Biology subjects

Sheng, X.

Publications and source records attributed to Sheng, X..

At least 37 records · Page 2Linked to original sources

bioRxiv2023

A Wireless Optoelectronic Probe Monitors Tissue Oxygenation in the Deep Brain

Real-time detection of tissue oxygenation in the nervous system is crucial for neuroscience exploration and clinical diagnostics. Compared to blood oxygenation, the partial pressure of oxygen in brain tissue (PbtO2) possesses more direct relevance to local neural activities and metabolic conditions. In this paper, we present an implantable optoelectronic probe that wirelessly and continuously monitors PbtO2 signals in the deep brain of living animals. The thin-film, microscale implant integrates a light-emitting diode and a photodetector coated with oxygen sensitive dyes. Powered by a battery or an inductive coil, a miniaturized circuit is capable of recording and wirelessly transmitting PbtO2 signals, which allows for simultaneous monitoring of PbtO2 levels in multiple freely moving rodents. The wireless micro-probe captures cerebral hypoxia states of mice in various scenarios, including altered inspired oxygen concentration, acute ischemia. Particularly, in mouse models with seizures, the micro-probe associates temporal PbtO2 variations in multiple brain regions with electrical stimulations imposed in the hippocampus. These materials and device strategies overcome the limits of existing oxygen sensing approaches and provide important insights into neurometabolic coupling.

bioengineering↗

bioRxiv2022

The photosystem I supercomplex from a primordial green alga Ostreococcus tauri harbors three light-harvesting complex trimers

As a ubiquitous picophytoplankton in the ocean and an early-branching green alga, Ostreococcus tauri is a model prasinophyte species for studying the functional evolution of the light-harvesting systems in photosynthesis. Here, we report the structure and function of the O. tauri photosystem I (PSI) supercomplex in the low light, where it expands its photon-absorbing capacity by assembling with the light-harvesting complexes I (LHCI) and a prasinophyte-specific light-harvesting complex (Lhcp). Its architecture exhibits hybrid features of the plant-type and the green algal-type PSI supercomplexes, consisting of a PSI core, a Lhca1-Lhca4-Lhca2-Lhca3 belt attached on one side and a Lhca5-Lhca6 heterodimer associated on the other side between PsaG and PsaH. Interestingly, nine Lhcp subunits, including one Lhcp1 monomer with a phosphorylated amino-terminal threonine and eight Lhcp2 monomers, oligomerize into three trimers and associate with PSI on the third side between Lhca6 and PsaK. The Lhcp1 phosphorylation and the light-harvesting capacity of PSI were subjected to reversible photoacclimation, suggesting that the formation of OtPSI-LHCI-Lhcp supercomplex is likely due to a state transition-like mechanism induced by light intensity change. Notably, this supercomplex did not exhibit far-red peaks in the 77 K fluorescence spectra, which is possibly due to weak coupling of the chlorophyll a603-a609 pair in OtLhca1-4.

plant biology↗

bioRxiv2022

Designing a Minimal Artificial Glycolytic Pathway

The canonical glycolysis generates two molecules of acetyl-coenzyme A (acetyl-CoA) from one glucose through eleven cascade biochemical reactions. Here, we designed and constructed a Minimal Artificial Glycolytic (MAG) pathway consisting of only three types of biochemical reactions, with phosphoketolase as the core, combined with phosphatase and isomerase as auxiliary enzymes. It could theoretically achieve a 100% carbon yield to acetyl-CoA from any monosaccharide by integrating one-carbon condensation reaction. We tested the MAG pathway in vitro and in vivo, demonstrating the catabolism of typical C1-C6 carbohydrates to acetyl-CoA with yields from 82% to 95%. This novel glycolytic pathway provides a promising route for biomanufacturing with stoichiometric productivity from multiple carbon sources in the future.

synthetic biology↗

bioRxiv2022

Accumulation of mitochondrial ROS drives reductive glutamine metabolism

Hypoxia, mitochondrial defect or extracellular matrix detachment induces reductive glutamine metabolism that can produce citrate by carboxylating the glutamine-derived ketoglutarate (-KG). Reductive carboxylation is required for maintaining redox homeostasis, lipogenesis and cancer cell growth. However, the fundamental mechanism(s) of how reductive glutamine metabolism may be controlled is not fully understood. This study here demonstrates that mitochondrial-derived reactive oxygen species (ROS) positively drives reductive carboxylation. Knockout of fatty acid synthase (FASN) causes increased mitochondrial ROS and significant reductive glutamine metabolism. Mitochondrial ROS accumulation is identified as a shared feature in cells that utilize reductive metabolism. Moreover, ROS scavenger could inhibit reductive carboxylation by decreasing ROS level in mitochondria. By contrast, ROS inducers activate reductive carboxylation via increasing mitochondrial ROS. Mitochondrial ROS level determines the degree of reductive carboxylation with a positive correlation. The results presented here not only reveal a fundamental mechanism of how reductive carboxylation is controlled, but also elucidate a critical role of ROS in reprogramming metabolism.

cell biology↗

bioRxiv2022

Associations of Minor Histocompatibility Antigens with Clinical Outcomes Following Allogeneic Hematopoietic Cell Transplantation

The role of minor histocompatibility antigens (mHAs) in mediating graft versus leukemia (GvL) and graft versus host disease (GvHD) following allogeneic hematopoietic cell transplantation (alloHCT) is recognized but not well-characterized. By implementing improved methods for mHA prediction in two large patient cohorts, this study aimed to comprehensively explore the role of mHAs in alloHCT by analyzing whether (1) the number of predicted mHAs, or (2) individual mHAs are associated with clinical outcomes using multi-variate survival models corrected for multiple testing. Cox proportional hazard results showed that patients with a class I mHA count greater than the population median had an increased hazard of GvHD mortality (HR=1.39, 95%CI 1.01, 1.77, P=0.046). Competing risk analyses identified the class I mHAs DLRCKYISL (gene GSTP), WEHGPTSLL (CRISPLD2) and STSPTTNVL (SERPINF2) were associated with increased GVHD death (HR=2.84, 95%CI 1.52, 5.31, P=0.01), decreased leukemia-free survival (LFS) (HR=1.94,95%CI 1.27, 2.95, P=0.044), and increased disease-related mortality (DRM) (HR=2.32, 95%CI 1.5, 3.6, P=0.008), respectively. One class II mHA YQEIAAIPSAGRERQ (TACC2) was associated with increased risk of treatment-related mortality (TRM) (HR=3.05, 95%CI 1.75, 5.31, P=0.02). WEHGPTSLL and STSPTTNVL were present in conjunction within HLA haplotype B*40:01-C*03:04 and showed a positive dose-response relationship with increased all-cause mortality and DRM and decreased LFS, indicating these two mHAs contribute to risk of mortality in an additive manner. Our study reports the first large scale investigation of the associations of predicted class I and class II mHA peptides with clinical outcomes following alloHCT. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=166 HEIGHT=200 SRC="FIGDIR/small/506092v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@1516a9aorg.highwire.dtl.DTLVardef@2db79aorg.highwire.dtl.DTLVardef@170e19aorg.highwire.dtl.DTLVardef@1eb7148_HPS_FORMAT_FIGEXP M_FIG C_FIG

genetics↗

bioRxiv2022

CRISPR/Cas9 mutants delineate roles of Populus FT and TFL1/CEN/BFT family members in growth, dormancy release and flowering

Vegetative and reproductive phase change and phenology are economically and ecologically important traits. Trees typically require several years of growth before flowering and once mature, seasonal control of the transition to flowering and flower development is necessary to maintain vegetative meristems and for reproductive success. Members of two related gene subfamilies, FLOWERING LOCUST (FT) and TERMINAL FLOWER1 (TFL1)/CENTRORADIALIS (CEN)/BROTHER OF FT AND TFL1 (BFT), have antagonistic roles in flowering in diverse species and roles in vegetative phenology in trees, but many details of their functions in trees have yet to be resolved. Here, we used CRISPR/Cas9 to generate single and double mutants involving the five Populus FT and TFL1/CEN/BFT genes. ft1 mutants exhibited wild-type-like phenotypes in long days and short days, but after chilling to release dormancy showed delayed bud flush and GA3 could compensate for the ft1 mutation. After rooting and generating some phytomers in tissue culture, both cen1 and cen1ft1 mutants produced terminal as well as axillary flowers, indicating that the cen1 flowering phenotype is independent of FT1. Some axillary meristems initially generated phytomers and in potted plants, the timing of flowering in these shoots correlated with upregulation of FT2 in maturing leaves, suggesting that, in long days, CEN1 antagonizes FT2 promotion of flowering but enables FT2 promotion of shoot growth by maintaining indeterminacy of the shoot apical meristem. CEN1 showed distinct circannual expression patterns in vegetative and reproductive tissues and comparison with the expression patterns of FT1 and FT2 suggest that the relative levels of CEN1 compared to FT1 and FT2 regulate multiple phases of vegetative and reproductive seasonal development.

plant biology↗

bioRxiv2022

Dissecting the genetic basis of the heterosis of Y900, an elite super-hybrid rice

Y900 is one of the top hybrid rice varieties with a yield exceeding 15 t/hm2. To dissect the mechanism of heterosis, the male parent line R900 and female parent line Y58S were sequenced using long-read and Hi-C technology. High-quality reference genomes of sizes of 396.41 Mb and 398.24 Mb were obtained for R900 and Y58S, respectively. Genome-wide variations between the parents were systematically identified, including 1,367,758 SNPs and 299,149 Indels. No megabase level structural variations exist. >75% of genes exhibited variation between the two parents. Compared with other two-line hybrids sharing the same female parent, the Geng/japonica-type genetic components from different male parents showed an increasing trend from phase 2-4 super-hybrid rice; Transcriptome analysis revealed that additive and dominance effects are the main genetic effects that constitute the heterosis of Y900. Allele-specific expression patterns and expression regulation patterns are quite dynamic in different tissues. For young panicle tissues, cis-regulation is dominant, while trans-regulation is more popular in leaf issues. Overdominance is more likely regulated by the trans-regulation mechanism. The differential gene expression and regulation pattern are closely related to Geng/japonica introgression. Additionally, R900 contained several excellent japonica haplotypes, such as NAL1, OsSPL13, Ghd8, OsBRI1, and DTH2, which make a good complement to Y58S. The fine tune mechanism through dynamic expression or regulation pattern change, especially on some key functional genes, is the base for heterosis.

plant biology↗

bioRxiv2022

Silicon Diode based Flexible and Bioresorbable Optoelectronic Interfaces for Selective Neural Excitation and Inhibition

The capability to selectively and precisely modulate neural activities represents a powerful tool for neuroscience research and clinical therapeutics. Traditional electrical stimulations associate with bulky and tethered implants, and optogenetic methods rely on genetic modification for cell targeting. Here, we report an optoelectronic, non-genetic strategy for exciting and inhibiting neural activities, accomplished by bioresorbable, thin-film silicon (Si) diodes. Under illumination, these devices establish polarity-dependent, positive or negative voltages at the semiconductor/solution interface. Such photovoltaic signals enable deterministic depolarization and hyperpolarization of cultured neurons, upregulating and downregulating intracellular calcium dynamics in vitro. Furthermore, flexible, thin-film Si based devices mounted on the nerve tissue selectively activate and silence in vivo activities, both in the peripheral nerve and the brain. Finally, these Si membranes naturally dissolve within the animal body. Such a Si-based material and device platform offers broad potential for biomedical applications.

bioengineering↗

bioRxiv2022

Sequential functional differentiation of luminal epithelial cells regulated by maternal and embryonic signaling in the mouse endometrium

Embryo implantation requires temporospatial maternal-embryo dialog to regulate the interactions between an activated blastocyst and a receptive endometrium; however, the details of the related cell-specific coordination is largely unknown because of the cellular complexity and dynamic developmental processes of both the embryo and endometrium during peri-implantation. By comparing single-cell RNA (scRNA) data obtained from entire uteri of pregnant and pseudo-pregnant mice with embryos that were in the oviduct (dpc2.5 days post-coitum [dpc]) or had entered the uterus (after 3.5 dpc), we found a maternal estrogen and progesterone signaling-dependent functional differentiation process in which progesterone induced estrogen-responsive luminal epithelial cells to differentiate into two new types of epithelial cells: adhesion epithelial cells (AECs) and supporting epithelial cells (SECs) on 2.5 dpc. In addition to maternal signaling data, the uterine scRNA and corresponding embryo bulk sequencing data were obtained, and analyses revealed that embryonic Pdgfa and Efna3/4 signaling activated AECs and SECs, enhancing the attachment of embryos to the endometrium after implantation. Specifically, embryonic signaling induced additional transformation of AECs by preventing adjacent AECs, but not AECs away from the embryo in the implantation chamber, from undergoing apoptosis. Furthermore, we demonstrated that epithelial cell differentiation and related regulatory signaling were largely conserved in humans and mice. In the human endometrium, developmental defects of SOX9-positive epithelial cells similar to luminal epithelial cells were related to thin endometrium. Our work provides comprehensive and systematic information on endometrial luminal epithelial cell development directed by maternal and embryonic signaling, which is important for endometrial receptivity and embryo implantation.

cell biology↗

bioRxiv2022

Inverted genomic regions between reference genome builds in humans impact imputation accuracy and decrease the power of association testing

Over the last two decades, the human reference genome has undergone multiple updates as we complete a linear representation of our genome. There are two versions of human references currently used in the biomedical literature, GRCh37/hg19 and GRCh38, and conversions between these versions are critical for quality control, imputation, and association analysis. In the present study we show that genomic coordinates for single nucleotide variants (SNVs) in regions inverted between different builds of the reference genome are erroneously converted by the TOPMed imputation server. Depending on the array type, we estimate the inappropriate conversions of variant coordinates would occur in about 2-5 Mb of the genome. Independent of the imputation server, however, in-house conversions of variant coordinates are routine yet impact of mapped variants to these inverted regions and its downstream analytical consequences are underrecognized. We observed that errors for palindromic variants in these inverted regions cannot be detected by standard quality control procedures and destabilize the local haplotype structure, leading to loss of imputation accuracy and power in association analyses. Though only a small proportion of the genome is affected, we show that these regions include important disease susceptibility variants that would be lost due to poor imputation. For example, we show that a known locus associated with prostate cancer on chr10 would have its association P-value drop from 2.86x10-7 to 0.0011 in a case-control analysis of 20,286 Africans and African Americans (10,643 cases and 9,643 controls). We devise a straight-forward heuristic based on the popular tool liftOver that can easily detect and correct these variants in the inverted regions between genome builds to locally improve imputation accuracy.

genomics↗

bioRxiv2022

Study on gene knockout mice and human mutant individual reveals absence of CEP78 causes photoreceptor and sperm flagella impairments

BackgroundCone-rod dystrophy (CRD) is a genetically inherited retinal disease characterized by photoreceptor degeneration. In some rare cases, CRD and hearing loss can be associated with male fertility, while the underlying mechanism is not well known. MethodsUsing CRISPR/Cas9 system, we generated Cep78-/- mice. And electroretinogram (ERG), immunofluorescence staining and transmission electron microscopy (TEM) were used to analyze visual function and photoreceptor ciliary structure changes in Cep78-/- mouse. HE/PAS staining, scanning-electron microscopy (SEM) were conducted to Cep78-/- mice and human CRD patient with CEP78 protein loss to illustrate male infertility and multiple morphological abnormalities of the sperm flagella (MMAF) caused by CEP78 deficiency. TEM and immunofluorescence staining were performed to characterize morphological and molecular changes of sperm flagella microtubule arrangement, centriole development and spermatid head shaping in Cep78-/- mice. Mass-spectrometry analyses were conducted to identify protein abnormalities after Cep78 deletion and Cep78 interacting proteins in spermiogenesis. Co-immunoprecipitation was used to show the Cep78-Ift20-Ttc21a trimer. The role of Cep78-Ift20-Ttc21a trimer in cilliogenesis and centriole elongation was assessed by cilia induction assay. ResultsCep78 knockout mice exhibited impaired function and morphology of photoreceptors, typified by reduced electroretinogram amplitudes, disrupted translocation of cone arrestin, attenuated and disorganized photoreceptor outer segments (OS) disks and widen OS bases, as well as interrupted cilia elongations and structures. Cep78 deletion also caused male infertility and MMAF, with disordered "9 + 2" structure and triplet microtubules in sperm flagella. CEP78 forms a trimer with intraflagellar transport (IFT) proteins IFT20 and TTC21A essential for sperm flagella formation, is essential for their interaction and stability, and recruits IFT20 to centrosome. Insufficiency of any component in the trimer causes centriole elongation and cilia shortening. Additionally, absence of CEP78 protein in human leaded to similar phenotypes in vision and MMAF as Cep78-/- mice. ConclusionsWe found CEP78 as the causative gene of CRD with MMAF in human and mouse. Cep78 forms a trimer with Ift20 and Ttc21a, and regulate the interaction, stability and localization of the trimer proteins, which regulate cilliogenesis, centriole length, and sperm flagella formation. FundingThis work was supported by the National Key R&D Program (2021YFC2700200 to X.G); National Natural Science Foundation of China (82020108006, 81730025 to C.Z, 81971439, 81771641 to X.G, 82070974 to X.C, 82060183 to X.S); Shanghai Outstanding Academic Leaders (2017BR013 to C.Z); and Six Talent Peaks Project in Jiangsu Province (YY-019 to X.G). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

developmental biology↗

bioRxiv2021

CHD4 is recruited by GATA4 and NKX2-5 silencers to repress non-cardiac gene programs in the developing heart

The Nucleosome Remodeling and Deacetylase (NuRD) complex is one of the central chromatin remolding complexes that mediate gene repression. NuRD is essential for numerous developmental events, including heart development. Clinical and genetic studies have provided direct evidence for the role of chromodomain helicase DNA-binding protein 4 (CHD4), the catalytic component of NuRD, in congenital heart disease (CHD), including atrial and ventricular septal defects. Further, it has been demonstrated that CHD4 is essential for mammalian cardiomyocyte formation and function. A key unresolved question is how CHD4/NuRD is localized to specific cardiac targets genes, as neither CHD4 nor NuRD can directly bind DNA. Here, we coupled a bioinformatics-based approach with mass spectrometry analyses to demonstrate that CHD4 interacts with the core cardiac transcription factors GATA4, NKX2-5 and TBX5 during embryonic heart development. Using transcriptomics and genome-wide occupancy data, we have characterized the genomic landscape of GATA4, NKX2-5 and TBX5 repression and defined the direct cardiac gene targets of GATA4-CHD4, NKX2-5-CHD4 and TBX5-CHD4 complexes. These data were used to identify putative cis-regulatory elements regulated controlled by these complexes. We genetically interrogated two of these silencers in vivo, Acta1 and Myh11. We show that deletion of these silencers leads to inappropriate skeletal and smooth muscle gene mis-expression, respectively, in the embryonic heart. These results delineate how CHD4/NuRD is localized to specific cardiac loci and explicates how mutations in the broadly expressed CHD4 protein lead to cardiac specific disease states.

genomics↗

bioRxiv2021

Colocalized, Bidirectional Optogenetic Modulations in Freely Behaving Animals with a Wireless Dual-Color Optoelectronic Probe

The precise control of neural activities at both cellular and circuit levels reveals significant impacts on the fundamental neuroscience explorations and medical applications. Optogenetic methods provide efficient cell-specific modulations, and the ability of simultaneous neural activation and inhibition in the same brain region of freely moving animals is highly desirable and being actively researched. Here we report bidirectional neuronal activity manipulation accomplished by a wireless, dual-color optogenetic probe in synergy with the co-expression of two spectrally distinct opsins (ChrimsonR and stGtACR2) in a rodent model. Based on vertically assembled, thin-film microscale light-emitting diodes (micro-LEDs) with a lateral dimension of 125 x 180 {micro}m2 on flexible substrates, the dual-color probe shows colocalized red and blue emissions and allows chronic in vivo operations with desirable biocompatibilities. In addition, we discover that neurons co-expressing the two opsins can be deterministically evoked or silenced under red or blue irradiations. Implanted in behaving mice, the wirelessly controlled dual-color probe interferes with dopaminergic neurons in the ventral tegmental area (VTA), increasing or decreasing dopamine levels with colocalized red and blue stimulations. Such bidirectional regulations further generate rewarding and aversive behaviors of freely moving mice in a place preference test and interrogate social interactions among multiple mice. The technologies established here will create numerous opportunities and profound implications for brain research.

bioengineering↗

bioRxiv2021

Genome-wide Association Study of Pancreatic Fat: The Multiethnic Cohort Adiposity Phenotype Study

Several studies have found associations between higher pancreatic fat content and adverse health outcomes, such as diabetes and the metabolic syndrome, but investigations into the genetic contributions to pancreatic fat are limited. This genome-wide association study, comprised of 804 participants with MRI-assessed pancreatic fat measurements, was conducted in the ethnically diverse Multiethnic Cohort-Adiposity Phenotype Study (MEC-APS). Two genetic variants reaching genome-wide significance, rs73449607 on chromosome 13q21.2 (Beta = -0.67, P = 4.50x10-8) and rs7996760 on chromosome 6q14 (Beta = -0.90, P = 4.91x10-8) were associated with percent pancreatic fat on the log scale. Rs73449607 was most common in the African American population (13%) and rs79967607 was most common in the European American population (6%). Rs73449607 was also suggestively associated with lower risk of type 2 diabetes (OR = 0.95, 95% CI = 0.89-1.00, P = 0.047) in the Population Architecture Genomics and Epidemiology (PAGE) Study and the DIAbetes Genetics Replication and Meta-analysis (DIAGRAM), which included substantial numbers of non-European ancestry participants (53,102 cases and 193,679 controls). Rs73449607 is located in an intergenic region between GSX1 and PLUT, and rs79967607 is in intron 1 of EPM2A. PLUT, a linkRNA, regulates transcription of an adjacent gene, PDX1, that controls beta-cell function in the mature pancreas, and EPM2A encodes the protein laforin, which plays a critical role in regulating glycogen production. If validated, these variants may suggest a genetic component for pancreatic fat and a common etiologic link between pancreatic fat and type 2 diabetes.

cell biology↗

bioRxiv2020

First demonstration of the FLASH effect with ultrahigh dose-rate high energy X-rays

Ultrahigh dose-rate (FLASH) radiotherapy has attracted immense attention because of its tumor control efficiency and healthy tissue protection during preclinical experiments with electrons, kilo-voltage X-rays, and protons. Using high-energy X-rays (HEXs) in FLASH is advantageous owing to its deep penetration, small divergence, and cost-effectiveness. This is the first report on the implementation of HEXs with FLASH (HEX-FLASH) and its corresponding application in vivo. With a high-current and high-energy superconducting linear accelerator, FLASH with a good dose rate and high penetration was achieved. Breast cancers artificially induced in BAL b/c mice were efficiently controlled, and normal tissues surrounding the thorax/abdomen in C57BL/6 mice were protected from radiation with HEX-FLASH. Theoretical analyses of cellular responses following HEX-FLASH irradiation were performed to interpret the experimental results and design further experiments. Thus, this study highlights the generation of HEX-FLASH for the first time and its potential in future clinical applications.

cancer biology↗

bioRxiv2020

Mapping the genetic architecture of human traits to cell types in the kidney identifies mechanisms of disease and potential treatments

The functional interpretation of GWAS remains challenging due to cell-type dependent influences of genetic variants. Here, we generated comprehensive maps of expression quantitative trait loci (eQTL) for 659 microdissected human kidney samples and identified cell-type eQTLs by mapping interactions between cell type abundance and genotype. Separately, we generated single cell open chromatin maps (by snATAC-seq) for human kidney samples. We highlight critical enrichment of proximal tubules in kidney function and endothelial cells and distal tubule segments in blood pressure by partitioning heritability using stratified LD-score regression to integrate GWAS with scRNA-seq and snATAC-seq data. Bayesian colocalization analysis nominated more than 200 genes for kidney function and hypertension. Our study clarifies the mechanism of the most commonly used antihypertensive and renal protective drugs and identifies drug repurposing opportunities for kidney disease. One Sentence SummaryWe define causal cell types, genes and mechanism for kidney dysfunction.

genetics↗

bioRxiv2020

Cardiac Sex Differences are Established Prior to Gonad Formation

Male and female disease states differ in their prevalence, treatment responses, and survival rates. In cardiac disease, women almost uniformly fare far worse than men. Though sex plays a critical role in cardiac disease, the mechanisms underlying sex differences in cardiac homeostasis and disease remain unexplained. Here, in adult and embryonic hearts we reveal sex-specific transcriptomes and proteomes and show that cardiac sex differences are predominately accounted for by post-transcriptional mechanisms. We found differential expression of male-female proteins in the cardiomyocytes. Using a quantitative proteomics-based approach, we characterized differential sex-specific enriched cardiac proteins, protein complexes, and biological sex processes in the context of global genetic diversity of the Collaborative Cross, an established surrogate for human diversity. We also found that sex differences in cardiac protein expression are established by both hormonal and sex chromosomal mechanisms. We have demonstrated the onset of sex-biased protein expression and discovered that sex disparities in heart tissue occur at the earliest stages of heart development at a period that preceeds mammalian gonadal development. Collectively, these findings may explain why congenital heart disease, a leading cause of death whose origin is often developmental, is sex biased. Our results reveal molecular foundations for differences in cardiac tissue that underlie sex disparities in health, disease, and treatment outcomes.

developmental biology↗

bioRxiv2020

Renal proximal tubule cell state and metabolism are coupled by nuclear receptors

Kidney disease development is poorly understood due to the complex cellular interactions of more than 25 different cell types, each with specialized functions. Here, we used single cell RNA-sequencing to resolve cell type-specific and cell fraction changes in kidney disease. Whole kidney RNA-sequencing results were strongly influenced by cell fraction changes, but minimally informative to detect cell type-specific gene expression changes. Cell type-specific differential expression analysis identified proximal tubule cells (PT cells) as the key vulnerable cell type in diseased kidneys. Through unbiased cell trajectory analyses, we show that PT cell differentiation state is altered in disease state. Lipid metabolism (fatty acid oxidation and oxidative phosphorylation) in PT cells showed the strongest and reproducible association with PT cells state. The coupling of cell state and metabolism is established by nuclear receptors such as PPARA and ESRRA that not only control cellular metabolism but also the expression of PT cell-specific genes in mice and patient samples.

cell biology↗