ORCID Profile
0000-0002-4810-2730
Current Organisation
Zhejiang University
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Publisher: Public Library of Science (PLoS)
Date: 13-07-2020
Publisher: Springer Science and Business Media LLC
Date: 06-02-2015
DOI: 10.1007/S00726-015-1928-Y
Abstract: Cell-penetrating peptides (CPPs) are well known as intracellular delivery vectors. However, unsatisfactory delivery efficiency and poor specificity are challenging barriers to CPP applications at the clinical trial stage. Here, we showed that S3, an EGFR-binding domain derived from vaccinia virus growth factor, when fused to a CPP such as HBD or TAT can substantially enhance its internalization efficiency and tumor selectivity. The uptake of S3-HBD (S3H) recombinant molecule by tumor cells was nearly 80 folds increased compared to HBD alone. By contrast, the uptake of S3H by non-neoplastic cells still remained at a low level. The specific recognition between S3 and its receptor, EGFR, as well as between HBD and heparan sulfate proteoglycans on the cell surface was essential for these improvements, suggesting a syngeneic effect between the two functional domains in conjugation. This syngeneic effect is likely similar to that of the heparin-binding epidermal growth factor, which is highly abundant particularly in metastatic tumors. The process that S3H entered cells was dependent on time, dosage, and energy, via macropinocytosis pathway. With excellent cell-penetrating efficacy and a novel tumor-targeting ability, S3H appears as a promising candidate vector for targeted anti-cancer drug delivery.
Publisher: Frontiers Media SA
Date: 31-05-2021
DOI: 10.3389/FGENE.2021.625466
Abstract: Zebrafish represent a valuable model for investigating the molecular and cellular basis of Fragile X syndrome (FXS). Reduced expression of the zebrafish FMR1 orthologous gene, fmr1 , causes developmental and behavioural phenotypes related to FXS. Zebrafish homozygous for the hu2787 non-sense mutation allele of fmr1 are widely used to model FXS, although FXS-relevant phenotypes seen from morpholino antisense oligonucleotide (morpholino) suppression of fmr1 transcript translation were not observed when hu2787 was first described. The subsequent discovery of transcriptional adaptation (a form of genetic compensation), whereby mutations causing non-sense-mediated decay of transcripts can drive compensatory upregulation of homologous transcripts independent of protein feedback loops, suggested an explanation for the differences reported. We examined the whole-embryo transcriptome effects of homozygosity for fmr1 h u 2787 at 2 days post fertilisation. We observed statistically significant changes in expression of a number of gene transcripts, but none from genes showing sequence homology to fmr1 . Enrichment testing of differentially expressed genes implied effects on lysosome function and glycosphingolipid biosynthesis. The majority of the differentially expressed genes are located, like fmr1 , on Chromosome 14. Quantitative PCR tests did not support that this was artefactual due to changes in relative chromosome abundance. Enrichment testing of the “leading edge” differentially expressed genes from Chromosome 14 revealed that their co-location on this chromosome may be associated with roles in brain development and function. The differential expression of functionally related genes due to mutation of fmr1 , and located on the same chromosome as fmr1 , is consistent with R.A. Fisher’s assertion that the selective advantage of co-segregation of particular combinations of alleles of genes will favour, during evolution, chromosomal rearrangements that place them in linkage disequilibrium on the same chromosome. However, we cannot exclude that the apparent differential expression of genes on Chromosome 14 genes was, (if only in part), caused by differences between the expression of alleles of genes unrelated to the effects of the fmr1 h u 2787 mutation and made manifest due to the limited, but non-zero, allelic ersity between the genotypes compared.
Publisher: Elsevier BV
Date: 12-2023
Publisher: Public Library of Science (PLoS)
Date: 11-2022
DOI: 10.1371/JOURNAL.PBIO.3001856
Abstract: Feingold syndrome type 1, caused by loss-of-function of MYCN, is characterized by varied phenotypes including esophageal and duodenal atresia. However, no adequate model exists for studying the syndrome’s pathological or molecular mechanisms, nor is there a treatment strategy. Here, we developed a zebrafish Feingold syndrome type 1 model with nonfunctional mycn , which had severe intestinal atresia. Single-cell RNA-seq identified a subcluster of intestinal cells that were highly sensitive to Mycn, and impaired cell proliferation decreased the overall number of intestinal cells in the mycn mutant fish. Bulk RNA-seq and metabolomic analysis showed that expression of ribosomal genes was down-regulated and that amino acid metabolism was abnormal. Northern blot and ribosomal profiling analysis showed abnormal rRNA processing and decreases in free 40S, 60S, and 80S ribosome particles, which led to impaired translation in the mutant. Besides, both Ribo-seq and western blot analysis showed that mTOR pathway was impaired in mycn mutant, and blocking mTOR pathway by rapamycin treatment can mimic the intestinal defect, and both L-leucine and Rheb, which can elevate translation via activating TOR pathway, could rescue the intestinal phenotype of mycn mutant. In summary, by this zebrafish Feingold syndrome type 1 model, we found that disturbance of ribosomal biogenesis and blockage of protein synthesis during development are primary causes of the intestinal defect in Feingold syndrome type 1. Importantly, our work suggests that leucine supplementation may be a feasible and easy treatment option for this disease.
Publisher: Public Library of Science (PLoS)
Date: 24-01-2020
Publisher: Elsevier BV
Date: 04-2023
Publisher: Cold Spring Harbor Laboratory
Date: 27-01-2021
DOI: 10.1101/2021.01.26.428321
Abstract: The most common cause of early-onset familial Alzheimer’s disease (EOfAD) is mutations in PRESENILIN 1 ( PSEN1 ) allowing production of mRNAs encoding full-length, but mutant, proteins. In contrast, a single known frameshift mutation in PSEN1 causes familial acne inversa (fAI) without EOfAD. The molecular consequences of heterozygosity for these mutation types, and how they cause completely different diseases, remains largely unexplored. To analyse brain transcriptomes of young adult zebrafish to identify similarities and differences in the effects of heterozygosity for psen1 mutations causing EOfAD or fAI. RNA sequencing was performed on mRNA isolated from the brains of a single family of 6-month-old zebrafish siblings either wild type or possessing a single, heterozygous EOfAD-like or fAI-like mutation in their endogenous psen1 gene. Both mutations downregulate genes encoding ribosomal subunits, and upregulate genes involved in inflammation. Genes involved in energy metabolism appeared significantly affected only by the EOfAD-like mutation, while genes involved in Notch, Wnt and neurotrophin signalling pathways appeared significantly affected only by the fAI-like mutation. However, investigation of direct transcriptional targets of Notch signalling revealed possible increases in γ-secretase activity due to heterozygosity for either psen1 mutation. Transcriptional adaptation due to the fAI-like frameshift mutation was evident. We observed both similar and contrasting effects on brain transcriptomes of the heterozygous EOfAD-like and fAI-like mutations. The contrasting effects may illuminate how these mutation types cause distinct diseases.
Publisher: Cold Spring Harbor Laboratory
Date: 29-05-2023
DOI: 10.1101/2023.05.29.542713
Abstract: During gastrulation, the mesendoderm is firstly specified by morphogens such as Nodal, and then segregates into endoderm and mesoderm in a Nodal concentration-dependent manner. However, so far, the underlying mechanism of this segregation remains unclear. Here, taking zebrafish prechordal plate (PP) and endoderm (Endo) as research model, using single cell multi-omics and live imaging analyses, we show that anterior endodermal progenitors originate directly from prechordal plate. Deconvolution analysis for bulk RNA-seq datasets of Nodal-injected explants reveals that the specification of anterior endoderm from PP was determined by a relatively lower Nodal signaling. And a single-cell transcriptomic trajectory analysis of wild-type, ndr1 knockdown and lefty1 knockout Nodal explants confirms the ersification of Endo fate from PP progenitors. Genstoe Ontology (GO) enrichment analysis indicates that chromatin organization potentially underlies the segregation of endodermal cell fate from PP. A further single-cell ATAC and RNA sequencing analysis suggests a positive correlation between Nodal activity and chromatin openness. We then identify two transcriptional regulators, gsc and ripply1 , which are differentially activated in PP and Endo, and manipulation of their expression levels tilts the cell fate decision between these two lineages. Collectively, our study suggests that different levels of Nodal activity promote transcriptional ersification between PP and Endo potentially through modulation of chromatin states, which eventually leads to ersification in cell fate decisions.
No related grants have been discovered for Yang Dong.