Publications by authors named "Dingding Han"

29 Publications

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Arhgef2 regulates neural differentiation in the cerebral cortex through mRNA mA-methylation of Npdc1 and Cend1.

iScience 2021 Jun 24;24(6):102645. Epub 2021 May 24.

Laboratory of Medical Systems Biology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 510623 Guangzhou, China.

-methyladenosine (mA) is emerging as a vital factor regulating neural differentiation. Here, we report that deficiency of , a novel cause of a neurodevelopmental disorder we identified recently, impairs neurogenesis, neurite outgrowth, and synaptic formation by regulating mA methylation. knockout decreases expression of and total mA level significantly in the cerebral cortex. mA sequencing reveals that loss of reduces mA methylation of 1,622 mRNAs, including and which are both strongly associated with cell cycle exit and terminal neural differentiation. deficiency decreases mA methylations of the and mRNAs via down-regulation of Mettl14, and thereby inhibits the translation of and nuclear export of mRNAs. Overexpression of Mettl14, Npdc1, and Cend1 rescue the abnormal phenotypes in knockout mice, respectively. Our study provides a critical insight into a mechanism by which defective mediates mA-tagged target mRNAs to impair neural differentiation.
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http://dx.doi.org/10.1016/j.isci.2021.102645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185223PMC
June 2021

Hypomorphic and hypermorphic mouse models of Fsip2 indicate its dosage-dependent roles in sperm tail and acrosome formation.

Development 2021 Jun 14;148(11). Epub 2021 Jun 14.

Laboratory of Medical Systems Biology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 510623 Guangzhou, China.

Loss-of-function mutations in multiple morphological abnormalities of the sperm flagella (MMAF)-associated genes lead to decreased sperm motility and impaired male fertility. As an MMAF gene, the function of fibrous sheath-interacting protein 2 (FSIP2) remains largely unknown. In this work, we identified a homozygous truncating mutation of FSIP2 in an infertile patient. Accordingly, we constructed a knock-in (KI) mouse model with this mutation. In parallel, we established an Fsip2 overexpression (OE) mouse model. Remarkably, KI mice presented with the typical MMAF phenotype, whereas OE mice showed no gross anomaly except for sperm tails with increased length. Single-cell RNA sequencing of the testes uncovered altered expression of genes related to sperm flagellum, acrosomal vesicle and spermatid development. We confirmed the expression of Fsip2 at the acrosome and the physical interaction of this gene with Acrv1, an acrosomal marker. Proteomic analysis of the testes revealed changes in proteins sited at the fibrous sheath, mitochondrial sheath and acrosomal vesicle. We also pinpointed the crucial motifs of Fsip2 that are evolutionarily conserved in species with internal fertilization. Thus, this work reveals the dosage-dependent roles of Fsip2 in sperm tail and acrosome formation.
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http://dx.doi.org/10.1242/dev.199216DOI Listing
June 2021

The strategy of modulation blood responses by surface modification with different functional groups on polyester film.

J Biomed Mater Res A 2021 Jun 3. Epub 2021 Jun 3.

Institute of Blood Transfusion, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.

A main problem in the design of blood-contacting biomaterials has been the deficiency of a systematic understanding of blood-biomaterial interactions and the strategy to modulate blood responses. In this work, different functional groups including carboxyl (COOH), hydroxyl (OH) and zwitterionic sulfobetaine group (⊕N((CH ) )(CH ) SO , SMDB) were grafted on the poly (butylene terephthalate) (PBT) film to study how the functional groups modulate blood responses and in terms of interaction with the coagulation system, the complement system, and platelets. The results showed protein absorption and platelet adhesion was stronger on the PBT bearing COOH group than PBT films bearing OH and zwitterionic sulfobetaine groups (total protein (μg/cm ): 32.92 ± 5.89 vs. 22.02 ± 1.44 vs. 19.09 ± 1.59; platelet adhesion (/mm ): 1,626.7 ± 120.1 vs. 1,395.6 ± 363.3 vs. 1,102.2 ± 373.7), which had a rougher and negatively charged surface, and the coagulation system was inhibited by binding fibrinogen (Fg) and coagulation factors. Meanwhile, PBT-PSMDB showed anticoagulant property and induced platelet activation. As a result, complement formation on these two films were less than PBT bearing OH groups by inhibiting the coagulation system (C3a (ng/ml): 3,745.4 ± 143.9 vs. 3,290.9 ± 249.7 vs. 4,887.9 ± 88.9; C5a (ng/ml): 22.1 ± 2.6 vs. 22.3 ± 1.8 vs. 27.9 ± 2.0). On the other hand, PBT bearing OH groups did not facilitate remarkable platelet adhesion and activation, and had no influence on platelet aggregation, hypotonic shock response, and coagulation system. The above results showed that the blood responses were highly interlinked, and could be modulated by grafting with different functional groups on the biomaterial surfaces. These findings may help identify a strategy to design materials with better hemocompatibility for blood contact, filtration, and purification applications.
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http://dx.doi.org/10.1002/jbm.a.37188DOI Listing
June 2021

In-depth analysis reveals complex molecular aetiology in a cohort of idiopathic cerebral palsy.

Brain 2021 Jun 2. Epub 2021 Jun 2.

Laboratory of Medical Systems Biology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 510623, Guangzhou, China.

Cerebral palsy is the most prevalent physical disability in children; however, its inherent molecular mechanisms remain unclear. In the present study, we performed in-depth clinical and molecular analysis on 120 idiopathic cerebral palsy families, and identified underlying detrimental genetic variants in 45% of these patients. In addition to germline variants, we found disease-related postzygotic mutations in approximately 6.7% of cerebral palsy patients. We found that patients with more severe motor impairments or a comorbidity of intellectual disability had a significantly higher chance of harboring disease-related variants. By a compilation of 114 known cerebral-palsy-related genes, we identified characteristic features in terms of inheritance and function, from which we proposed a dichotomous classification system according to the expression patterns of these genes and associated cognitive impairments. In two patients with both cerebral palsy and intellectual disability, we revealed that the defective TYW1, a tRNA hypermodification enzyme, caused primary microcephaly and problems in motion and cognition by hindering neuronal proliferation and migration. Furthermore, we developed an algorithm and demonstrated in mouse brains that this malfunctioning hypermodification specifically perturbed the translation of a subset of proteins involved in cell cycling. This finding provided a novel and interesting mechanism for congenital microcephaly. In another cerebral palsy patient with normal intelligence, we identified a mitochondrial enzyme GPAM, the hypomorphic form of which led to hypomyelination of the corticospinal tract in both human and mouse models. In addition, we confirmed that the aberrant Gpam in mice perturbed the lipid metabolism in astrocytes, resulting in suppressed astrocytic proliferation and a shortage of lipid contents supplied for oligodendrocytic myelination. Taken together, our findings elucidate novel aspects of the etiology of cerebral palsy and provide insights for future therapeutic strategies.
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http://dx.doi.org/10.1093/brain/awab209DOI Listing
June 2021

Upregulation of Nogo-B by hypoxia inducible factor-1 and activator protein-1 in hepatocellular carcinoma.

Cancer Sci 2021 May 8. Epub 2021 May 8.

Department of Clinical Laboratory, Shanghai Children's Hospital, Shanghai Jiaotong University, Shanghai, China.

Nogo-B is an important regulator of tumor angiogenesis. Expression of Nogo-B is remarkably upregulated in multiple tumor types, especially hepatocellular carcinoma (HCC). Here, we show the transcriptional regulation mechanisms of Nogo-B in liver cancer. In response to hypoxia, expression of Nogo-B significantly increased in HCC tissues and cells. The distal hypoxia-responsive element in the promoter was essential for transcriptional activation of Nogo-B under hypoxic conditions, which is the specific site for hypoxia inducible factor-1α (HIF-1α) binding. In addition, Nogo-B expression was associated with c-Fos expression in HCC tissues. Nogo-B expression was induced by c-Fos, yet inhibited by a dominant negative mutant A-Fos. Deletion and mutation analysis of the predicted activator protein-1 binding sites revealed that functional element mediated the induction of Nogo-B promoter activity, which was confirmed by ChIP. These results indicate that HIF-1α and c-Fos induce the expression of Nogo-B depending on tumor microenvironments, such as hypoxia and low levels of nutrients, and play a role in upregulation of Nogo-B in tumor angiogenesis.
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http://dx.doi.org/10.1111/cas.14941DOI Listing
May 2021

Bi-allelic mutation in Fsip1 impairs acrosome vesicle formation and attenuates flagellogenesis in mice.

Redox Biol 2021 Jul 16;43:101969. Epub 2021 Apr 16.

Laboratory of Medical Systems Biology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 510623, Guangzhou, China. Electronic address:

Fibrous sheath interacting protein 1 (Fsip1) is a cytoskeletal structural protein of the sperm flagellar proteome. A few studies have reported that it plays a vital role in the tumorigenesis and cancer progression. However, little is known about the role of Fsip1 in spermatogenesis and mammalian sperm flagellogenesis. Fsip1 protein showed the highest expression in round spermatids, and was translocated from nucleus to the anterior region of the elongating spermatid head. To investigate its role we constructed homozygous Fsip1 null (Fsip1) mice. We found that the homozygous Fsip1 mutant mice were infertile, with a low sperm count and impaired motility. Interestingly, a subtle phenotype characterized by abnormal head shape, and flagella deformities was observed in the sperm of Fsip1 mutant mice similar to the partial globozoospermia phenotype. Electron microscopy analysis of Fsip1 sperm revealed abnormal accumulation of mitochondria, disrupted axoneme and retained cytoplasm. Testicular sections showed increased cytoplasmic vacuoles in the elongated spermatid of Fsip1mice, which indicated an intraflagellar transport (IFT) defect. Using proteomic approaches, we characterized the cellular components and the mechanism underlying this subtle phenotype. Our result indicated that Fsip1downregulates the formation of acrosomal membrane and vesicles proteins, intraflagellar transport particles B, and sperm flagellum components. Our results suggest that Fsip1 is essential for normal spermiogenesis, and plays an essential role in the acrosome biogenesis and flagellogenesis by attenuating intraflagellar transport proteins.
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http://dx.doi.org/10.1016/j.redox.2021.101969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099781PMC
July 2021

Variation of microRNA expression in the human placenta driven by population identity and sex of the newborn.

BMC Genomics 2021 Apr 20;22(1):286. Epub 2021 Apr 20.

Skolkovo Institute of Science and Technology, 121205, Moscow, Russia.

Background: Analysis of lymphocyte cell lines revealed substantial differences in the expression of mRNA and microRNA (miRNA) among human populations. The extent of such population-associated differences in actual human tissues remains largely unexplored. The placenta is one of the few solid human tissues that can be collected in substantial numbers in a controlled manner, enabling quantitative analysis of transient biomolecules such as RNA transcripts. Here, we analyzed microRNA (miRNA) expression in human placental samples derived from 36 individuals representing four genetically distinct human populations: African Americans, European Americans, South Asians, and East Asians. All samples were collected at the same hospital following a unified protocol, thus minimizing potential biases that might influence the results.

Results: Sequence analysis of the miRNA fraction yielded 938 annotated and 70 novel miRNA transcripts expressed in the placenta. Of them, 82 (9%) of annotated and 11 (16%) of novel miRNAs displayed quantitative expression differences among populations, generally reflecting reported genetic and mRNA-expression-based distances. Several co-expressed miRNA clusters stood out from the rest of the population-associated differences in terms of miRNA evolutionary age, tissue-specificity, and disease-association characteristics. Among three non-environmental influenced demographic parameters, the second largest contributor to miRNA expression variation after population was the sex of the newborn, with 32 miRNAs (3% of detected) exhibiting significant expression differences depending on whether the newborn was male or female. Male-associated miRNAs were evolutionarily younger and correlated inversely with the expression of target mRNA involved in neuron-related functions. In contrast, both male and female-associated miRNAs appeared to mediate different types of hormonal responses. Demographic factors further affected reported imprinted expression of 66 placental miRNAs: the imprinting strength correlated with the mother's weight, but not height.

Conclusions: Our results showed that among 12 assessed demographic variables, population affiliation and fetal sex had a substantial influence on miRNA expression variation among human placental samples. The effect of newborn-sex-associated miRNA differences further led to expression inhibition of the target genes clustering in specific functional pathways. By contrast, population-driven miRNA differences might mainly represent neutral changes with minimal functional impacts.
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http://dx.doi.org/10.1186/s12864-021-07542-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059241PMC
April 2021

The Interface Motion and Hydrodynamic Shear of the Liquid Slosh in Syringes.

Pharm Res 2021 Feb 22;38(2):257-275. Epub 2021 Feb 22.

Department of Mechanical Engineering, Purdue University, West Lafayette, Indiana, USA.

Purpose: Interface motion and hydrodynamic shear of the liquid slosh during the insertion of syringes upon autoinjector activation may damage the protein drug molecules. Experimentally validated computational fluid dynamics simulations are used in this study to investigate the interfacial motion and hydrodynamic shear due to acceleration and deceleration of syringes. The goal is to explore the role of fluid viscosity, air gap size, syringe acceleration, syringe tilt angle, liquid-wall contact angle, surface tension and fill volume on the interface dynamics caused by autoinjector activation.

Methods: A simplified autoinjector platform submerged in water is built to record the syringe and liquid motion without obstruction of view. The syringe kinematics is imported to the simulations based on OpenFOAM InterIsoFoam solver, which is used to study the effects of various physical parameters.

Results: The simulations agree with experiments on the air-liquid interface profile and interface area. The interfacial area and the volume of fluid subject to high strain rate decrease with the solution viscosity, increase with the air gap height, syringe velocity, tilt angle and syringe wall hydrophobicity, and hardly change with the surface tension and liquid column height. The hydrodynamic shear mainly occurs near the syringe wall and entrained bubbles.

Conclusion: For a given dose of drug solution, the syringe with smaller radius and larger length will generate less liquid slosh. Reducing the air volume and syringe wall hydrophobicity are also helpful to reduce interface area and effective shear. The interface motion is reduced when the syringe axis is aligned with the gravitational direction.
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http://dx.doi.org/10.1007/s11095-021-02992-3DOI Listing
February 2021

Single-cell-resolution transcriptome map of human, chimpanzee, bonobo, and macaque brains.

Genome Res 2020 05 18;30(5):776-789. Epub 2020 May 18.

Skolkovo Institute of Science and Technology, Moscow, 143028, Russia.

Identification of gene expression traits unique to the human brain sheds light on the molecular mechanisms underlying human evolution. Here, we searched for uniquely human gene expression traits by analyzing 422 brain samples from humans, chimpanzees, bonobos, and macaques representing 33 anatomical regions, as well as 88,047 cell nuclei composing three of these regions. Among 33 regions, cerebral cortex areas, hypothalamus, and cerebellar gray and white matter evolved rapidly in humans. At the cellular level, astrocytes and oligodendrocyte progenitors displayed more differences in the human evolutionary lineage than the neurons. Comparison of the bulk tissue and single-nuclei sequencing revealed that conventional RNA sequencing did not detect up to two-thirds of cell-type-specific evolutionary differences.
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http://dx.doi.org/10.1101/gr.256958.119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263190PMC
May 2020

Generation of an induced pluripotent stem cell line SYSUi-004-A from a child of microcephaly with TYW1 mutations.

Stem Cell Res 2020 05 7;45:101783. Epub 2020 Apr 7.

Laboratory of Medical Systems Biology, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China. Electronic address:

We generated an induced human pluripotent stem cell line from a child with microcephaly carrying compound heterozygous mutations of TYW1 inherited from healthy parents. This iPS cell line showed typical embryonic stem cell-like morphology, expressed pluripotent markers that comparable to human embryonic stem cells. Moreover, these cells have the ability to differentiate into three germ layers and maintain a normal karyotype.
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http://dx.doi.org/10.1016/j.scr.2020.101783DOI Listing
May 2020

[Preparation and characterization of a hemostatic porous platelet-rich plasma chitosan/silk fibroin wound dressing].

Sheng Wu Gong Cheng Xue Bao 2020 Feb;36(2):332-340

Institute of Blood Transfusion, Peking Union Medical Collage, Chinese Academy of Medical Science, Chengdu 610052, Sichuan, China.

In order to further improve the hemostatic performance of wound dressings, human platelet-rich plasma (PRP) containing various growth factors was introduced into chitosan solution. The silk fibroin solutions with different volume ratios (1:1, 1:3, 3:1 and 1:0) were added to improve the porosity and hemostasis of materials. The hPRP-chitosan/silk wound dressings with different ratios was prepared by freeze-drying and pure chitosan dressing was considered as the control group to study the effects of PRP and silk fibroin in different proportions on the hemostasis properties and the growth factors burst release. The hemostasis of chitosan dressing was improved by introducing PRP, but the porous structure and water absorption were not significantly improved. If silk fibroin solution was added in the ratio of 1:1, the more uniform porous structure and better hemostatic performance could be obtained. The porosity and water absorption could reach 86.83%±3.84% and 1 474%±114% respectively. In addition, the dressings with ratio of 1:1 had positive effects on reducing the burst release of growth factors on initial stage. Therefore, PRP-chitosan/silk fibroin composite dressing can become a kind of wound dressing that can achieve rapid hemostasis and promote wound healing.
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http://dx.doi.org/10.13345/j.cjb.190190DOI Listing
February 2020

Organoid single-cell genomic atlas uncovers human-specific features of brain development.

Nature 2019 10 16;574(7778):418-422. Epub 2019 Oct 16.

Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany.

The human brain has undergone substantial change since humans diverged from chimpanzees and the other great apes. However, the genetic and developmental programs that underlie this divergence are not fully understood. Here we have analysed stem cell-derived cerebral organoids using single-cell transcriptomics and accessible chromatin profiling to investigate gene-regulatory changes that are specific to humans. We first analysed cell composition and reconstructed differentiation trajectories over the entire course of human cerebral organoid development from pluripotency, through neuroectoderm and neuroepithelial stages, followed by divergence into neuronal fates within the dorsal and ventral forebrain, midbrain and hindbrain regions. Brain-region composition varied in organoids from different iPSC lines, but regional gene-expression patterns remained largely reproducible across individuals. We analysed chimpanzee and macaque cerebral organoids and found that human neuronal development occurs at a slower pace relative to the other two primates. Using pseudotemporal alignment of differentiation paths, we found that human-specific gene expression resolved to distinct cell states along progenitor-to-neuron lineages in the cortex. Chromatin accessibility was dynamic during cortex development, and we identified divergence in accessibility between human and chimpanzee that correlated with human-specific gene expression and genetic change. Finally, we mapped human-specific expression in adult prefrontal cortex using single-nucleus RNA sequencing analysis and identified developmental differences that persist into adulthood, as well as cell-state-specific changes that occur exclusively in the adult brain. Our data provide a temporal cell atlas of great ape forebrain development, and illuminate dynamic gene-regulatory features that are unique to humans.
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http://dx.doi.org/10.1038/s41586-019-1654-9DOI Listing
October 2019

Self-awareness control effect of cooperative epidemics on complex networks.

Chaos 2019 May;29(5):053123

School of Information Science and Technology, Fudan University, Shanghai 200433, China.

Coinfection mechanism is a common interacting mode between multiple diseases in real spreading processes, where the diseases mutually increase their susceptibility, and has aroused widespread studies in network science. We use the bond percolation theory to characterize the coinfection model under two self-awareness control strategies, including immunization strategy and quarantine strategy, and to study the impacts of the synergy effect and control strategies on cooperative epidemics. We find that strengthening the synergy effect can reduce the epidemic threshold and enhance the outbreak size of coinfected networks. On Erdős-Rényi networks, the synergy effect will induce a crossover phenomenon of phase transition, i.e., make the type of phase transition from being continuous to discontinuous. Self-awareness control strategies play a non-negligible role in suppressing cooperative epidemics. In particular, increasing immunization or the quarantine rate can enhance the epidemic threshold and reduce the outbreak size of cooperative epidemics, and lead to a crossover phenomenon of transition from being discontinuous to continuous. The impact of quarantine strategy on cooperative epidemics is more significant than the immunization strategy, which is verified on scale-free networks.
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http://dx.doi.org/10.1063/1.5063960DOI Listing
May 2019

Nogo-B promotes tumor angiogenesis and provides a potential therapeutic target in hepatocellular carcinoma.

Mol Oncol 2018 12 26;12(12):2042-2054. Epub 2018 Oct 26.

State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China.

Tumor angiogenesis is one of the hallmarks of cancer as well as an attractive target for cancer therapy. Characterization of novel pathways that act in parallel with the VEGF/VEGFR axis to promote tumor angiogenesis may provide insights into novel anti-angiogenic therapeutic targets. We found that the expression level of Nogo-B is positively correlated with tumor vessel density in hepatocellular carcinoma (HCC). While Nogo-B depletion inhibited tumor angiogenesis, Nogo-B overexpression promoted tumor angiogenesis in a tumor xenograft subcutaneous model of the human HCC cell line. Mechanically, Nogo-B regulates tumor angiogenesis based on its association with integrin α β and activation of focal adhesion kinase. Moreover, Nogo-B antibody successfully abolished the function of Nogo-B in tumor angiogenesis in vitro and in vivo. Collectively, our results strongly suggest that Nogo-B is an important tumor angiogenic factor and blocking Nogo-B selectively inhibits tumor angiogenesis.
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http://dx.doi.org/10.1002/1878-0261.12358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6275258PMC
December 2018

Conservation, evolution, and regulation of splicing during prefrontal cortex development in humans, chimpanzees, and macaques.

RNA 2018 04 23;24(4):585-596. Epub 2018 Jan 23.

Center for Data-Intensive Biomedicine and Biotechnology, Skolkovo Institute of Science and Technology, Moscow 143028, Russia.

Changes in splicing are known to affect the function and regulation of genes. We analyzed splicing events that take place during the postnatal development of the prefrontal cortex in humans, chimpanzees, and rhesus macaques based on data obtained from 168 individuals. Our study revealed that among the 38,822 quantified alternative exons, 15% are differentially spliced among species, and more than 6% splice differently at different ages. Mutations in splicing acceptor and/or donor sites might explain more than 14% of all splicing differences among species and up to 64% of high-amplitude differences. A reconstructed -regulatory network containing 21 RNA-binding proteins explains a further 4% of splicing variations within species. While most age-dependent splicing patterns are conserved among the three species, developmental changes in intron retention are substantially more pronounced in humans.
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http://dx.doi.org/10.1261/rna.064931.117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5855957PMC
April 2018

Comprehensive transcriptome analysis of neocortical layers in humans, chimpanzees and macaques.

Nat Neurosci 2017 Jun 17;20(6):886-895. Epub 2017 Apr 17.

Skolkovo Institute of Science and Technology, Skolkovo, Russia.

While human cognitive abilities are clearly unique, underlying changes in brain organization and function remain unresolved. Here we characterized the transcriptome of the cortical layers and adjacent white matter in the prefrontal cortexes of humans, chimpanzees and rhesus macaques using unsupervised sectioning followed by RNA sequencing. More than 20% of detected genes were expressed predominantly in one layer, yielding 2,320 human layer markers. While the bulk of the layer markers were conserved among species, 376 switched their expression to another layer in humans. By contrast, only 133 of such changes were detected in the chimpanzee brain, suggesting acceleration of cortical reorganization on the human evolutionary lineage. Immunohistochemistry experiments further showed that human-specific expression changes were not limited to neurons but affected a broad spectrum of cortical cell types. Thus, despite apparent histological conservation, human neocortical organization has undergone substantial changes affecting more than 5% of its transcriptome.
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http://dx.doi.org/10.1038/nn.4548DOI Listing
June 2017

Disruption of an Evolutionarily Novel Synaptic Expression Pattern in Autism.

PLoS Biol 2016 Sep 29;14(9):e1002558. Epub 2016 Sep 29.

CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai, China.

Cognitive defects in autism spectrum disorder (ASD) include socialization and communication: key behavioral capacities that separate humans from other species. Here, we analyze gene expression in the prefrontal cortex of 63 autism patients and control individuals, as well as 62 chimpanzees and macaques, from natal to adult age. We show that among all aberrant expression changes seen in ASD brains, a single aberrant expression pattern overrepresented in genes involved synaptic-related pathways is enriched in nucleotide variants linked to autism. Furthermore, only this pattern contains an excess of developmental expression features unique to humans, thus resulting in the disruption of human-specific developmental programs in autism. Several members of the early growth response (EGR) transcription factor family can be implicated in regulation of this aberrant developmental change. Our study draws a connection between the genetic risk architecture of autism and molecular features of cortical development unique to humans.
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http://dx.doi.org/10.1371/journal.pbio.1002558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5042529PMC
September 2016

Changes in snoRNA and snRNA Abundance in the Human, Chimpanzee, Macaque, and Mouse Brain.

Genome Biol Evol 2016 Mar 23;8(3):840-50. Epub 2016 Mar 23.

CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai, China Skolkovo Institute for Science and Technology, Skolkovo, Russia Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany School of Life Science and Technology, ShanghaiTech University, Shanghai, China

Small nuclear and nucleolar RNAs (snRNAs and snoRNAs) are known to be functionally and evolutionarily conserved elements of transcript processing machinery. Here, we investigated the expression evolution of snRNAs and snoRNAs by measuring their abundance in the frontal cortex of humans, chimpanzees, rhesus monkeys, and mice. Although snRNA expression is largely conserved, 44% of the 185 measured snoRNA and 40% of the 134 snoRNA families showed significant expression divergence among species. The snRNA and snoRNA expression divergence included drastic changes unique to humans: A 10-fold elevated expression ofU1snRNA and a 1,000-fold drop in expression ofSNORA29 The decreased expression ofSNORA29might be due to two mutations that affect secondary structure stability. Using in situ hybridization, we further localizedSNORA29expression to nucleolar regions of neuronal cells. Our study presents the first observation of snoRNA abundance changes specific to the human lineage and suggests a possible mechanism underlying these changes.
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http://dx.doi.org/10.1093/gbe/evw038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4824147PMC
March 2016

Adaption to High Altitude: An Evaluation of the Storage Quality of Suspended Red Blood Cells Prepared from the Whole Blood of Tibetan Plateau Migrants.

PLoS One 2015 4;10(12):e0144201. Epub 2015 Dec 4.

Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu, Sichuan, China.

Hypoxia has been reported to cause the significant enhancement of hemoglobin (Hb) and hematocrit (Hct), which stabilizes at relatively high levels after an individual ascends to a high altitude. However, the quality of the suspended red blood cells (SRBCs) obtained from individuals at high altitudes such as Tibetan plateau migrants after storage has not been studied. In this study, we compared the storage quality of SRBCs prepared from Tibetan plateau and Deyang lowland populations by adding a normal volume of mannitol-adenine-phosphate (MAP), which is a common additive solution used in blood storage in Asian countries. The storage cell characteristics were examined on days 1, 7, 14 and 35.We found higher Hct and Hb levels and viscosity in the high altitude samples. The metabolic rates, including those for electrolytes and lactate, were higher in plateau SRBCs than in lowland SRBCs; these findings were consistent with the higher osmotic fragility and hemolysis of plateau SRBCs throughout the entire storage period. In addition, the reduction rates of 2,3-diphosphoglycerate (2,3-DPG) and oxygen tension to attain 50% oxygen saturation of Hb (P50) in plateau SRBCs were higher than those in lowland SRBCs, and the oxygen delivering capacity in plateau SRBCs was weaker than that in lowland SRBCs. We concluded that the storage quality of plateau SRBCs was inferior to that of lowland SRBCs when using the same concentration of MAP. We suggested that the optimal formula, including the MAP concentration or even a new additive solution, to store the plateau SRBCs must be assessed and regulated.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0144201PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4670121PMC
June 2016

Conserved expression of lincRNA during human and macaque prefrontal cortex development and maturation.

RNA 2014 Jul 20;20(7):1103-11. Epub 2014 May 20.

CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai 200031, China Max Planck Institute for Evolutionary Anthropology, 04103 Leipzig, Germany.

The current annotation of the human genome includes more than 12,000 long intergenic noncoding RNAs (lincRNA). While a handful of lincRNA have been shown to play important regulatory roles, the functionality of most remains unclear. Here, we examined the expression conservation and putative functionality of lincRNA in human and macaque prefrontal cortex (PFC) development and maturation. We analyzed transcriptome sequence (RNA-seq) data from 38 human and 40 macaque individuals covering the entire postnatal development interval. Using the human data set, we detected the expression of 5835 lincRNA annotated in GENCODE and further identified 1888 novel lincRNA. Most of these lincRNA show low DNA sequence conservation, as well as low expression levels. Remarkably, developmental expression patterns of these lincRNA were as conserved between humans and macaques as those of protein-coding genes. Transfection of development-associated lincRNA into human SH-SY5Y cells affected gene expression, indicating their regulatory potential. In brain, expression of these putative target genes correlated with the expression of the corresponding lincRNA during human and macaque PFC development. These results support the potential functionality of lincRNA in primate PFC development.
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http://dx.doi.org/10.1261/rna.043075.113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4074677PMC
July 2014

TCP10L acts as a tumor suppressor by inhibiting cell proliferation in hepatocellular carcinoma.

Biochem Biophys Res Commun 2014 Mar 21;446(1):61-7. Epub 2014 Feb 21.

State Key Laboratory of Genetic Engineering, Institute of Genetics, Fudan University, Shanghai 200433, PR China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, PR China. Electronic address:

TCP10L (T-complex 10 (mouse)-like) has been identified as a liver and testis-specific gene. Although a potential transcriptional suppression function of TCP10L has been reported previously, biological function of this gene still remains largely elusive. In this study, we reported for the first time that TCP10L was significantly down-regulated in clinical hepatocellular carcinoma (HCC) samples when compared to the corresponding non-tumorous liver tissues. Furthermore, TCP10L expression was highly correlated with advanced cases exceeding the Milan criteria. Overexpression of TCP10L in HCC cells suppressed colony formation, inhibited cell cycle progression through G0/G1 phase, and attenuated cell growth in vivo. Consistently, silencing of TCP10L promoted cell cycle progression and cell growth. Therefore, our study has revealed a novel suppressor role of TCP10L in HCC, by inhibiting proliferation of HCC cells, which may facilitate the diagnosis and molecular therapy in HCC.
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http://dx.doi.org/10.1016/j.bbrc.2014.02.049DOI Listing
March 2014

p53 Represses transcription of RING finger LIM domain-binding protein RLIM through Sp1.

PLoS One 2013 1;8(5):e62832. Epub 2013 May 1.

State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, PR China.

RLIM acts as a negative regulator of LIM-Homeodomain proteins either by recruiting Sin3A/Histone Deacetylase (HDAC) co-repressor complex or through degradation of CLIM coactivator, thus playing an important role in embryonic development. Recent studies by different research groups have shown that RLIM acts as an X-encoded, dose-dependent inducer of X chromosome inactivation in mouse embryonic stem cells. However, until now, very little is known about the expression regulation of RLIM gene, and we tried to study the transcriptional regulation of RLIM gene. In the present study, we identified RLIM as a novel target of p53 and demonstrated that p53 repressed both mRNA and protein levels of RLIM. Expression of wild type p53, but not p53 mutants, led to repression of the RLIM promoter activity. We further identified four putative Sp1 elements (S1 to S4) on the RLIM promoter that are essential for p53-mediated repression of RLIM. Although p53 does not directly bind to the RLIM promoter, it physically interacts with and prevents the binding of Sp1 to the RLIM promoter. Thus, RLIM is a novel target of p53, and p53 exerts its inhibitory effect on RLIM expression by interfering with Sp1-mediated transcriptional activation on RLIM. Our results provided data to enlarge the knowledge of transcriptional regulation of RLIM and suggested a new pathway by which physiological and pathological activators of p53 may affect development.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0062832PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3641103PMC
November 2013

DNAJC25 is downregulated in hepatocellular carcinoma and is a novel tumor suppressor gene.

Oncol Lett 2012 Dec 10;4(6):1274-1280. Epub 2012 Sep 10.

State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai 200433, P.R. China.

HSP40, also known as DnaJ, is one of the subfamilies of the heat shock protein family. DnaJ/Hsp40 proteins act as co-chaperones by binding to the chaperone Hsp70 through their J domain and stimulating ATP hydrolysis to aid protein translation, folding, unfolding, translocation and degradation. They are implicated in various human diseases, including neurodegenerative disorders and cancer. In the present study, we cloned and identified a new gene, DnaJ (HSP40) homolog, subfamily C, member 25 (DNAJC25), which is localized to the cytoplasm. Real-time PCR revealed that the expression of DNAJC25 is particularly high in the liver and is down-regulated in hepatocellular carcinoma (HCC) compared with adjacent normal tissues. The overexpression of DNAJC25 led to an inhibition of colony growth both in quantity and size. Flow cytometry analysis indicated that DNAJC25 also significantly increased cell apoptosis. Our data, therefore, indicate that DNAJC25 plays an important role in hepatocellular carcinogenesis, and should be further studied as a potential tumor suppressor candidate.
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http://dx.doi.org/10.3892/ol.2012.903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3506724PMC
December 2012

Metallothionein MT1M is a tumor suppressor of human hepatocellular carcinomas.

Carcinogenesis 2012 Dec 12;33(12):2568-77. Epub 2012 Sep 12.

State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, PR China.

Members of the metallothionein (MT) family are short, cysteine-rich proteins involved in metal metabolism and detoxification, suggesting that MT proteins protect cells from damage caused by electrophilic carcinogens and thereby constitute a critical surveillance system against carcinogenesis. However, the roles of MT proteins in human hepatocellular carcinoma (HCC) are not fully understood. We identified a member of the MT family, termed MT1M. MT1M is expressed in various normal tissues with the highest level in the liver. MT1M expression can be induced by heavy metals and protect Escherichia coli from heavy metal toxicity. However, MT1M expression markedly decreased in human HCC specimens. A methylation profiling analysis indicated that the MT1M promoter is methylated in the majority of HCC tumors examined. Moreover, restored expression of MT1M in the HCC cell line Hep3B, which lacks endogenous MT1M expression, suppressed cell growth in vitro and in vivo and augmented apoptosis induced by tumor necrosis factor α. Furthermore, stable expression of MT1M in Hep3B cells blocked tumor necrosis factor α-induced degradation of IκBα and transactivation of NF-κB. We conclude that MT1M is a novel member of the MT family. Frequent downregulation of MT1M in human HCC may contribute to liver tumorigenesis by increasing cellular NF-κB activity.
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http://dx.doi.org/10.1093/carcin/bgs287DOI Listing
December 2012

Zinc finger transcription factor 191, directly binding to β-catenin promoter, promotes cell proliferation of hepatocellular carcinoma.

Hepatology 2012 Jun;55(6):1830-9

State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, PR China.

Unlabelled: Activation of β-catenin, the central effector of the canonical wingless-type (Wnt) pathway, has been implicated in hepatocellular carcinoma (HCC). However, the transcription regulation mechanism of the β-catenin gene in HCC remains unknown. Here we report that human zinc finger protein 191 (ZNF191) is a potential regulator of β-catenin transcription. ZNF191, a Krüppel-like protein, specifically interacts with the TCAT motif, which constitutes the HUMTH01 microsatellite in the tyrosine hydroxylase (TH) gene ex vivo. We demonstrate that ZNF191 is significantly overexpressed in human HCC specimens and is associated with growth of human HCC cells. Global profiling of gene expression in ZNF191 knockdown human hepatic L02 cells revealed that the important Wnt signal pathway genes β-catenin and cyclin D1 messenger RNAs (mRNAs) are significantly down-regulated. In agreement with transcription level, β-catenin and cyclin D1 proteins are also down-regulated in transient and stable ZNF191 knockdown L02 and hepatoma Hep3B cell lines. Moreover, significant correlation between ZNF191 and β-catenin mRNA expression was detected in human HCCs. Promoter luciferase assay indicated that ZNF191 can increase transcription activity of the full-length β-catenin (CTNNB1) promoter, and nucleotide (nt)-1407/-907 of the CTNNB1 promoter exhibited the maximum transcriptional activity. Electrophoretic mobility shift assay showed that purified ZNF191 protein can directly bind to the CTNNB1 promoter, and the binding region is located at nt-1254/-1224. Finally, we demonstrate that the key binding sequence of ZNF191 in vivo is ATTAATT.

Conclusion: ZNF191 can directly bind to the CTNNB1 promoter and activate the expression of β-catenin and its downstream target genes such as cyclin D1 in hepatoma cell lines. This study uncovers a new molecular mechanism of transcription regulation of the β-catenin gene in HCC.
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http://dx.doi.org/10.1002/hep.25564DOI Listing
June 2012

Characterization of neuritin as a novel angiogenic factor.

Biochem Biophys Res Commun 2011 Dec 31;415(4):608-12. Epub 2011 Oct 31.

State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai 200433, PR China.

Neuritin (NRN1), a neurotrophic factor, plays an important role in neurite growth and neuronal survival. In this study, we identify a new function of neuritin as a novel angiogenic factor in vitro and in vivo. Recombinant neuritin protein had no effect on the proliferation and adhesion of human umbilical vein endothelial cells (HUVEC), but it dose-dependently increased endothelial cell migration. Furthermore, overexpression of neuritin significantly promoted tumor angiogenesis, and surprisingly, it inhibited tumor growth in a xenograft tumor model. Thus, our results indicate that neuritin may act as an important angiogenic factor and serve as a potential target for cancer therapy.
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http://dx.doi.org/10.1016/j.bbrc.2011.10.118DOI Listing
December 2011

PIDD4, a novel PIDD isoform without the LRR domain, can independently induce cell apoptosis in cytoplasm.

Biochem Biophys Res Commun 2011 Apr 28;407(1):86-91. Epub 2011 Feb 28.

State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai 200433, PR China.

PIDD1 (P53-induced death domain) is a pro-apoptotic gene which can be induced by p53. So far, three alternative splicing products of human PIDD gene have been identified. Here we report a new splicing variant of this gene and named it PIDD4. The coding sequence of PIDD4 contains intron 3 and a 60 bp insert at the 5' of exon 3. Each insertion has an in-frame stop codon, which makes PIDD4 get translated from exon 5 then. Therefore, PIDD4 protein lacks the 32 KD N-terminal peptide, missing the LRR domain found in the other three isoforms. In this study, we have shown that the expression of PIDD4 is also regulated by p53, and as PIDD2, it is not expressed in heart either. Moreover, PIDD4 is the only isoform which is expressed in skeletal muscle. This isoform mainly localizes in the cytoplasm, and produces a relatively higher proportion of PIDD-CC fragment. Overexpression of PIDD4 independently promotes apoptosis.
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http://dx.doi.org/10.1016/j.bbrc.2011.02.114DOI Listing
April 2011

Functional identification of a novel 14-3-3 epsilon splicing variant suggests dimerization is not necessary for 14-3-3 epsilon to inhibit UV-induced apoptosis.

Biochem Biophys Res Commun 2010 May 22;396(2):401-6. Epub 2010 Apr 22.

State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai 200433, PR China.

14-3-3 proteins function as a dimer and have been identified to involve in diverse signaling pathways. Here we reported the identification of a novel splicing variant of human 14-3-3 epsilon (14-3-3 epsilon sv), which is derived from a novel exon 1' insertion. The insertion contains a stop codon and leads to a truncated splicing variant of 14-3-3 epsilon. The splicing variant is translated from the exon 2 and results in the deletion of an N-terminal alpha-helix which is crucial for the dimerization. Therefore, the 14-3-3 epsilon sv could not form a dimer with 14-3-3 zeta. However, after UV irradiation 14-3-3 epsilon sv could also support cell survival, suggesting monomer of 14-3-3 epsilon is sufficient to protect cell from apoptosis.
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http://dx.doi.org/10.1016/j.bbrc.2010.04.104DOI Listing
May 2010

Cloning of a novel human NHEDC1 (Na+/H+ exchanger like domain containing 1) gene expressed specifically in testis.

Mol Biol Rep 2006 Sep;33(3):175-80

Institute of Genetics, School of Life Sciences, Fudan University, Shanghai 200433, China.

The Na+/H+ exchangers (NHEs) catalyze the transport of Na+ in exchange for H+ across membranes in organisms and are required for numerous physiological processes. Here we report the cloning and characterization of a novel human NHEDC1 (Na+/H+ exchanger like domain containing 1) gene, which was mapped to human chromosome 4p24. This cDNA is 1859 bp in length, encoding a putative protein of 515 amino acids. The NHEDC1 proteins are highly conserved in mammals including human, mouse, rat, and Macaca fascicularis. One remarkable characteristic of human NHEDC1 gene is that it is exclusively expressed in the testis by RT-PCR analysis. Western blot analysis showed that the molecular weight of NHEDC1 is about 56 KDa.
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http://dx.doi.org/10.1007/s11033-006-0010-yDOI Listing
September 2006