mechanics. SignificanceIntermediate filaments are key structural elements within cells; they are known to form networks that can be crosslinked by divalent cations, but the interactions between the ions and the filaments are not well understood. By measuring the effects that two divalent cations, zinc and calcium, have on the structure and mechanics of vimentin intermediate filaments (VIFs), we show that although both have concentration-dependent effects on VIFs, much more calcium is needed to achieve the same effect as a small amount of zinc. Furthermore, when mixtures of the ions are present, the results suggest that there is binding competition. Thus, cells may use the presence of different cation species to precisely control their internal mechanical properties.

biophysics↗

bioRxiv2019

GSMN-ML- a genome scale metabolic network reconstruction of the obligate human pathogen Mycobacterium leprae

Leprosy, caused by Mycobacterium leprae, has plagued humanity for thousands of years and continues to cause morbidity, disability and stigmatization in two to three million people today. Although effective treatment is available, the disease incidence has remained approximately constant for decades so new approaches, such as vaccine or new drugs, are urgently needed for control. Research is however hampered by the pathogens obligate intracellular lifestyle and the fact that it has never been grown in vitro. Consequently, despite the availability of its complete genome sequence, fundamental questions regarding the biology of the pathogen, such as its metabolism, remain largely unexplored. In order to explore the metabolism of the leprosy bacillus with a long-term aim of developing a medium to grow the pathogen in vitro, we reconstructed an in silico genome scale metabolic model of the bacillus, GSMN-ML. The model was used to explore the growth and biomass production capabilities of the pathogen with a range of nutrient sources, such as amino acids, glucose, glycerol and metabolic intermediates. We also used the model to analyze RNA-seq data from M. leprae grown in mouse foot pads, and performed Differential Producibility Analysis (DPA) to identify metabolic pathways that appear to be active during intracellular growth of the pathogen, which included pathways for central carbon metabolism, co-factor, lipids, amino acids, nucleotides and cell wall synthesis. The GSMN-ML model is thereby a useful in silico tool that can be used to explore the metabolism of the leprosy bacillus, analyze functional genomic experimental data, generate predictions of nutrients required for growth of the bacillus in vitro and identify novel drug targets.\n\nAuthor SummaryMycobacterium leprae, the obligate human pathogen is uncultivable in axenic growth medium, and this hinders research on this pathogen, and the pathogenesis of leprosy. The development of novel therapeutics relies on the understanding of growth, survival and metabolism of this bacterium in the host, the knowledge of which is currently very limited. Here we reconstructed a metabolic network of M. leprae-GSMN-ML, a powerful in silico tool to study growth and metabolism of the leprosy bacillus. We demonstrate the application of GSMN-ML to identify the metabolic pathways, and metabolite classes that M. leprae utilizes during intracellular growth.

microbiology↗

bioRxiv2019

ER stress sensor Ire1 deploys a divergent transcriptional program in response to lipid bilayer stress

Membrane integrity at the endoplasmic reticulum (ER) is tightly regulated and is implicated in metabolic diseases when compromised. Using an engineered sensor that exclusively activates the unfolded protein response (UPR) during aberrant ER membrane lipid composition, we identified pathways beyond lipid metabolism that are necessary to maintain ER integrity in yeast and are conserved in C. elegans. To systematically validate yeast mutants disrupting ER membrane homeostasis, we identified a lipid bilayer stress (LBS) sensing switch in the UPR transducer protein Ire1, located at the interface of the amphipathic and transmembrane helices. Furthermore, transcriptome and chromatin immunoprecipitation (ChIP) analyses pinpoint the UPR as a broad-spectrum compensatory pathway in which LBS and proteotoxic stress-induced UPR deploy divergent transcriptional programs. Together, these findings reveal the UPR program as the sum of two independent stress events and could be exploited for future therapeutic intervention.

cell biology↗

bioRxiv2019

Cross-disorder GWAS meta-analysis for Attention Deficit/Hyperactivity Disorder, Autism Spectrum Disorder, Obsessive Compulsive Disorder, and Tourette Syndrome

Attention Deficit/Hyperactivity Disorder (ADHD), Autism Spectrum Disorder (ASD), Obsessive-Compulsive Disorder (OCD), and Tourette Syndrome (TS) are among the most prevalent neurodevelopmental psychiatric disorders of childhood and adolescence. High comorbidity rates across these four disorders point toward a common etiological thread that could be connecting them across the repetitive behaviors-impulsivity-compulsivity continuum. Aiming to uncover the shared genetic basis across ADHD, ASD, OCD, and TS, we undertake a systematic cross-disorder meta-analysis, integrating summary statistics from all currently available genome-wide association studies (GWAS) for these disorders, as made available by the Psychiatric Genomics Consortium (PGC) and the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH). We present analysis of a combined dataset of 93,294 individuals, across 6,788,510 markers and investigate associations on the single-nucleotide polymorphism (SNP), gene and pathway levels across all four disorders but also pairwise. In the ADHD-ASD-OCD-TS cross disorder GWAS meta-analysis, we uncover in total 297 genomewide significant variants from six LD (linkage disequilibrium) -independent genomic risk regions. Out of these genomewide significant association results, 199 SNPs, that map onto four genomic regions, show high posterior probability for association with at least three of the studied disorders (m-value>0.9). Gene-based GWAS meta-analysis across ADHD, ASD, OCD, and TS identified 21 genes significantly associated under Bonferroni correction. Out of those, 15 could not be identified as significantly associated based on the individual disorder GWAS dataset, indicating increased power in the cross-disorder comparisons. Cross-disorder tissue-specificity analysis implicates the Hypothalamus-Pituitary-Adrenal axis (stress response) as possibly underlying shared pathophysiology across ADHD, ASD, OCD, and TS. Our work highlights genetic variants and genes that may contribute to overlapping neurobiology across the four studied disorders and highlights the value of re-defining the framework for the study across this spectrum of highly comorbid disorders, by using transdiagnostic approaches.

genetics↗

bioRxiv2019

TRIM21 and PHLDA3 Negatively Regulate the Cross-Talk between the PI3K/AKT Pathway and PPP Metabolism

PI3K/AKT signaling is known to regulate cancer metabolism but whether metabolic pathway feedbacks and regulates the PI3K/AKT pathway is unclear. Here, we demonstrate the important reciprocal cross-talks between the PI3K/AKT signal and PPP branching metabolic pathways. PI3K/AKT activation stabilizes G6PD, the rate-limiting enzyme of PPP, by inhibiting a newly identified E3 ligase TIRM21, and promotes PPP. PPP metabolites, in turn, reinforce AKT activation and further promote cancer metabolic reprogramming by blocking the expression of an AKT inhibitor PHLDA3. Knockout TRIM21 or PHLDA3 promotes the cross-talks and cell proliferation. Importantly, PTEN null human cancer cells and in vivo murine models are sensitive to anti-PPP treatments, suggesting the importance of PPP in maintaining AKT activation even in the presence of a constitutively activated PI3K pathway. Our study suggests that blockade of these reciprocal cross-talks may have a therapeutic benefit for cancers with PTEN loss or PI3K/AKT activation.

cancer biology↗