Biology subjects

Chu, Q.

Publications and source records attributed to Chu, Q..

22 records · Page 2Linked to original sources

bioRxiv2019

STK11 is required for the normal program of ciliated cell differentiation in airways

The functional properties of mucosal surfaces are dependent on establishing the correct proportions of specialized epithelial cell types. Multiciliated cells (also known as ciliated cells) are evolutionarily conserved and functionally indispensable epithelial cells, as suggested by the link between ciliated cell dysfunction and chronic human disease. Ciliated cell differentiation is an ordered process that involves initial cell fate determination and multiciliogenesis. STK11, a serine/threonine kinase, has been reported to be down-regulated in human diseases associated with ciliopathies and functions as a tumor suppressor. Here, we show that STK11 is a physiological factor for the normal program of ciliated cell differentiation by phosphorylating MARK3, which directly suppresses ERK1/2 mediated pRB inactivation. Loss of Stk11 in airway progenitors impairs the differentiation of ciliated cells in both embryonic and adult airways. Our study establishes that STK11/MARK3/ERK1/2 signaling cascade is a key regulator to integrate ciliated cell fate commitment and the subsequent process of multiciliogenesis.

developmental biology↗

bioRxiv2019

An Improved Human smORF Annnotation Workflow Combining De Novo Transcriptome Assembly and Ribo-Seq

Protein-coding small open reading frames (smORFs) are emerging as an important class of genes, however, the coding capacity of smORFs in the human genome is unclear. By integrating de novo transcriptome assembly and Ribo-Seq, we confidently annotate thousands of novel translated smORFs in three human cell lines. We find that smORF translation prediction is noisier than for annotated coding sequences, underscoring the importance of analyzing multiple experiments and footprinting conditions. These smORFs are located within non-coding and antisense transcripts, the UTRs of mRNAs, and unannotated transcripts. Analysis of RNA levels and translation efficiency during cellular stress identifies regulated smORFs, providing an approach to select smORFs for further investigation. Sequence conservation and signatures of positive selection indicate that encoded microproteins are likely functional. Additionally, proteomics data from enriched human leukocyte antigen complexes validates the translation of hundreds of smORFs and positions them as a source of novel antigens. Thus, smORFs represent a significant number of important, yet unexplored human genes.

genomics↗

bioRxiv2018

Coordinative Metabolism of Glutamine Carbon and Nitrogen in proliferating Cancer Cells Under Hypoxia

Under hypoxia, most of glucose is converted to secretory lactate, which leads to the lack of carbon source from glucose and thus the overuse of glutamine-carbon. However, under such a condition how glutamine nitrogen is disposed to avoid releasing potentially toxic ammonia remains to be determined. Here we identify a metabolic flux of glutamine to secretory dihydroorotate under hypoxia. We found that glutamine nitrogen is indispensable to nucleotide biosynthesis, but enriched in dihyroorotate and orotate rather than processing to its downstream uridine monophosphate under hypoxia. Dihyroorotate, not orotate, is then secreted out of cells. The specific metabolic pathway occurs in vivo and is required for tumor growth. Such a metabolic pathway renders glutamine mainly to acetyl coenzyme A for lipogenesis, with the rest carbon and nitrogen being safely removed. Our results reveal how glutamine carbon and nitrogen are coordinatively metabolized under hypoxia, and provide a comprehensive understanding on glutamine metabolism.\n\nSignificanceTumor cells often addict to glutamine, and particularly utilize its carbon for lipogenesis under hypoxia. We reveal that tumor cells package the excessive glutamine-nitrogen into secretory dihydroorotate, instead of toxic ammonia. This specifically reprogrammed pathway supports in vivo tumor growth, and could offer diagnostic markers and therapeutic targets for cancers.

biochemistry↗

bioRxiv2018

Electron transfer dictates metabolic reprogramming in proliferating cells under hypoxia

Metabolic reprogramming extensively occurs in proliferating cancer cells. This phenomenon occurs highly heterogeneously, but its origin has remained unclear. Here we use a physicochemical concept of free electron potential (FEP) and its equation of state to profile metabolites. We demonstrate that FEP change between substrates and products exactly reflects electrons dissipated in a metabolic transformation. Based on the law of conservation of electron in chemical reactions, a function of FEP change for central metabolism in proliferating cells are further derived, and it can accurately predict metabolic behaviors under hypoxia by maximizing the cellular FEP change to consume electrons. Therefore, enabling electron transfer dictates metabolic reprogramming in hypoxic cells, which underlies the major findings in cancer metabolism and is supported by our experiments. Importantly, our model established on FEP helps to reveal a combination of promising targets to inhibit tumor growth under hypoxia by blocking electron consumption, and could also guide future studies on cancer metabolism under hypoxia.

biochemistry↗