Research

1. Introduction

To integrate rapidly growing approaches of the human genome research into the exploration of complex diseases, Beijing Institute of Genomics (BIG) of Chinese Academy of Sciences (CAS) made the decision to establish the" Institute Key Laboratory of Disease Genomics and Individualized Medicine" in 2010. A key laboratory in research systems usually refers to a research center with several to a couple of tens of research groups leading by principal investigators (PIs). The research of our key lab includes mainly the discovery and functional analysis of genomic and epigenomic variations that contribute to cancer and various diseases. With our exciting achievements on the evolution and selection of somatic mutations in cancer genome as well as the coordination function of genomic and epigenomic alternations in tumor and in metabolic diseases, etc, this center was assigned as the CAS Key Laboratory of Genomic and Precision Medicine in summer of 2014.

2. Research directions

According to the major aims in field of public health in the CAS 135 plan, as well as taking the advantage of epigenetic research, high throughput sequencing, and data analysis and computation in the institute, the research directions of the CAS Key Laboratory of Genomic and Precision Medicine include four categories as briefly stated below.

(1) Characterization of tumor heterogeneity and approaches in diagnosis and medicine

Based on previously important results on the somatic mutation spectrum and lineage analysis, we will focus on cancer mutational patterns, analysis of cfDNA and circulating tumor cells, and the development of novel therapies.

(2) Genomic and epigenomic analyses of complex traits and diseases

Based on previous important results on epigenomics studies, we will focus on the function and mechanism of epigenetic variations including histone modification and their roles in leukemia development, RNA methylation in development and diseases, and the dynamic patterns of DNA methylation in tumorgenesis.

(3) Big data mining and construction of precision medicine model

Through interpreting and integrating multi-dimensional data of genome and phenotypes from cohort and clinical samples, we attempt to construct precision medicine platform including individualized assessment for disease risk based on genotype and phenotype analysis.

3. Organization

The key laboratory implements director responsibility system which under the direction of the institute and the academic advisory committee:

Director: WANG Qianfei

Associate Director: CI Weimin

Academic Committee

Chair: SHEN Yan, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences

Associate Chair: ZENG Yixin, Chinese Academy of Medical Sciences, Peking Union Medical College

Members (ordered alphabetically):

CHEN Runsheng, Institute of Biophysics, Chinese Academy of Sciences

DU Jie, Beijing Anzhen Hospital, Capital Medical University

GU Dongfeng, Fuwai Hospital, Chinese Academy of Medical Sciences

JI Jiafu, Peking University Institute of Clinical Oncology

LI Lin, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences

LIN Dongxi, Chinese Academy of Medical Sciences & Peking Union Medical College Tumor Hospital

PENG Xiaozhong, Institute of basic medicine, Chinese Academy of Medical Sciences

SHI Yufang, Shanghai Institutes for Biological Sciences; Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine

WANG Qianfei, Beijing Institute of Genomics, Chinese Academy of Sciences/China National Center for Bioinformation

WANG Xiaoning, Chinese PLA General Hospital

WANG Xiaomin, Capital Medical University

WANG Yongjun, Beijing Tian Tan Hospital, Capital Medical University

WU Hong, Peking University

WU Chung-I, Beijing Institute of Genomics, Chinese Academy of Sciences/China National Center for Bioinformation

XU Guoliang, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences

XU Tao, Institute of Biophysics, Chinese Academy of Sciences

YANG Yungui, Beijing Institute of Genomics, Chinese Academy of Sciences/China National Center for Bioinformation

ZENG Changqing, Beijing Institute of Genomics, Chinese Academy of Sciences/China National Center for Bioinformation

ZHANG Xuemin, Institute of Toxicology and Medicine, Academy of Military Medical Sciences

ZHOU Qi, Institute of Zoology, Chinese Academy of Sciences

ZHU Bing, Institute of Biophysics, Chinese Academy of Sciences

4. Annual research progress

(1) Characterization of tumor heterogeneity and approaches in diagnosis and medicine

We uncovered a novel HLH predisposing gene, NBAS, which can be used to screen children with poor prognosis. This study may have a substantial impact on updating the diagnostic criteria for HLH in both pediatric and adult patients. And China Daily commented that “the research is the latest example of China's intensified research efforts to rescue millions of patients with rare diseases in the country.” (Journal of Hematology & Oncology, 2022). We also identified genetic features and their significance on prognostic stratification in EBV-T/NK-LPDs (Journal of Allergy and Clinical Immunology, 2022). We further revealed the mechanism that small peptides from lncRNA affect cancer progression and drug resistance by regulating DNA damage response pathway (Molecular Cell, 2022).

We first demonstrated that vitamin C played critical roles in renal homeostasis, and represented an epigenetic therapy in the prevention and treatment of patients with a high risk of developing kidney injuries. (Journal of the American Society of Nephrology, 2022). We also found the tissue resident memory CD8+ T cells might be a potential immunotherapeutic marker for kidney cancer (Genome Biology, 2022). Through single-cell RNA sequencing (scRNA-seq) of primary tumor tissues from 14 patients with untreated advanced prostate cancer, we discovered that every tumor contained malignant cells corresponding to different transcriptional states, further revealing that both tumor cell transcriptomic heterogeneity and cellular ecosystem diversity are linked to features of poor prognosis (Advanced Science, 2022). It was found that UTUC and UCB have very similar DNA methylation profiles, and unsupervised DNA methylation classification identified two epi-clusters, Methy-High and Methy-Low, associated with distinct muscle-invasive statuses and patient outcomes, which provides mechanistic rational for evaluating SGI-110 in treating UC patients in the clinic. (BMC Medicine, 2022). We further developed a computational method to model immune evasion, and predicted therapeutic response of mUC treated in the IMvigor210 immunotherapy cohort, further providing potential therapeutic targets for immunotherapy in UC patients (Theranostics, 2022).

(2) Genomic and epigenomic analyses of complex traits and diseases

It was summarized the characteristics of scDART-seq technology and its discovery and application at the single-cell level, as well as the prospect of single-cell sequencing technology in the field of RNA epigenetics in the future (Molecular Cell, 2022). We developed a photocatalytic reaction based f5C RNA modification labeling and sequencing technology to provide a simple method for in situ labeling of RNA modification in cells and to achieve single base resolution determination (Angewandte Chemie International Edition in English, 2022).

We revealed a new mechanism of RNA helicase Ddx3xb regulating maternal mRNA translation through phase separation during early embryonic development in zebrafish (Cell Research, 2022). And Dynamic changes in RNA structure regulate YRDC translation through an ELAVL1-dependent mechanism, thereby regulating a new mechanism for the regulation of EGFR-TKIs drug resistance in non-small cell lung cancer (Genomics Proteomics & Bioinformatics, 2022). We also found that the m6A reader protein YTHDF3 promotes the translation of its target transcript CTNNB1, which promotes the proliferation and migration of ocular melanoma through m6A methylation (Oncogene, 2022). METTL3 attenuates the progression of endothelial atherosclerosis through m6A-dependent stabilization of EGFR mRNA (Elife, 2022). The distribution and function of m6A modification in Chlamydomonas mRNAs and provide new evolutionary insights into m6A modification during sexual reproduction in other plant organisms. (Genomics Proteomics & Bioinformatics, 2022). We further mapped the appearance of DNA 5hmC and RNA m5C during fetal organogenesis, and revealed the potential interaction between DNA modification and RNA methylation, thus ensuring the normal development of the fetus (Genomics Proteomics & Bioinformatics, 2022).

By constructing a heterochronic parabiosis model of aged and young mice, the study drew a comprehensive single-cell transcriptome atlas to reveal that exposure to young blood could effectively improve the tissue microenvironment of different organs in aged individuals，as well as restore the vitality of multiple adult stem cells. This study provided abundant data resources, key markers, and novel strategies for the development of aging warning and intervention. Additionally, this work also presents a new research paradigm for discovering the body's "rejuvenation factor" from a systems biology perspective (Cell Stem Cell, 2022). We further identified that the "entropy increase" of chromatin and the abnormal expression of placental-specific genes were the key drivers and new molecular markers of cell aging (Developmental Cell, 2022). Moreover, we demonstrated that the small-molecule metabolite uridine could significantly enhance the self-renewal capacity of aging human mesenchymal stem cells (Cell Discovery, 2022). By comparing the placental transcriptome of Tibetan, plain Han and Han plateau immigrants, we found that Tibetan placental makes efficient use of material and energy (Molecular Biology And Evolution, 2022).

(3) Big data mining and construction of precision medicine model

We developed ASCancer Atlas, which is the first human cancer alternative splicing function disorder of knowledge base, and is the important resources in the splicing disorder in cancer research (Nucleic Acids Research, 2022). The Brain Catalog, the largest and most comprehensive database of brain-related traits resources, was constructed to provide a one-stop comprehensive analysis of genetic loci, genes, and risk factors. The identified causal loci, causal genes and risk factors contribute to the understanding of disease mechanisms and are expected to be targets for gene function studies and future drug development (Nucleic Acids Research, 2022). We also developed the scCapsNet-mask, and extends its applicability in functional analysis on fate bias prediction in less differentiated cells and cell type assignment in spatial transcriptomics (BMC Bioinformatics, 2022). We further developed a set of SMART, a hybrid STR atlas analysis system with completely independent intellectual property rights, which greatly improved the utilization rate of mixed STR map results (Forensic Science and Technology, 2022).

(4) Study on COVID-19

We drew the multi-organ differential transcription map of rhesus monkeys infected with SARS-CoV-2 in the early stage, and analyzed the specific expression of NRP1 receptor in the cerebral cortex and the close signal transmission between tissues, as well as revealing the underlying mechanism of viral encephalitis potentially caused by enhanced inflammation and innate immune response (Protein & Cell, 2022). Combined with appropriate library preparation methods and decontamination algorithms, we found a method to obtain high-quality metagenomic data from trace DNA samples less than 1 ng (BMC Biology, 2022).

5. Annual awards and honors

WANG Qianfei, Second prize of Jiangsu Science and Technology Award in 2021.
CI Weimin, Second prize of Beijing Natural Science Award in 2021.
YANG Ying, Excellent member of Youth Innovation Promotion Association of Chinese Academy of Sciences in 2022.
CHEN Yusheng, Member of Youth Innovation Promotion Association of Chinese Academy of Sciences in 2022.
ZHAO Shilei, Second prize of Di 'ao Scholarship, 2022
ZHOU Jiayi and WU Ying, National Graduate Scholarship, 2022