Biology subjects

Sun, T.

Publications and source records attributed to Sun, T..

6 recordsLinked to original sources

bioRxiv2018

TP promotes malignant progression in hepatocellular carcinoma through pentose Warburg effect

Tumor progression is dependent on metabolic reprogramming. Metastasis and vasculogenic mimicry (VM) are typical tumor progression. The relationship of metastasis, VM and metabolic reprogramming is not clear. In this study, we identified the novel role of Twist1, a VM regulator, in the transcriptional regulation of the expression of thymidine phosphorylase (TP). We demonstrated that TP promoted extracellular thymidine metabolization into ATP and amino acids through pentose Warburg effect by coupling the pentose phosphate pathway and glycolysis. Moreover, Twist1 relied on TP-induced metabolic reprogramming to promote hepatocellular carcinoma (HCC) metastasis and VM formation mediated by VE-Cad, VEGFR1, and VEGFR2 in vitro and in vivo. TP inhibitor tipiracil reduced promotion effect of TP enzyme activity on HCC VM formation and metastasis. Our findings demonstrate that TP, transcriptionally activated by Twist1, promotes HCC VM formation and metastasis through pentose Warburg effect, contributing to tumor progression.

cell biology↗

bioRxiv2018

Hierarchical multiscale simulation of DNA condensation

DNA condensation and phase separation is of utmost importance for DNA packing in vivo with important applications in medicine, biotechnology and polymer physics. The presence of hexagonally ordered DNA is observed in virus capsids, sperm heads and in dinoflagellates. Rigorous modelling of this process in all-atom MD simulations is presently difficult to achieve due to size and time scale limitations. We used a hierarchical approach for systematic multiscale coarse-grained (CG) simulations of DNA phase separation induced by the three-valent cobalt(III)-hexammine (CoHex3+). Solvent-mediated effective potentials for a CG model of DNA were extracted from all-atom MD simulations. Simulations of several hundred 100-bp-long CG DNA oligonucleotides in the presence of explicit CoHex3+ ions demonstrated aggregation to a liquid crystalline hexagonally ordered phase. Following further coarse-graining and extraction of effective potentials, we conducted modelling at mesoscale level. In agreement with electron microscopy observations, simulations of an 10.2-kbp-long DNA molecule showed phase separation to either a toroid or a fibre with distinct hexagonal DNA packing. The mechanism of toroid formation is analysed in detail. The approach used here is based only on the underlying all-atom force field and uses no adjustable parameters and may be generalized to modelling chromatin up to chromosome size.

biophysics↗

bioRxiv2018

MicroRNA miR-7 and miR-17-92 in POMC neurons are associated with sex-specific regulation of diet-induced obesity

Proopiomelanocortin (POMC) neurons in the arcuate nucleus (ARC) in mammalian hypothalamus play important roles in regulating appetite, energy expenditure, and glucose and fat metabolisms. Diet-induced obesity often show sex-specific difference. But the underlying mechanisms remain unclear. Here we show that microRNA (miRNA) miR-7 and miR-17-92 are expressed in the mouse ARC, and mostly in POMC neurons. Knockdown of miR-7 and knockout of miR-17-92 specifically in POMC neurons aggravate diet-induced obesity only in females and males, respectively. Moreover, gene expression profile analysis identifies sex-differential genes in male and female ARCs in wildtype adult mice. Interestingly, these genes that normally show low-expression in the female and male ARCs display upregulated expression in female miR-7 knockdown and male miR-17-92 knockout mice, respectively. Our results demonstrate an important role of miRNAs in regulating sex-specific diet-induced obesity, likely through modulating expression of target genes that show sex-differential expression in the ARC of hypothalamus.

neuroscience↗

bioRxiv2018

Mammalian stringent-like response mediated by the cytosolic NADPH phosphatase MESH1

Nutrient deprivation triggers stringent response in bacteria, allowing rapid reallocation of resources from proliferation toward stress survival. Critical to this process is the accumulation/degradation of (p)ppGpp regulated by the RelA/SpoT homologues. While mammalian genomes encode MESH1, a homologue of the bacterial (p)ppGpp hydrolase SpoT, neither (p)ppGpp nor its synthetase has been identified in mammalian cells. Therefore, the function of MESH1 remains a mystery. Here, we report that human MESH1 is an efficient cytosolic NADPH phosphatase, an unexpected enzymatic activity that is captured by the crystal structure of the MESH1-NADPH complex. MESH1 depletion promotes cell survival under ferroptosis-inducing conditions by sustaining the level of NADPH, an effect that is reversed by the simultaneous depletion of the cytosolic NAD(H) kinase, NADK, but not its mitochondrial counterpart NADK2. Importantly, MESH1 depletion also triggers extensive transcriptional changes that are distinct from the canonical integrated stress response but resemble the bacterial stringent response, implicating MESH1 in a previously uncharacterized stress response in mammalian cells.

biochemistry↗

bioRxiv2018

Large-scale gene losses underlie the genome evolution of parasitic plant Cuscuta australis

Dodders (Cuscuta spp., Convolvulaceae) are globally distributed root- and leafless parasitic plants that parasitize a wide range of hosts. The physiology, ecology, and evolution of these obligate parasites are still poorly understood. A high-quality reference genome (size 266.74 Mb and contig N50 of 3.63 Mb) of Cuscuta australis was assembled. Our analyses reveal that Cuscuta experienced accelerated evolution, and Cuscuta and the convolvulaceous morning glory (Ipomoea) shared a common whole-genome triplication event before their divergence. Importantly, C. australis genome harbors only 19805 protein-coding genes, and 11.7% of the conserved orthologs in autotrophic plants are lost in C. australis. Many of these gene loss events likely result from the plants parasitic lifestyle and large changes in its body plan. Moreover, comparison of the gene expression patterns in Cuscuta prehaustoria/haustoria and various tissues of closely related autotrophic plants suggests that Cuscuta haustorium genes largely evolved from roots. The C. australis genome provides important resources for studying the evolution of parasitism, regressive evolution, and evo-devo in plant parasites.

genomics↗

bioRxiv2017

Single-cell analysis of clonal dynamics in direct lineage reprogramming: a combinatorial indexing method for lineage tracing

Single-cell technologies are offering unprecedented insight into complex biology, revealing the behavior of rare cell populations that are typically masked in bulk population analyses. The application of these methodologies to cell fate reprogramming holds particular promise as the manipulation of cell identity is typically inefficient, generating heterogeneous cell populations. One current limitation of single-cell approaches is that lineage relationships are lost as a result of cell processing, restricting interpretations of the data collected. Here, we present a single-cell resolution lineage-tracing approach based on the combinatorial indexing of cells, CellTagging. Application of this method, in concert with high-throughput single-cell RNA-sequencing, reveals the transcriptional dynamics of direct reprogramming from fibroblasts to induced endoderm progenitors. These analyses demonstrate that while many cells initiate reprogramming, complete silencing of fibroblast identity and transition to a progenitor-like state represents a rare event. Clonal analyses uncover a remarkable degree of heterogeneity arising from individual cells. Overall, very few cells fully reprogram to generate expanded populations with a low degree of clonal diversity. Extended culture of these engineered cells reveals an instability of the reprogrammed state and reversion to a fibroblast-like phenotype. Together, these results demonstrate the utility of our lineage-tracing approach to reveal dynamics of lineage reprogramming, and will be of broad utility in many cell biological applications.

genomics↗