CAS Key Laboratory of Genomic and Precision Medicine

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: ZENG Changqing

Associate Director: YANG Yungui, WANG Qianfei

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

In study of tumors of urinary system, AA subtype, which is a marker for a low-risk group, was found being able to be ascertained by low coverage sequencing in urinary cell-free DNA. This finding raise the potential for early diagnosis and detection through mutation signature analysis in urine (Theranostics, 2020).

For analyses on cancer of digestive tract, based on probe capture and deep sequencing, a method to enrich the chimeric fragments of HBV integration was developed (Hepatol Int, 2020). Furthermore, using this new method cfDNA of hepatocellular carcinoma (HCC) patients was enriched and followed by low-coverage bisulfite DNA sequencing. A hypo-methylation status at regions of HBV integration was revealed, suggesting a new strategy of non-invasive detection for early stage of HCC (BMC Medicine, 2020). On the other hand, through comparing the DNA methylation profiles of colorectal adenoma and cancer samples, a gene promoter was found as a potential DNA methylation marker for colorectal cancer. In particular, the evaluation accuracy in public dataset showed a better performance of this marker than the current cfDNA commercial marker SEPT9. Therefore, this is expected to be a new target for early diagnosis of colorectal cancer (Clin epigenetics, 2020).

In the study for a group of early onset patients of mantle cell lymphoma (MCL), the germline mutations in DNA repair system was found highly correlated to early development of MCL. DNA repair defects plus B cell function related germline mutations was further found to be linked with early onset of MCL. Therefore, germline mutations on DNA repair system in combination with other mutations in specific tissues, such a double-hit may cause early-onset tumor formation was proposed, which provides a new idea for tumor diagnosis and treatment (Oncogenes, 2020).

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

It was found that the m6A writer Mettl3 or the nuclear reader Ythdc1 in mouse embryonic stem cells increases chromatin accessibility and activates transcription in an m6A-dependent manner, which provide a new idea and perspective for the study of the complex epigenomic regulatory network of organisms (Science, 2020). Elavl1a regulating maternal RNA stability in an RNA structure-dependent fashion, further regulation of maternal-to-zygotic transition and early embryonic development of zebrafish, reveal a broad and fundamental role of RNA post-transcriptional regulation in vertebrate early embryogenesis (Genome Biol, 2020). We first build up mRNA m5C profile in rice and discover OsNSUN2 is the major mRNA m5C methyltransferase in rice. OsNUSN2-dependent m5C modification of mRNA enhances rice adaptation to high temperature (Dev Cell, 2020).

Through comprehensive single-cell and single-nucleus transcriptomic atlases across various rat tissues undergoing aging and CR, we found that CR attenuated aging-related changes in cell type composition, gene expression, and core transcriptional regulatory networks, and chronic inflammation is a common feature of mammalian body and organ aging, which provides early warning of aging new biological markers (Cell, 2020). Through a single-cell transcriptomic survey of aortas and coronary arteries in young and old cynomolgus monkeys, FOXO3A, a longevity-associated transcription factor, was characterized the transcriptional landmarks that regulate vascular senility and position (Nat Commu, 2020).

A single cell capsule network (scCapsNet) model based on deep learning method is constructed to identify subcellular-type more stably and efficiently (Nature Machine Intelligence, 2020). From this a cell cloning strategy favorable for single-cell genomic dissection was further developed, which can be applied for the characteristics of somatic mutations and the dynamic phylogenetic lineages in normal or tumor cells (Comput Struct Biotec, 2020).

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

TheAging Atlas database-the First Multi-omics Database in Aging Biology was constructed from different levels such as conventional transcriptome, transcriptomics (RNA-seq), single-cell transcriptomics (scRNA-seq), epigenomics (ChIP-seq), proteomics (protein-protein interaction), and pharmacogenomics (geroprotective compounds), which make the convergence and fusion of gene expression regulation with aging trends under different conditions a reality (Nucleic Acids Res, 2020).

Through genetic prediction modelling of eye, hair and skin color considering phenotype correlations in addition to the DNA predictors, we found that using truly observed correlated pigmentation phenotypes as additional predictors increased the DNA-based prediction accuracies (Forensic Sci Int-Gen, 2020).

(4) Study on COVID-19

We found that SARS-CoV-2 infection strongly altered the transcriptome of lung cells, causing hypercytokinemia and increases in activated dendritic cells and neutrophils. These host responses to SARS-CoV-2 infection could further our understanding of disease pathogenesis and point toward antiviral strategies (Cell Host &Microbe, 2020). Through an integrative genomic, epidemiological, demographic, and serological analysis of data from infected patients, their close contacts, and enviromental samples, which showed that contaminated cold-chain food could be the possible origin of COVID-19 resurgence in Beijing, thereby highlights the possibility of an environment-to-human transmission route (Natl Sci Rev, 2020).

Cooperating with Huawei and other research teams to carry out a virtual drug screening study for all proteins of the SARS-CoV2, an interactive online platform (https://shennongproject.com:11443/#/home) was constructed, which visually displays about 180,000 virtual screening results and can be used as an evaluation tool for new drug discovery.

5. Annual awards and honors

YANG Yungui became the member of the Academia Europaea.

The curriculum “Research Ethics, Bioethics, and Survival Skills for A Research Career” by ZENG Changqing, was awarded as the University “Excellent Course for Graduate Students”

The curriculum “Molecular Genetics and Epigenetics” by REN Jie, ZHANG Weiqi, JIANG Lan, and YANG Ying, was awarded as the University “Excellent Course for Graduate Students”

YANG Ying became the member of Beijing Nova program.

ZHANG Li and NIU Kaifeng became the member of 2021 Youth Innovation Promotion Association of CAS.

LIU Qi, SHEN Zijie and ZHANG Ting won the National Scholarship.

CHEN Chuanyuan and SHI Boyang won Outstanding Award of president of Chinese Academy of Sciences.

ZHONG Jiaxin won Zhu Liyuehua Scholarship.

SHI Boyang won the Outstanding Graduate of Beijing and the University of the Chinese Academy of Sciences.