Research
CAS Key Laboratory of Genomic and Precision Medicine
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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. At various administration levels, a key laboratory usually refers to a research center with a few 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 research aims in field of public health in 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 CAS Key Laboratory of Genomic and Precision Medicine include four categories as briefly stated below.

(1) Heterogeneity and genome evolution in cancer

Depending on previously important results on the mutation spectrum and lineage of tumor mutation and improved analytical approaches by integrating population genetics and evolutionary theory, we will investigate the mutational patterns and their influence on tumor development, and further explore more therapies.

(2) Epigenetic variations and their roles in disease development

Based on previous important results on various levels of epigenomics studies, we will focus to understand the function and mechanism of epigenetic variations including histone modification and their roles in leukemia development, RNA methylation mechanism and their influences in the development and diseases, the dynamic patterns of DNA methylation during development and tumor genesis.

(3) Integrative analysis of big data and construction of precision medical data platform

Through interpreting and integrating multi-level data of genome and phenotype from large-scale prospective cohort and clinical samples, we attempt to construct precision medical data platform based on human genome records and previous relevant research achievements for diagnosis, therapeutics, and precision medicine, which supported by the advantages of the institute and CAS.

(4) Functional annotation for complex physiological traits and individualized patterns

The ultimate goal of human genome research is to maintain the state of health, and to achieve early prevention, early diagnostic, and accurate treatment for diseases. By precision and functional annotation in certain genes of several complex traits in our previous results, our future studies involves in two main directions: the impacts of alterations in the genome stability on tumor development and drug resistance and the functional annotation of genes associated with hypoxia adaptation and tumor microenvironment.

3. Organization

The 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
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
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
WANG Xiaoning, Chinese PLA General Hospital
WU Hong, Peking University
WU Chung-I, Beijing Institute of Genomics, Chinese Academy of Sciences
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
ZENG Changqing, Beijing Institute of Genomics, Chinese Academy of Sciences
ZHANG Xuemin, Academy of Military Medical Sciences
ZHOU Qi, Institute of Zoology, Chinese Academy of Sciences

4. Annual research progress

(1) Establishment of a cohort of Chinese Academy of Sciences (CAS) and electronic health record and genetic reports based on whole-genome analysis

New 400 population volunteers were recruited in 2017 from six institutions such as the CAS headquarters, the Administrative Bureau of CAS and Center for Space Science and Applied Research of CAS. We have obtained a total nearly 1000 DNA samples with high quality, and completed genome sequencing and analysis of more than half of them. A genetic report group composed of nine independent research teams was established. Through discussing repeatedly the report content and carrying out the genetic risk analysis, as well as evaluating the suggestions, we released the genetic report v1.0 for 380 volunteers successfully and got good feedback.

(2) Cancer genomics and evolution

To further test the hypothesis of neutral evolution, we select a hepatocellular carcinoma tumor that has large intratumor SNV and CNV (single nucleotide variation and copy number variation, respectively) diversity. We observe that intratumor divergence in gene expression profile lags far behind genetic divergence, indicating insufficient phenotypic differences for selection to operate. All these expression analyses corroborate that natural selection does not operate effectively within tumors, supporting recent interpretations of within-tumor diversity (MBE, 2017).

(3) Variations of epigenetic modifications in disease

We have established an improved RNA m5C single base resolution high-throughput sequencing and bioinformatics analysis technology, and revealed the distribution pattern of mRNA m5C. m5C in mRNA is mainly enriched at the regions immediately following the translation initiation site, and displays conserved, tissue-specific and dynamic features. We identified the main methyltransferase (writer) NSUN2 and the first m5C binding protein (reader) ALYREF, and further demonstrated the important role of m5C in promoting mRNA export, providing valuable resources for deciphering the potential biological significance of RNA m5C methylation (Cell Research, 2017a).

We applied the established Tandem affinity purification, TAP/MS (TAP/MS) and GST pull-down assay, and identified direct interaction between YTHDF3 and ribosomal 40S and 60S subunits. YTHDF3 significantly regulates translation of YTHDF1/3 common targets. Additional evidence demonstrated that cytoplasmic m6A reader YTHDF3 promotes mRNA translation through interacting with ribosomal proteins, in cooperation with YTHDF1 (Cell Research, 2017b).

In the collaborative study with Professor ZHOU Qi, we have found that depletion of Mettl3 affected the expression of associated genes at early-spermatogenesis, including spermatogonial maintainance, differentiation and meiosis.Mettl3-mediated m6A regulates the expression and alternative splicing of those genes and thereby regulates mouse spermatogenesis (Cell Research, 2017c).

In the collaborative study with Professor LIU Feng, we found a significantly decreased m6A levels and blocked emergence of HSPCs in mettl3-deficient embryos. The YTHDF2-RIP-Seq and the single base resolution m6A-miCLIP-Seq analyses revealed that the delayed YTHDF2-mediated mRNA decay of the arterial endothelial genes notch1a contributes to this deleterious effect. The continuous activation of Notch signaling in arterial endothelial cells of mettl3-deficient embryos blocks EHT, thereby repressing the generation of the earliest HSPCs. Those findings demonstrating the critical function of m6A modification in HSPC specification in vertebrates provide valuable resource for deciphering the physiological biological significance of RNA methylation and theoretical guidance for the in vitro induction of hematopoietic stem cells(Nature, 2017).

Utilizing an Asxl2-knockout murine model to determine disease phenotypes of Asxl2 loss and effects on histone modifications and transcriptome, we found that Asxl2 loss led to a myelodysplastic syndrome-like disease and myeloid leukemia in mice. Aberrantly expressed genes in hematopoietic stem/progenitor cells (HSPCs) from Asxl2-/- mice were associated with HSC function, cell apoptosis, and myelopoiesis. Importantly, the altered gene expression was associated with these dysregulated H3K27ac and H3K4me1/2. These data demonstrated that ASXL2 regulates hematopoietic transcriptional program through histone modifications, to maintain normal HSC functions and suppress myeloid malignancies (Nature Communications, 2017). Using Mll-AF9 knock-in AML mouse model, we found genome-wide H3K36me3 reduction and H3K79me2 elevation by SETD2 loss-of–function. This differentially regulated gene expression: down-regulating tumor suppressor genes such as ASXL1 and up-regulating oncogenes such as ERG, thus accelerate MLL leukemogenesis (Leukemia, 2017).

(4) The mechanism of genomic variations and their functions in disease progressions

By integrating genomic and transcriptomic analyses as well as a series of functional assays, we found that mutations in the JAK-STAT signaling pathway are the primary factors fueling cellular metabolism in ANKL leukemia cells. Inhibition of JAK/STAT-MYC-biosynthesis Axis could significantly decrease the in vitro proliferation of leukemia cells. Targeting JAK-STAT signaling and nucleotide metabolism may offer new treatment strategies for ANKL patients (Cell Research, 2017).

Familial platelet disorder (FPD), haboring a monoallelic RUNX1 mutation, is a rare genetic disorder characterized by defective MK and platelet development. Using integrative genomic analysis of hematopoietic progenitor cells generated from FPD derived induced pluripotent stem cells (iPSCs), and mutation-corrected isogenic controls, we identifed NOTCH4 as a newly discovered RUNX1 target gene negatively regulates megakaryopoiesis. Unlocking this inhibitory effect by small molecule inhibitors can promote MK production ex vivo, which has important scientific significance and clinical implications in regenerative medicine (Blood, 2017).

Combining co-immunoprecipitation and Mass Spectrometry, we have identified a novel post-translational O-linked-N-acetyl glucosamine (O-GlcNAc) modification at Thr457 in human DNA polymerase Polηgoverningits timely removal from replication forks after DNA lesion bypass to maintain genome stability in vivo, implicating a significant role of glycometabolismon genome stability and tumor chemoresistance (Nature Communications, accepted).

5. Awards and Honors

ZENG Changqing served as Associated Chair of Precision Medcine Subcommittee, Chinese Association of Geriatric Research.
The epigenetic research team heading by CI Weimin received “Lu Jiaxi international team project” of Wang Kuancheng first talent plan in 2017.
YANG Yungui received 2016 “innovative talent promotion plan” of Ministry of Science and Technology.
YANG Yungui was selected as the Expert Member of the NSFC major research program “Dynamic modification and chemical intervention of biological macromolecules”.
YANG Yungui was selected as Expert Member of the CAS strategic pilot program “Organ reconstruction and manufacturing” LI Mingkun received professor of “2017 Thousand Young Talents Program”.
HAN Dali received professor of “Hundred Talent Program” of Chinese Academy of Sciences.
CHEN Ke received “Excellent member” of 2017 Youth Innovation Promotion Association of CAS.
LI Yueying was selected as the members of 2017 Youth Innovation Promotion Association of CAS.