The center for molecular systems biology was established in 2006. The mission of the center is to pursue research related to human health and agricultural development using multidisciplinary approaches comprising computational biology, bioinformatics, systems biology, structural biology, evolutionary genetics and omics. Research at the center focuses on the hidden regulatory mechanisms underlying gene expression, the assembly, modification and dynamics of macromolecules, the noise and robustness of biological systems. In 2016, the center has received research funds from the 973 program, the 863 program, the key research projects of NSFC and the strategic projects of CAS. The center has two patents approved, and has made substantive progresses in a variety of research directions with 19 SCI papers published. The center, as participants, received the second prize of National Natural Science Awards and the first prize of S&T Excellent Achievement Awards for Universities. Two graduate students of the center won the National Scholarship.
Transcriptomics: Xiujie Wang’s group reports that ubiquitously expressed genes participate in cell-specific functions via alternative promoter usage. They identified 110 mouse embryonic stem cell (mESC) specifically expressed transcripts with cell-stage-specific alternative transcription start sites (SATS isoforms) from 104 ubiquitously expressed genes, majority of which have active epigenetic modification-or stem cell-related functions. These SATS isoforms are specifically expressed in mESCs, and tend to be transcriptionally regulated by key pluripotency factors through direct promoter binding. Knocking down the SATS isoforms of Nmnat2 or Usp7 leads to differentiation-related phenotype in mESCs. These results demonstrate that cell-type-specific transcription factors are capable to produce cell-type-specific transcripts with alternative transcription start sites from ubiquitously expressed genes, which confer ubiquitously expressed genes novel functions to involve in the establishment or maintenance of cell-type-specific features.
Functional Proteomics: Yingchun Wang’s group focuses on the study of growth factor-Induced nucleocytoplasmic shuttling proteins. They identified 203 nucleocytoplasmic shuttling proteins containing 46 imported proteins and 157 exported proteins in response to epidermal growth factor (EGF) stimulation using quantitative proteomics techniques. More than a half of the exported proteins contain predicted nuclear export sequence (NES). Furthermore, they found that phosphorylation of Serine 1055 of XPO1, a potential substrate of RSK2, plays an important role in nucleocytoplasmic shuttling.
Structural Biology: Yuhang Chen’s group focuses on the structural and functional studies of CENP-A anti-loading factor Ccp1 in centromeres. CENP-A is a centromere-specific histone H3 variant and also localized in centromere. Ccp1 could prevent CENP-A from improperly loading into chromosome in centromere and non-centromeric regions. According to molecular replacement and single wave length anomalous diffraction, they solved the structure of Ccp1. Ccp1 is belonged to NAP family and forms a homodimer in solution. Ccp1 is composed of three domains and has a ‘headphone’ topology. Long α1 helix in N terminal is dimerization domain, responsible for binding two Ccp1 monomers. Five α helixes and four β sheets form a hydrophobic core. The C terminal of Ccp1 is highly flexible for its abundance in acidic amino acids. By introducing mutation into Ccp1, they disrupted the dimer structure, resulting in loss of function in vivo. In order to explore the interaction between Ccp1 and histones, we respectively reconstituted the CENP-A/H4 dimer and H3/H4 dimer in vitro. The evidence from pull-down experiment demonstrated that Ccp1 prioritized to bind CENP-A rather than H3. This finding may explain how the Ccp1 regulate the CENP-A assembly in centromeric regions.
Evolutionary Genomics: Wenfeng Qian’s group revealed the impact of individual synonymous codons on mRNA levels by a codon-resolution analysis. They attempted to quantify this impact using 3,556 synonymous variants of the heterologous gene encoding green fluorescent protein (GFP) and 523 synonymous variants of the endogenous gene (TDH3) in yeast. They found the mRNA level to be strongly correlated with codon usage bias (CUB) for both genes, demonstrating a direct role of CUB in regulating the transcript concentration, likely via regulating mRNA degradation. They further estimated that the impact of CUB on mRNA level explains ~36% of the correlation between CUB and mRNA level among yeast genes. Their study revealed pleiotropic effects of synonymous codon usage, provided an alternative explanation for the well-known correlation between CUB and gene expression level, and called for re-evaluation of the theories on the evolution of CUB.
Systems Developmental Biology: Zhuo Du’s group analyzed the developmental properties and dynamics of cell position noise during embryogenesis. Using live imaging, automated lineage tracing and quantitative single-cell analyses they have systematically measured and analyzed the noise of cell positions during every minute of the first half of embryogenesis in C. elegans. Results show that each cell’s position exhibits characteristic and dynamic noise profile during the course of embryogenesis. Noise of cell positions is largely independent of cell division pattern, localization, migration distance, movement velocity and cell fate, but is strongly coupled to the lineage identity, lineage distance, and morphological organization. These findings establish that instead of being stochastic, noise of cell position is subjected to tight developmental constraints. On the basis of these results they are performing mechanistic analyses to explore the regulation and implications of cellular noise during embryogenesis.
QiangTu’s group performs a systematic functional analysis of long non-coding RNAs in medaka embryonic development and sex determination. They identified 890 lncRNA genes with dynamic expression profiles during embryogenesis, 104 lncRNA genes with sexually dimorphic expression patterns during sex determination stages. They also characterized many spatial expression patterns of these lncRNA genes. They are employing a functional analysis strategy combining both multiplex knockdown screening and individual knockout in vivo, together with bioinformatics and developmental biology techniques, to perform a large-scale analysis of lncRNAs in embryonic development and sex determination in medaka. Their study could gain a better understanding of the biological function of lncRNAs in vertebrate development.
