Bioscience

Progress on Mechanism of Interspecies Transmission for Avian Influenza

George F. Gao’s group in the Institute of Microbiology, CAS, comprehensively explored the influenza virus in depth, including virus origin, bioinformatics analysis, functional and structural dissections of envelope proteins of influenza virus, construction of flu database,etc.. They continually acquired the important progress. The group studied the binding affinities of hemagglutinins (HAs) from wildtype and mutant H5N1 viruses to avian or human receptor analog by surface plasmon resonance method. They found that the wildtype HA preferentially binds avian receptor, while the mutant HA switches to bind human receptor and also retains a dramatically reduced affinity to avian receptor. It indicates that the mutant virus has the potential to infect the upper airway of mammals, and then to infect the lower airway to cause severe disease. With the help of staffs from Shanghai Synchrotron Radiation Facility (SSRF) and Japan Energy Accelerator Research Organization (KEK), they determined the structures of wildtype and mutant HAs in complex with avian and human receptor analogs. They elucidated the structural basis of both wildtype and mutant HAs bound to avian and human receptors, and found that Q226L amino acid substitution was a key determinant for the receptor binding switch and further revealed the molecular mechanism. They also proved that the other three amino acid substitutions in mutant HA are important for the airborne transmission of mutant H5 virus. For the first time, this research dissected the phenomenon that key residue substitutions in HA could confer the ability of airborne transmission to H5N1 virus at molecular level, which was a breakthrough in the field of interspecies transmission of avian influenza virus. This research also provided important information for the study of avian H7N9 influenza virus. On May 2, George F. Gao’s group published the achievement in Science Express, titled “An Airborne Transmissible Avian Influenza H5 Hemagglutinin Seen at the Atomic Level”.

Direct Conversion of Fibroblasts into Neural Progenitor-like Cells

Many stem cells grow into three-dimensional (3D) spheres or colonies, such as neural progenitor cells (NPCs) and embryonic stem cells (ESCs). Sphere morphology helps maintaining the stemness of stem cells. The previous study demonstrated that forced growth of RT4 and HEK293 cells into 3D sphere on low attachment surface could induce stem cell properties. The close relationship between 3D sphere morphology and stem cell stemness drives us to hypothesize that 3D sphere formation induces fibroblasts reprogramming. The key gene Sox2 for reprogramming fibroblasts into NPCs was found to be overexpressed in 3D sphere cultured mouse fibroblasts. These cells exhibited similar morphological and molecular features to NPCs in vitro, were capable of differentiating into neurons, astrocytes and oligodendrocytes, and could generate long-term expandable neurospheres while maintaining differentiation capability. When engrafted into hippocampus of adult rat brain, the 3D sphere cells differentiated into neural cells. Thus, NPCs can be generated from fibroblasts directly through a physical approach without introducing exogenous reprogramming factors. The result was achieved jointly by Su Guannan, Zhao Yannan, Wei Jianshu, et. el. from the State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, CAS, CAS Graduate School, Department of Neurosurgery of Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Department of Pathology, St. Joseph's Hospital, USA, which was published on magazine Biomaterials (Volume 34, Issue 24, August 2013, Pages 5897–5906).

Breakthrough in Epigenetic Inheritance

One long standing question in biological field is whether epigenetic information can be inherited by the offspring. Zebrafish is well known as a model for the vertebrate development. 85% of Zebrafish genome is similar to human genome. Dr. Liu Jiang with his colleagues from the Beijing Institute of Genomics, CAS, gained breakthrough discovery in epigenetic inheritance. The team generated nine single-base resolution DNA methylomes, including zebrafish gametes and early embryos. The oocyte methylome is significantly hypomethylated compared to sperm. Strikingly, zebrafish early embryos selectively inherit sperm methylomes by midblastula stage, while discarding oocyte methylome. Then, new DNA methylome reprogramming occurs after midblastula stage. But the reprogramming is based on the sperm methylation pattern, which is limited to specific regions. As a result, embryos can differentiate to different somatic cells, tissues, and organ. Moreover, inheritance of the sperm methylome facilitates the epigenetic regulation of embryogenesis. To evaluate the significance of paternal epigenetic inheritance, the team find that enucleated oocytes can only initiate development following transfer of a sperm nucleus, but not an oocyte nucleus, implying a fundamental epigenetic asymmetry that is consistent with the sperm methylome being in a competent state. Therefore, besides DNA sequences, sperm DNA methylome is also inherited in zebrafish early embryos. The finding will help unravel how one fertilized egg can be developing to an adult animal. This innovative work will give us a new theoretical foundation for the development of stem cell and translational medicine. Cell published the discovery as the story on May 9.