Biology subjects

Yao, C.

Publications and source records attributed to Yao, C..

At least 55 records · Page 3Linked to original sources

bioRxiv2022

A genetically encoded tool to increase cellular NADH/NAD+ ratio in living cells

Impaired reduction/oxidation (redox) metabolism is a key contributor to the etiology of many diseases, including primary mitochondrial disorders, cancer, neurodegeneration, and aging. However, mechanistic studies of redox imbalance remain challenging due to limited strategies which can perturb cellular redox metabolism and model pathology in various cellular, tissue, or organismal backgrounds without creating additional and potentially confounding metabolic perturbations. To date, most studies involving impaired redox metabolism have focused on oxidative stress and reactive oxygen species (ROS) production; consequently, less is known about the settings where there is an overabundance of reducing equivalents, termed reductive stress. NADH reductive stress has been modeled using pharmacologic inhibition of the electron transport chain (ETC) and ethanol supplementation. Still, both these methods have significant drawbacks. Here, we introduce a soluble transhydrogenase from E. coli (EcSTH) as a novel genetically encoded tool to promote NADH overproduction in living cells. When expressed in mammalian cells, EcSTH, and a mitochondrially-targeted version (mitoEcSTH), can elevate the NADH/NAD+ ratio in a compartment-specific manner. Using this tool, we determine the metabolic and transcriptomic signatures of NADH reductive stress in mammalian cells. We also find that cellular responses to NADH reductive stress, including blunted proliferation, are dependent on cellular background and identify the metabolic reactions that sense changes in the cellular NADH/NAD+ balance. Collectively, our novel genetically encoded tool represents an orthogonal strategy to perturb redox metabolism and characterize the impact on normal physiology and disease states.

bioengineering↗

bioRxiv2022

MHA, an interactive website for scRNA-seq data of male genitourinary development and disease

The development of single-cell sequencing technology has expanded the understanding of cell heterogeneity and disease progression in the male genitourinary system. However, complex processing processes and unprofessional analytical annotations limit the daily use and wildly sharing of published datasets. Here, we describe the Male Health Atlas (MHA), an easy-to-operate online visual website focused on the male genitourinary system, allowing researchers to quickly search for expression patterns of one or multiple genes, and dynamic changes of gene expression during tissue development or under pathological states. At present, the MHA includes nine objects, two species, five types of male genitourinary tissues/organs, and 258,777 single-cell profiles. Compared with other single-cell databases, the MHA has the following advantages: (1) It is easy to operate, and users can complete retrieval and output of results within 5 min without any bioinformatics skills; (2) The selection and analysis of data are under professional supervision of researchers in the male genitourinary field; (3) It contains most of the main male-specific organs and will continue to be updated; (4) MHA provides multi-dimensional output patterns, including tSNE/UMAP, violin, and bubble plot output for displaying single or multiple genes. MHA is the first single-cell database website in the field of andrology and male reproduction, providing researchers with scRNA-seq resources and an accessible tool. MHA is freely available at http://malehealthatlas.cn/.

molecular biology↗

bioRxiv2022

Identification of genetic loci in lettuce mediating quantitative resistance to fungal pathogens

Lactuca sativa L. (lettuce) is an important leafy vegetable crop grown and consumed globally. Chemicals are routinely used to control major pathogens, including the causal agents of grey mould (Botrytis cinerea) and lettuce drop (Sclerotinia sclerotiorum). With increasing prevalence of pathogen resistance to fungicides and environmental concerns, there is an urgent need to identify sources of genetic resistance to B. cinerea and S. sclerotiorum in lettuce. We demonstrated genetic variation for quantitative resistance to B. cinerea and S. sclerotiorum in a set of 97 diverse lettuce and wild relative accessions, and between the parents of lettuce mapping populations. Transcriptome profiling across multiple lettuce accessions enabled us to identify genes with expression correlated with resistance, predicting the importance of post-transcriptional gene regulation in the lettuce defence response. We identified five genetic loci influencing quantitative resistance in a F10 mapping population derived from a Lactuca serriola (wild relative) x lettuce cross, which each explained 5-10% of the variation. Differential gene expression analysis between the parent lines, and integration of data on correlation of gene expression and resistance in the diversity set, highlighted potential causal genes underlying the quantitative trait loci. Key MessageWe demonstrate genetic variation for quantitative resistance against important fungal pathogens in lettuce and its wild relatives, map loci conferring resistance and predict key molecular mechanisms using transcriptome profiling.

plant biology↗

bioRxiv2022

Impact of cell culture on the transcriptomic programs of primary and iPSC-derived human alveolar type 2 cells

The alveolar epithelial type 2 cell (AEC2) is the facultative progenitor of lung alveoli tasked to maintain distal lung homeostasis. AEC2 dysfunction has been implicated in the pathogenesis of a number of pulmonary diseases, including idiopathic pulmonary fibrosis (IPF), highlighting the importance of human in vitro models of the alveolar epithelium. However, AEC2-like cells captured in cell culture have yet to be directly compared to their in vivo counterparts at single cell resolution. Here, we apply single cell RNA sequencing to perform head-to-head comparisons between the global transcriptomes of freshly isolated primary (1{degrees}) adult human AEC2s, their isogenic cultured progeny, and human iPSC-derived AEC2s (iAEC2s) cultured in identical conditions. We find each population occupies a distinct transcriptomic space with both types of cultured AEC2s (1{degrees} and iAEC2s) exhibiting similarities to and differences from freshly purified 1{degrees} cells. Across each cell type, we find an inverse relationship between proliferative states and AEC2 maturation states, with uncultured 1{degrees} AEC2s being most quiescent and mature, their cultured progeny being more proliferative/less mature, and cultured iAEC2s being most proliferative/least mature. iAEC2s also express significantly lower levels of major histocompatibility complex (MHC) genes compared to 1{degrees} cells, suggesting immunological immaturity. Cultures of either type of human AEC2 (1{degrees} or iAEC2) do not generate detectable type 1 alveolar cells in these defined conditions; however, iAEC2s after co-culture with fibroblasts can give rise to a subset of cells expressing "transitional cell markers" recently described in fibrotic lung tissue of patients with pulmonary fibrosis or in mouse models of pulmonary fibrosis. Hence, we provide direct comparisons of the transcriptomic programs of 1{degrees} and engineered AEC2s, two in vitro model systems that can be harnessed for studies of human lung health and disease.

cell biology↗

bioRxiv2022

Single cell sequencing reveals microglia induced angiogenesis by specific subsets of endothelial cells following spinal cord injury

Spinal cord injury (SCI) results in dynamic alterations of the microenvironment at the lesion site, which inevitably leads to neuron degeneration and functional deficits. The prominent deterioration of the milieu, derived from the destruction of spinal vascular system, not only activates innate immunity but also makes cells in the lesion lose nutrient supports. Limited endogenous angiogenesis happens after SCI, but the cell events at the lesion site underpinning this process have not been delineated so far. Here, we conducted single-cell RNA sequencing (scRNA-seq) of tissues in the spinal lesion at different time points after rat SCI. After performing clustering and cell-type identification, we focused on the vascular endothelial cells (ECs), which play a pivot role in angiogenesis, and drew a comprehensive cellular and molecular atlas for endogenous angiogenesis after SCI. We found that microglia and macrophage promote endogenous angiogenesis by regulating EC subsets through SPP1 and IGF1 signal pathways. Our results indicated that immune cells promotes angiogenesis by the regulation of specific cell subsets of vascular ECs, which provides new clues for the development of interventions for SCI.

neuroscience↗

bioRxiv2021

Metabolic regulation by prostaglandin E2 impairs lung group 2 innate lymphoid cell responses

Group 2 innate lymphoid cells (ILC2s) play a critical role in asthma pathogenesis. Non-steroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NERD) is associated with reduced signaling via EP2, a receptor for prostaglandin E2 (PGE2). However, the respective roles for the PGE2 receptors EP2 and EP4 (both share same downstream signaling) in the regulation of lung ILC2 responses has yet been deciphered. Here, we find that deficiency of EP2 rather than EP4 augments IL-33-induced lung ILC2 responses and eosinophilic inflammation in vivo. In contrast, exogenous agonism of EP4 but not EP2 markedly restricts IL-33- and Alternaria alternata-induced lung ILC2 responses and eosinophilic inflammation. Mechanistically, PGE2 directly suppresses IL-33-dependent ILC2 activation through the EP2/EP4-cAMP pathway, which downregulates STAT5 and MYC pathway gene expression and ILC2 energy metabolism. Blocking glycolysis diminishes IL-33-dependent ILC2 responses in mice lacking endogenous PG synthesis but not in PG-competent mice. Together, we have defined a mechanism for optimal suppression of lung ILC2 responses by endogenous PGE2-EP2 signaling which underpins the clinical findings of defective EP2 signaling in patients with NERD. Our findings also indicate that exogenously targeting the PGE2-EP4-cAMP and energy metabolic pathways may provide novel opportunities for treating ILC2-initiated lung inflammation in asthma and NERD. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=178 SRC="FIGDIR/small/474031v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@17dd2caorg.highwire.dtl.DTLVardef@199ce97org.highwire.dtl.DTLVardef@ca1f67org.highwire.dtl.DTLVardef@1d3a49f_HPS_FORMAT_FIGEXP M_FIG C_FIG Schematic of potential roles for activation of EP2 and EP4 by endogenous versus exogenous ligands in regulation of lung ILC2 immune responses. Endogenous PGE2 in the lung preferentially activates EP2 rather than EP4 to inhibit ILC2 responses and eosinophilic inflammation, and ablation of EP2 enhances lung ILC2 responses. Conversely, lung ILC2 responses are not altered by EP4 deficiency. However, they are markedly inhibited by EP4 agonism but not EP2 agonism. Mechanistically, PGE2-EP2/EP4 signaling activates the cAMP pathway which inhibits ILC2 energy metabolism, possibly through interruption of NF-{kappa}B (reported in Nagashima H, et al. Immunity 2019;51:682-695) and STAT5 signaling, leading to decline of ILC2 survival, proliferation and type 2 cytokine production.

immunology↗

bioRxiv2021

CFIm25 regulates human stem cell function independently of its role in mRNA alternative polyadenylation

It has recently been shown that CFIm25, a canonical mRNA 3 processing factor, could play a variety of physiological roles through its molecular function in the regulation of mRNA alternative polyadenylation (APA). Here, we used CRISPR/Cas9-mediated gene editing approach in human embryonic stem cells (hESCs) for CFIm25, and obtained three gene knockdown/mutant cell lines. CFIm25 gene editing resulted in higher proliferation rate and impaired differentiation potential for hESCs, with these effects likely to be directly regulated by the target genes, including the pluripotency factor rex1. Mechanistically, we unexpected found that perturbation in CFIm25 gene expression did not significantly affect cellular mRNA 3 processing efficiency and APA profile. Rather, we provided evidences that CFIm25 may impact RNA polymerase II (RNAPII) occupancy at the body of transcribed genes, and promote the expression level of a group of transcripts associated with cellular proliferation and/or differentiation. Further study indicated that CFIm25 association with LEO1, an RNAPII associated factor, might contribute to the effect. Taken together, these results reveal novel mechanisms underlying CFIm25s modulation in determination of cell fate, and provide evidence that the process of mammalian gene transcription may be regulated by an mRNA 3 processing factor.

molecular biology↗

bioRxiv2021

Subfamily-specific differential contribution of individual monomers and the tether sequence to mouse L1 promoter activity

BackgroundThe internal promoter in L1 5UTR is critical for autonomous L1 transcription and initiating retrotransposition. Unlike the human genome, which features one contemporarily active subfamily, four subfamilies (A_I, Gf_I and Tf_I/II) have been amplifying in the mouse genome in the last one million years. Moreover, mouse L1 5UTRs are organized into tandem repeats called monomers, which are separated from ORF1 by a tether domain. In this study, we aim to compare promoter activities across young mouse L1 subfamilies and investigate the contribution of individual monomers and the tether sequence. ResultsWe observed an inverse relationship between subfamily age and the average number of monomers among evolutionarily young mouse L1 subfamilies. The youngest subgroup (A_I and Tf_I/II) on average carry 3-4 monomers in the 5UTR. Using a single-vector dual-luciferase reporter assay, we compared promoter activities across six L1 subfamilies (A_I/II, Gf_I and Tf_I/II/III) and established their antisense promoter activities in a mouse embryonic fibroblast cell line. Using consensus promoter sequences for three subfamilies (A_I, Gf_I and Tf_I), we dissected the differential roles of individual monomers and the tether domain in L1 promoter activity. We validated that, across multiple subfamilies, the second monomer consistently enhances the overall promoter activity. For individual promoter components, monomer 2 is consistently more active than the corresponding monomer 1 and/or the tether for each subfamily. Importantly, we revealed intricate interactions between monomer 2, monomer 1 and tether domains in a subfamily-specific manner. Furthermore, using three-monomer 5UTRs, we established a complex nonlinear relationship between the length of the outmost monomer and the overall promoter activity. ConclusionsThe laboratory mouse is an important mammalian model system for human diseases as well as L1 biology. Our study extends previous findings and represents an important step toward a better understanding of the molecular mechanism controlling mouse L1 transcription as well as L1s impact on development and disease.

genomics↗

bioRxiv2021

Cryobanking of human distal lung epithelial cells for preservation of their phenotypic and functional characteristics.

The epithelium lining airspaces of the human lung is maintained by regional stem cells including basal cells of pseudostratified airways and alveolar type 2 pneumocytes (AT2) of the alveolar gas-exchange region. Despite effective methods for long-term preservation of airway basal cells, methods for efficient preservation of functional epithelial cell types of the distal gas-exchange region are lacking. Here we detail a method for cryobanking of epithelial cells from either mouse or human lung tissue for preservation of their phenotypic and functional characteristics. Flow cytometric profiling, epithelial organoid-forming efficiency, and single cell transcriptomic analysis, were used to compare cells recovered from cryopreserved tissue with those of freshly dissociated tissue. Alveolar type 2 cells within single cell suspensions of enzymatically digested cryobanked distal lung tissue retained expression of the pan-epithelial marker CD326 and the AT2 cell surface antigen recognized by monoclonal antibody HTII-280, allowing antibody-mediated enrichment and downstream analysis. Isolated AT2 cells from cryobanked tissue were comparable with those of freshly dissociated tissue both in their single cell transcriptome and their capacity for in vitro organoid formation in 3D cultures. We conclude that the cryobanking method described herein allows long-term preservation of distal human lung tissue for downstream analysis of lung cell function and molecular phenotype, and is ideally suited for creation of an easily accessible tissue resource for the research community.

cell biology↗

bioRxiv2021

Tiam1-mediated synaptic plasticity drives comorbid depressive symptoms in chronic pain

Hyperactivity in the anterior cingulate cortex (ACC) drives comorbid depressive symptoms in chronic pain, but the cause of ACC hyperactivity is currently unclear. Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, induces rapid and sustained antidepressant-like effects in chronic pain-induced depression in both patients and animal models. However, the mechanisms underlying ketamines sustained antidepressant effects remain elusive. Here, we show that Tiam1, a Rac1-specific guanine nucleotide exchange factor (GEF) that was previously identified as a critical mediator of NMDAR-dependent dendritic spine development, is activated in the ACC in chronic pain mice displaying depressive-like behaviors. Conditional deletion of Tiam1 from postnatal forebrain excitatory neurons, specific deletion of Tiam1 from ACC neurons, or pharmacological inhibition of the Tiam1-Rac1 signaling pathway prevents chronic pain-induced depressive-like behaviors in mice. Biochemical, morphological, and electrophysiological assays reveal that Tiam1 orchestrates synaptic structural and functional remodeling in ACC neurons via actin cytoskeleton reorganization and synaptic NMDAR stabilization. This Tiam1-coordinated synaptic plasticity underpins ACC hyperactivity and drives chronic pain-induced depressive-like behaviors. Ketamine induces sustained antidepressant effects in chronic pain by blocking Tiam1-mediated synaptic structural and functional plasticity in ACC neurons. Our results reveal Tiam1 as a key factor in the pathophysiology of chronic pain-induced depression and in the sustained antidepressant effects of ketamine in ACC neurons. These findings highlight Tiam1 as a potential therapeutic target for the treatment of comorbid depressive symptoms in chronic pain.

neuroscience↗

bioRxiv2021

Serine/arginine-rich splicing factor 7 plays oncogenic roles through specific regulation of m6A RNA modification

Serine/Arginine-Rich Splicing Factor 7 (SRSF7), which is previously recognized as a splicing factor, has been revealed to play oncogenic roles in multiple cancers. However, the mechanisms underlying its oncogenic roles have not been well addressed. Here, based on N6-methyladenosine (m6A) co-methylation network analysis across diverse cell lines, we found SRSF7 positively correlated with glioblastoma cell-specific m6A methylation. We then proved SRSF7 is a novel m6A regulator that specifically facilitates the m6A methylation near its binding sites on the mRNAs involved in cell proliferation and migration through recruiting methyltransferase complex. Moreover, SRSF7 promotes the proliferation and migration of glioblastoma cells largely dependent on the m6A methyltransferase. The two single-nucleotide m6A sites on PBK are regulated by SRSF7 and partially mediate the effects of SRSF7 on glioblastoma cells through recognition by IGF2BP2. Together, our discovery revealed a novel role of SRSF7 in regulating m6A and timely confirmed the existence and functional importance of RNA binding protein (RBP) mediated specific regulation of m6A.

molecular biology↗

bioRxiv2021

Epithelial Plasticity and Innate Immune Activation Promote Lung Tissue Remodeling following Respiratory Viral Infection.

Epithelial plasticity has been suggested in lungs of mice following genetic depletion of stem cells but is of unknown physiological relevance. Viral infection and chronic lung disease share similar pathological features of stem cell loss in alveoli, basal cell (BC) hyperplasia in small airways, and innate immune activation, that contribute to epithelial remodeling and loss of lung function. We show that a novel subset of distal airway secretory cells, intralobar serous (IS) cells, are activated to assume BC fates following influenza virus infection. Injury-induced hyperplastic BC (hBC) differ from pre-existing BC by high expression of IL-22Ra1 and undergo IL-22-dependent expansion for colonization of injured alveoli. Resolution of virus-elicited inflammation resulted in BC>IS re-differentiation in repopulated alveoli, and increased local expression of antimicrobial factors, but failed to replace normal alveolar epithelium. Epithelial plasticity therefore protects against mortality from acute respiratory viral infection but results in distal lung remodeling and loss of lung function.

cell biology↗

bioRxiv2021

The transcription factor Zeb2 drives differentiation of age-associated B cells

Age-associated B-cells (ABCs) accumulate during infection, aging and autoimmunity, contributing to lupus pathogenesis. Here, we screen for transcription factors driving ABC formation and find Zeb2 is required for human and mouse ABC differentiation in-vitro. ABCs are reduced in ZEB2 haploinsufficient individuals and in mice lacking Zeb2 in B-cells. In mice with TLR7-driven lupus, Zeb2 is essential for ABC formation and autoimmune pathology. Zeb2 binds to the +20kb intronic enhancer of Mef2b, repressing Mef2b-mediated germinal center B-cell differentiation and promoting ABC formation. Zeb2 also targets genes important for ABC specification and function including Itgax. Zeb2-driven ABC differentiation requires Jak-Stat signaling, and treatment with the Jak1/3 inhibitor tofacitinib reduces ABC accumulation in autoimmune mice and patients. Zeb2 thus emerges as a driver of B-cell autoimmunity. One-Sentence SummaryZeb2 is essential for Age-associated B cells differentiation and function.

immunology↗

bioRxiv2021

CRISPRa screen on a genetic risk locus shared by multiple autoimmune diseases identifies a dysfunctional enhancer that affects IRF8 expression through cooperative lncRNA and DNA methylation machinery

Dysregulated transcription factors represent a major class of drug targets that mediate the abnormal expression of many critical genes involved in SLE and other autoimmune diseases. Although strong evidence suggests that natural human genetic variation affects basal and inducible gene expression, it is still a considerable challenge to establish a biological link between GWAS-identified non-coding genetic risk variants and their regulated gene targets. Here, we combine genetic data, epigenomic data, and CRISPR activation (CRISPRa) assays to screen for functional variants regulating IRF8 expression. Using CRISPR-mediated deletion and 3D chromatin structure analysis, we demonstrate that the locus containing rs2280381 is a cell-type-specific distal enhancer for IRF8 that spatially interacts with the IRF8 promoter. Further, rs2280381 mediates IRF8 expression through enhancer RNA AC092723.1, which recruits TET1 to the IRF8 promoter to modulate IRF8 expression by affecting methylation levels. The alleles of rs2280381 modulate PU.1 binding and chromatin state to differentially regulate AC092723.1 and IRF8 expression. Our work illustrates a strategy to define the functional genetic variants modulating transcription factor gene expression levels and identifies the biologic mechanism by which autoimmune diseases risk genetic variants contribute to the pathogenesis of disease.

genetics↗

bioRxiv2021

Prostaglandin E2 directly inhibits the conversion of inducible regulatory T cells through EP2 and EP4 receptors via antagonizing TGF-β signalling

Background and PurposeRegulatory T (Treg) cells are essential for control of inflammatory processes by suppressing Th1 and Th17 cells. The bioactive lipid mediator prostaglandin E2 (PGE2) promotes inflammatory Th1 and Th17 cells and exacerbates T cell-mediated autoimmune diseases. However, the actions of PGE2 on the development and function of Treg cells, particularly under inflammatory conditions, are debated. In this study, we examined whether PGE2 had a direct action on T cells to modulate de novo differentiation of Treg cells. Experimental ApproachWe employed an in vitro T cell culture system of TGF-{beta}-dependent Treg induction from naive T cells. PGE2 and selective agonists for its receptors, and other small molecular inhibitors were used. Mice with specific lack of EP4 receptors in T cells were used to assess Treg cell differentiation in vivo. Human peripheral blood T cells from healthy individuals were used to induce differentiation of inducible Treg cells. Key ResultsTGF-{beta}-induced Foxp3 expression and Treg cell differentiation in vitro was markedly inhibited by PGE2, which was due to interrupting TGF-{beta} signalling. EP2 or EP4 agonism mimicked suppression of Foxp3 expression in WT T cells, but not in T cells deficient in EP2 or EP4, respectively. Moreover, deficiency of EP4 in T cells impaired iTreg cell differentiation in vivo. PGE2 also appeared to inhibit the conversion of human iTreg cells. Conclusion and ImplicationsOur results show a direct, negative regulation of iTreg cell differentiation by PGE2, highlighting the potential for selectively targeting the PGE2-EP2/EP4 pathway to control T cell-mediated inflammation. What is already knownPGE2 promotes inflammatory Th1 and Th17 cells and facilitates T cell-mediated immune inflammation, but the action of PGE2 on Treg cells is debated. What does this study addPGE2 directly acts on T cells to inhibit inducible Treg cell differentiation in vitro and in vivo through its receptors EP2 and EP4 and by antagonising TGF-{beta} signalling. What is the clinical significanceTherapeutically blocking the EP4 receptor may be beneficial for management of T cell-mediated autoimmune inflammation.

immunology↗

bioRxiv2021

Genetically independent phenotype analysis identifies LPA and VCAM1 as drug targets for human ageing

The length and quality of life is important to us all, yet identification of promising drug targets for human ageing using genetics has had limited success. Here, we combine six large European-ancestry genome-wide association studies (GWAS) of human ageing traits--healthspan, father and mother lifespan, exceptional longevity, frailty index, and self-rated health--in a principal component framework that maximises their shared genetic architecture. The first principal component (GIP1) is more heritable than the original studies and shows strong genetic correlations with length of life as well as multiple indices of mental and physical wellbeing. We identify 27 genomic regions associated with GIP1, and provide additional, independent evidence for an effect on human ageing for loci near HTT and MAML3 using a study of Finnish and Japanese subject survival. Across the genome, GIP1 associations are enriched in genes involved in haem metabolism and pathways related to transcription, neurogenesis, homeostasis, proteolysis, intracellular signalling, immunity, and the muscle system. Finally, using proteome-wide two-sample Mendelian randomisation and colocalisation, we provide robust evidence for a detrimental effect of blood levels of apolipoprotein(a) (LPA) and vascular cell adhesion molecule 1 (VCAM1) on GIP1. Together, our results demonstrate that combining multiple ageing traits using genetic principal components enhances power to detect biological targets for human ageing.

genomics↗

bioRxiv2020

Cardiovascular Disease Related Proteomic Biomarkers of Alcohol Consumption

The relationship between alcohol consumption, circulating proteins, and cardiovascular disease (CVD) risk has not been well studied. We performed association analyses of alcohol consumption with three CVD risk factors and 71 CVD-related circulating proteins measured in 6,745 Framingham Heart Study participants (mean age, 49 years; 53% women). We found that an increase in alcohol consumption was associated with a higher risk of incident hypertension (P=7.2E-3) but a lower risk of incident obesity (P=5.7E-4) and type 2 diabetes (P=1.4E-5) in a 14-year of follow-up. Using independent discovery (n=4,348) and validation (n=2,397) samples, we identified 20 alcohol-associated proteins (FDR<0.05 in discovery and P<0.05/n in validation), with majority (18 of 20 proteins) inversely associated with alcohol consumption. The alcohol-protein associations remained similar after removing heavy drinkers. Four proteins demonstrated consistent triangular relationships, as expected, with alcohol consumption and CVD risk factors. For example, a greater level of APOA1, which was associated with a higher alcohol consumption (P=1.2E-65), was associated with a lower risk of type 2 diabetes (P=3.1E-5). However, several others showed inconsistent triangular relationships, e.g., a greater level of GDF15, which was associated with a lower alcohol consumption (P=1.0E-13), was associated with an increased risk of hypertension (P=2.4E-4). In conclusion, we identified 20 alcohol-associated proteins and demonstrated complex relationships between alcohol consumption, circulating proteins and CVD risk factors. Future studies with integration of more proteomic markers and larger sample size are warranted to unravel the complex relationship between alcohol consumption and CVD risk.

bioinformatics↗

bioRxiv2020

Low XIST expression in Sertoli cells of Klinefelter syndrome patients caused the high susceptibility of these cells to an extra X chromosome

Klinefelter syndrome (KS) is the most common genetic cause of human male infertility. Patients suffer from heterogeneous testicular atrophy with loss of both germ cells and Sertoli cells. However, the mechanism by which the extra X chromosome causes failure of spermatogenesis remains poorly understood. Here, we profiled testicular single-cell transcriptomes from three KS patients and compared the results with those of healthy donors. Among different somatic cells, Sertoli cells showed the greatest changes in KS patients. Further analysis showed that XIST, a key long intergenic non-coding RNA that inactivates one X chromosome in female mammals, was widely expressed in somatic cells, except for Sertoli cells, leading to an increase in X-inactivation genes in these cells, which may cause Sertoli cells death and disruption of the spermatogenic microenvironment. Our study proposed a new mechanism to explain the unique pathological manifestations of KS in the testes and provided a theoretical basis for subsequent research and related treatment.

genomics↗