Developmental systems biology flourishing on new technologies

Organism development is a systems level process. It has benefited greatly from the recent technological advances in the field of systems biology. DNA microarray, phenome, interactome and transcriptome mapping, the new generation of deep sequencing technologies, and faster and better computational and modeling approaches have opened new frontiers for both systems biologists and developmental biologists to reexamine the old developmental biology questions, such as pattern formation, and to tackle new problems, such as stem cell reprogramming. As showcased in the International Developmental Systems Biology Symposium organized by Chinese Academy of Sciences, developmental systems biology is flourishing in many perspectives, from the evolution of developmental systems, to the underlying genetic and molecular pathways and networks, to the genomic, epigenomic and noncoding levels, to the computational analysis and modeling. We believe that the field will continue to reap rewards into the future with these new approaches.

ABO blood type,diabetes and risk of gastrointestinal cancer in northern China

AIM:To explore the potential risk factors related to gastrointestinal cancer in northern China.METHODS:A total of 3314 cases of gastrointestinal cancer(esophageal,gastric,pancreatic and biliary) and 2223 controls(including healthy individuals,glioma and thyroid cancer) were analyzed by case-control study.Multivariable logistic regression analysis was applied to evaluate the association between different cancers and hepatitis B surface antigen,sex,age,blood type,diabetes,or family history of cancer.RESULTS:Type 2 diabetes was significantly associated with gastric,biliary and pancreatic cancer with an OR of 2.0-3.0.Blood type B was significantly associated with esophageal cancer [odd ratio(OR) = 1.53,95% confidence interval(CI) = 1.10-2.14] and biliary cancer(OR = 1.49,95% CI = 1.09-2.05).The prevalence of type 2 diabetes was significantly higher in gastric,biliary and pancreatic cancers compared with other groups,with ORs ranging between 2.0 and 3.0.Family history of cancer was strongly associated with gastrointestinal compared with other cancers.CONCLUSION:Blood type B individuals are susceptible to esophageal and biliary cancer.Type 2 diabetes is significantly associated with gastric,biliary and especially pancreatic cancer.

PRMT5 regulates Golgi apparatus structure through methylation of the golgin GM130

Maintenance of the Golgi apparatus （GA） structure and function depends on Golgi matrix proteins. The posttranslational modification of Golgi proteins such as phosphorylation of members of the golgin and GRASP families is important for determining Golgi architecture. Some Golgi proteins including golgin-84 are also known to be methylated, but the function of golgin methylation remains unclear. Here, we show that the protein arginine methyltransferase 5 （PRMT5） localizes to the GA and forms complexes with several components involved in GA ribbon formation and vesicle tethering. PRMT5 interacts with the golgin GM130, and depletion of PRMT5 causes defects in Golgi ribbon formation. Furthermore, PRMT5 methylates N-terminal arginines in GM130, and such arginine methylation appears critical for GA ribbon formation. Our findings reveal a molecular mechanism by which PRMT5-dependent arginine methylation of GM130 controls the maintenance of GA architecture.

Smad2 mediates Activin/Nodal signaling in mesendoderm differentiation of mouse embryonic stem cells

Although Activin/Nodal signaling regulates pluripotency of human embryonic stem （ES） cells, how this signaling acts in mouse ES cells remains largely unclear. To investigate this, we confirmed that mouse ES cells possess active Smad2-mediated Activin/Nodal signaling and found that Smad2-mediated Activin/Nodal signaling is dispensable for self-renewal maintenance but is required for proper differentiation toward the mesendoderm lineage. To gain insights into the underlying mechanisms, Smad2-associated genes were identified by genome-wide chromatin immu- noprecipitation-chip analysis. The results showed that there is a transcriptional correlation between Smad2 binding and Activin/Nodal signaling modulation, and that the development-related genes were enriched among the Smad2- bound targets. We further identified Tapbp as a key player in mesendoderm differentiation of mouse ES cells acting downstream of the Activin/Nodal-Smad2 pathway. Taken together, our findings suggest that Smad2-mediated Activin/Nodal signaling orchestrates mesendoderm lineage commitment of mouse ES cells through direct modulation of corresponding developmental regulator expression.

Transgenic expression of DwMYB2 impairs iron transport from root to shoot in Arabidopsis thaliana

In plant, iron uptake and homeostasis are tightly regulated to ensure its absorption from soil and to avoid excess iron in the cell. Many genes involved in this process have been identified during past several years, but there are many problems remain unsolved in the genetic regulation of whole plant iron trafficking and allocation. MYB transcription factors contain tandem repeats of a -50 amino acid DNA-binding motif （R） and are involved in the regulation of many aspects of plant development, hormone signaling and metabolism. Here, we report that the ectopic expression of orchid R2R3-MYB gene DwMYB2 in Arabidopsis thaliana confers the transgenic plants hypersensitivity to iron deficiency. In DwMYB2 transgenic plants, the iron content in root is two-fold higher compared to that in wild-type root, while the reverse is true in shoot. This imbalance of iron content in root and shoot suggested that the translocation of iron from root to shoot was affected by the expression of DwMYB2 in the transgenic plants. Consistently, gene chip and reverse transcription-polymerase chain reaction analysis revealed that the ferric-chelate reductase gene, AtFRO2, and the iron transporter gene, AtlRT1 and AtlRT2, are up-regulated by DwMYB2 expression, while other potential iron transporters such as AtlREG1, AtFRD3 and NRAMP1 are down-regulated. In addition, the expression of several putative peptide transporters and transcription factors are also altered in the 35S：：DwMYB2 transgenic lines. These data provide us insight into the whole plant translocation of iron and identify candidate genes for iron homeostasis in plants despite the fact that a heterologous gene was expressed.

Transgenic analyses of TGIF family proteins in Drosophila imply their role in cell growth

TG-interacting factors （TGIFs） belong to a family of TALE-homeodomain proteins including TGIF, TGIF2, and TGIF2LX/Y （TGIF2 like on X or Y chromosome） in human. They potentially play important functions in various tissues during development. Mutations in TGIF are frequently associated with malformation of forebrain and facial structures; TGIF2 proteins are over-expressed in many ovarian cancer cell lines; and TGIF2LX/Y are specifically expressed in adult testis. The molecular functions of these proteins have been investigated mostly in cultured cells. TGIF and TGIF2 have been found as transcriptional repressors that modulate TGF-beta signaling. However these findings are far from sufficient to explain their mutant phenotypes or expression patterns, and the functions of TGIF2LX/Y have never been reported. Here we use Drosophila as a model system to explore the functions of TGIF family proteins in vivo. We observed in fly tissues such as fat body, epithelia, and neuronal cells, that expressing human TGIF2 or human TGIF2LX generally inhibited cell growth in size and number. Co-expressing Drosophila Myc, Cyclin E, or human c-MycS partially rescued the growth inhibition induced by human TGIFs, whereas activated insulin pathway signaling did not. Taken together, we provide in vivo evidence for the potential functions of human TGIF2 and TGIF2LX in growth control. Additionally, we confirmed that Drosophila TGIFs are transcriptional activators by assaying their activities in spermatogenesis.

New players in the regulation of ecdysone biosynthesis

Insect ecdysone steroid hormone regulates major developmental transitions, such as molting and metamorphosis. The production of ecdysone correlates well with the timing of these transitions. Finding out how the ecdysone biosynthesis is regulated is crucial to fully understand these sophisticated developmental switches. Here we summarized recent findings in the regulation of ecdysone biosynthesis from the aspects of cell signaling, key biosynthetic enzymes and substrate cholesterol trafficking.

The tea plant CsLHT1 and CsLHT6 transporters take up amino acids, as a nitrogen source, from the soil of organic tea plantations

Organic tea is more popular than conventional tea that originates from fertilized plants.Amino acids inorganic soils constitute a substantial pool nitrogen(N)available for plants.However,the amino-acid contents in soils of tea plantations and how tea plants take up these amino acids remain largely unknown.In this study,we show that the amino-acid content in the soil of an organic tea plantation is significantly higher than that of a conventional tea plantation.Glutamate,alanine,valine,and leucine were the most abundant amino acids in the soil of this tea plantation.When 15 N-glutamate was fed to tea plants,it was efficiently absorbed and significantly increased the contents of other amino acids in the roots.We cloned seven CsLHT genes encoding amino-acid transporters and found that the expression of CsLHT1,CsLHT2,and CsLHT6 in the roots significantly increased upon glutamate feeding.Moreover,the expression of CsLHT1 or CsLHT6 in a yeast amino-acid uptake-defective mutant,22Δ10α,enabled growth on media with amino acids constituting the sole N source.Amino-acid uptake assays indicated that CsLHT1 and CsLHT6 are H^(+)-dependent high-and low-affinity amino-acid transporters,respectively.We further demonstrated that CsLHT1 and CsLHT6 are highly expressed in the roots and are localized to the plasma membrane.Moreover,overexpression of CsLHT1 and CsLHT6 in Arabidopsis significantly improved the uptake of exogenously supplied 15 N-glutamate and 15 N-glutamine.Taken together,our findings are consistent with the involvement of CsLHT1 and CsLHT6 in amino-acid uptake from the soil,which is particularly important for tea plants grown inorganic tea plantations.

Understanding biological functions through molecular networks

The completion of genome sequences and subsequent high-throughput mapping of molecular networks have allowed us to study biology from the network perspective. Experimental, statistical and mathematical modeling approaches have been employed to study the structure, function and dynamics of molecular networks, and begin to reveal important links of various network properties to the functions of the biological systems. In agreement with these functional links, evolutionary selection of a network is apparently based on the function, rather than directly on the structure of the network. Dynamic modularity is one of the prominent features of molecular networks. Taking advantage of such a feature may simplify network-based biological studies through construction of process-specific modular networks and provide functional and mechanistic insights linking genotypic variations to complex traits or diseases, which is likely to be a key approach in the next wave of understanding complex human diseases. With the development of ready-to-use network analysis and modeling tools the networks approaches will be infused into everyday biological research in the near future.

Reconstruction and Dynamics of the Human Intestinal Microbiome Observed In Situ

The human gut microbiome has primarily been studied through the use of fecal samples,a practice that has generated vital knowledge on the composition and functional capacities of gastrointestinal microbial communities.However,this reliance on fecal materials limits the investigation of microbial dynamics in other locations along the gastrointestinal tract(in situ),and the infrequent availability of fecal samples prevents analysis at finer temporal scales(e.g.,hours).In our study,we utilized colonic transendoscopic enteral tubing,a technology originally developed for fecal microbiota transplantation,to sample the ileocecal microbiome twice daily;metagenomic and metatranscriptomic analyses were then conducted on these samples.A total of 43 ileocecal and 28 urine and fecal samples were collected from five healthy volunteers.The ileocecal and fecal microbiomes,as profiled in the five volunteers,were found to be similar in metagenomic profiling,yet their active genes(metatranscriptome)were found to be highly distinct.Both microbiomes were perturbed after laxative exposure;over time,they exhibited reduced dissimilarity to their pre-treatment state,thereby demonstrating resilience as an innate property of the gut microbiome,although they did not fully recover within our observation time window.Sampling of the ileocecal microbiome during the day and at night revealed the existence of diurnal rhythms in a series of bacterial species and functional pathways,particularly those related to short-chain fatty acid production,such as Propionibacterium acnes and coenzyme A biosynthesis Ⅱ.Autocorrelation analysis and fluctuations decomposition further indicated the significant periodicity of the diurnal oscillations.Metabolomic profiling in the fecal and urine samples mirrored the perturbance and recovery in the gut microbiome,indicating the crucial contribution of the gut microbiome to many key metabolites involved in host health.This study provides novel insights into the human gut microbiome and its inner resilience and diurnal rhythms,as well as the potential consequences of these to the host.

Instability of Nucleic Acids in Airborne Microorganisms under Far Infrared Radiation

Emergence of zoonotic-human pathogens is proven to be a lethal threat to public health, and RNA virus including influenza viruses, severe acute respiratory syndrome coronavirus, middle east respiratory syndrome coronavirus, and COVID-19, plays a pivotal role. As those viruses as airborne microorganisms spread mainly by tiny airborne particles, it is important to de-active those airborne particles before their entry into human bodies. In this study, we investigated the effect of far infrared (FIR) radiation on inhibition of airborne microorganisms. The result confirmed that double stand DNA from airborne microorganisms containing RNA viruses was stable under mild FIR radiation. However, single strand RNA from them was found to be sensitive to FIR radiation, indicating that RNA virus in airborne particles is instable under FIR radiation. Based on this observation, two models on usage of FIR radiation to prevent RNA virus transmission by air and cure RNA virus infection were proposed. Then, this study suggests that FIR radiation has the potential to be a cheap, convenient, and efficient method in clinic to treat RNA virus.

Inaugural Editorial:Seed Biology

Seed is the most important reproductive organ in plant.Since its first emergence approximately 370 million years ago,seed plant had overwhelming advantage to non-seed plants in reproduction,spreading and colonization in terrestrial land.Beside its essential function in the sexual reproduction of plants,seed is the most economically important agricultural product,offering necessity food for human and wildlife,nutritious feed for livestock.Seeds and grains also provide massive amount of raw materials for manufactured goods,such as coffee,starch,and oil.Seeds also play a pivotal role in development of fruits which supplement significant portion of food and nutrition for human and wildlife.

Haem Oxygenase 1 is a potential target for creating etiolated/albino tea plants (Camellia sinensis) with high theanine accumulation

Theanine content is highly correlated with sensory quality and health benefits of tea infusion.The tender shoots of etiolated and albino tea plants contain higher theanine than the normal green tea plants and are valuable materials for high quality green tea processing.However,why these etiolated or albino tea plants can highly accumulate theanine is largely unknown.In this study,we observed an Arabidopsis etiolated mutant hy1–100(mutation in Haem Oxygenase 1,HO1)that accumulated higher levels of glutamine(an analog of theanine).We therefore identified CsHO1 in tea plants and found CsHO1 is conserved in amino acid sequences and subcellular localization with its homologs in other plants.Importantly,CsHO1 expression in the new shoots was much lower in an etiolated tea plants‘Huangkui’and an albino tea plant‘Huangshan Baicha’than that in normal green tea plants.The expression levels of CsHO1 were negatively correlated with theanine contents in these green,etiolated and albino shoots.Moreover,CsHO1 expression levels in various organs and different time points were also negatively correlated with theanine accumulation.The hy1–100 was hypersensitive to high levels of theanine and accumulated more theanine under theanine feeding,and these phenotypes were rescued by the expression of CsHO1 in this mutant.Transient knockdown CsHO1 expression in the new shoots of tea plant using antisense oligonucleotides(asODN)increased theanine accumulation.Collectively,these results demonstrated CsHO1 negatively regulates theanine accumulation in tea plants,and that low expression CsHO1 likely contributes to the theanine accumulation in etiolated/albino tea plants.

Emerging roles and therapeutic potentials of sphingolipids in pathophysiology:emphasis on fatty acyl heterogeneity

Sphingolipids not only exert structural roles in cellular membranes,but also act as signaling molecules in various physiological and pathological processes.A myriad of studies have shown that abnormal levels of sphingolipids and their metabolic enzymes are associated with a variety of human diseases.Moreover,blood sphingolipids can also be used as biomarkers for disease diagnosis.This review summarizes the biosynthesis,metabolism,and pathological roles of sphingolipids,with emphasis on the biosynthesis of ceramide,the precursor for the biosynthesis of complex sphingolipids with different fatty acyl chains.The possibility of using sphingolipids for disease prediction,diagnosis,and treatment is also discussed.Targeting endogenous ceramides and complex sphingolipids along with their specific fatty acyl chain to promote future drug development will also be discussed.

GreenPhos,a universal method for in-depth measurement of plant phosphoproteomes with high quantitative reproducibility

Protein phosphorylation regulates a variety of important cellular and physiological processes in plants.In-depth profiling of plant phosphoproteomes has been more technically challenging than that of animal phosphoproteomes.This is largely due to the need to improve protein extraction efficiency from plant cells,which have a dense cell wall,and to minimize sample loss resulting from the stringent sample clean-up steps required for the removal of a large amount of biomolecules interfering with phosphopeptide purification and mass spectrometry analysis.To this end,we developed a method with a streamlined workflow for highly efficient purification of phosphopeptides from tissues of various green organisms including Arabidopsis,rice,tomato,and Chlamydomonas reinhardtii,enabling in-depth identification with high quantitative reproducibility of about 11000 phosphosites,the greatest depth achieved so far with single liquid chromatography-mass spectrometry(LC-MS)runs operated in a data-dependent acquisition(DDA)mode.The mainstay features of the method are the minimal sample loss achieved through elimination of sample clean-up before protease digestion and of desalting before phosphopeptide enrichment and hence the dramatic increases of time-and cost-effectiveness.The method,named GreenPhos,combined with single-shot LC-MS,enabled in-depth quantitative identification of Arabidopsis phosphoproteins,including differentially phosphorylated spliceosomal proteins,at multiple time points during salt stress and a number of kinase substrate motifs.GreenPhos is expected to serve as a universal method for purification of plant phosphopeptides,which,if samples are further fractionated and analyzed by multiple LC-MS runs,could enable measurement of plant phosphoproteomes with an unprecedented depth using a given mass spectrometry technology.

A zebrafish tufm mutant model for the COXPD4 syndrome of aberrant mitochondrial function

Mitochondrial dysfunction is a critical factor leading to a wide range of clinically heterogeneous and often severe disorders due to its central role in generating cellular energy.Mutations in the TUFM gene are known to cause combined oxidative phosphorylation deficiency 4(COXPD4),a rare mitochondrial disorder characterized by a comprehensive quantitative deficiency in mitochondrial respiratory chain(MRC)complexes.The development of a reliable animal model for COXPD4 is crucial for elucidating the roles and mechanisms of TUFM in disease pathogenesis and benefiting its medical management.In this study,we construct a zebrafish tufm−/−mutant that closely resembles the COXPD4 syndrome,exhibiting compromised mitochondrial protein translation,dysfunctional mitochondria with oxidative phosphorylation defects,and significant metabolic suppression of the tricarboxylic acid cycle.Leveraging this COXPD4 zebrafish model,we comprehensively validate the clinical relevance of TUFM mutations and identify probucol as a promising therapeutic approach for managing COXPD4.Our data offer valuable insights for understanding mitochondrial diseases and developing effective treatments.

Erratum to “Lipidome Atlas of the Developing Heart Uncovers Dynamic Membrane Lipid Attributes Underlying Cardiac Structural and Metabolic Maturation”

Main Text In the Research Article“Lipidome Atlas of the Developing Heart Uncovers Dynamic Membrane Lipid Attributes Underlying Cardiac Structural and Metabolic Maturation”[1],there was an error in Fig.2B.The authors mistakenly repeated the chord diagram designated for P7 with that from P1.The figure amendment did not affect the in-text discussion of the figure,which was focused on changes between P0 and P21,and did not alter the conclusion.Figure 2B has now been corrected in the PDF and HTML(full text).

Results of the Second Life Metabolism Travel Awards 2024

This year is the second year of the Life Metabolism Travel Prize Awards for PhD students and postdocs.The three 700 US$awards are generously sponsored by Sable Systems-Promethion(China)who manufacture metabolic chambers.Before I announce the winners and their interesting projects,I will just reiterate how the judging of the awards works.We first remove anything from the submission that would identify the sex,affiliation,or ethnicity of the applicant.

The retromer component SNX6 interacts with dynactin p150Glued and mediates endosome-to-TGN transport

The retromer is a protein complex that mediates retrograde transport of transmembrane cargoes from endosomes to the trans-Golgi network （TGN）. It is comprised of a cargo-selection subcomplex of Vps26, Vps29 and Vps35 and a membrane-binding coat subcomplex of sorting nexins （SNXs）. Previous studies identified SNX1/2 as one of the components of the SNX subcomplex, and SNX5/6 as candidates for the second SNX. How the retromer-associated cargoes are recognized and transported by molecular motors are largely unknown. In this study, we found that one of SNX1/2＇s dimerization partners, SNX6, interacts with the p150Gued subunit of the dynein/dynactin motor complex. We present evidence that SNX6 is a component of the retromer, and that recruitment of the motor complex to the membrane-associated retromer requires the SNX6-pl50Gued interaction. Disruption of the SNX6-pl50Glued interaction causes failure in formation and detachment of the tubulovesicular sorting structures from endosomes and results in block of CI-MPR retrieval from endosomes to the TGN. These observations indicate that in addition to SNX1/2, SNX6 in association with the dynein/dynactin complex drives the formation and movement of tubular retrograde intermediates.

Molecular analysis of rice plants harboring a multi-functional T-DNA tagging system

About 25,000 rice T-DNA insertional mutant lines were generated using the vector pCAS04 which has both promoter-trapping and activation-tagging function. Southern blot analysis revealed that about 40% of these mutants were single copy integration and the average T-DNA insertion number was 2.28. By extensive phenotyping in the field, quite a number of agronomically important mutants were obtained. Histochemical GUS assay with 4,310 primary mutants revealed that the GUS-staining frequency was higher than that of the previous reports in various tissues and especially high in flowers. The T-DNA flanking sequences of some mutants were isolated and the T-DNA insertion sites were mapped to the rice genome. The flanking sequence analysis demonstrated the different integration pattern of the right border and left border into rice genome. Compared with Arabidopsis and poplar, it is much varied in the T-DNA border junctions in rice.