Join Us to Combat Brain Aging

Opengings for graduate and undergraduate students

We are recruiting bioinformatics, biotechnology, molecular biology, and neuroscience students to co-develop pioneering single-cell and spatial multiomics technologies, brain organoid models, animal models, analyze human brains, and combat Alzheimer's Disease. Both graduate and undergraduate students are welcome to apply.


About the PI

Sheng Zhong is a Professor of Bioengineering at UC San Diego. He received an NIH Director's Pioneer Award and an NIDDK Catalyst Award. He serves as the director for UCSD Center for Liquid Biopsy Research and the director for the organizational hub of the NIH funded 4D Nucleome (4DN) Program. He leads a Transformative Technology Development team for the Human BioMolecular Atlas Program (HuBMAP). Nine of his previous trainees are contributing to science on tenure-track faculty positions.


About the lab

Our lab invented the MUSIC (Multi-Nucleic Acid Interaction Mapping in Single Cell) technique for concurrent profiling of multiplex chromatin interactions, gene expression, and RNA-chromatin associations within a single nucleus (Nature, 2024). Applying MUSIC to human brain specimens, we reported chromatin conformation signatures of ageing and Alzheimer's disease.

We invented the MARIO (Mapping RNA interactome in vivo) technology to massively reveal RNA-RNA interactions from human tissue (Nature Comm, 2016) and the MARGI (Mapping RNA-Genome Interactions) technology for revealing thousands of chromatin-associated RNAs (caRNA) and their respective genomic interaction sites (Current Biology, 2017; Nature Protocols, 2019; eLife, 2024). Leveraging MARGI, our collaborators and we characterized caRNA’s roles in modulating the 3-dimensional genome organization (Nature Comm, 2023; Molecular Cell, 2023), regulating gene expression during the progression of diabetes (Nature Comm, 2020), mediating mitochondrial-to-nuclear signaling (eLife, 2024), and the biogenesis of fusion RNAs (PNAS 2019a). These results inspired the idea that caRNA is a layer of the epigenome (Trends Genetics, 2018).

We developed SILVER-seq for extracellular RNA (exRNA) sequencing from ultra-small volumes of liquid biopsy, solidifying a basis for future in vitro diagnostic trials using finger-prick blood for monitoring cancer recurrence (PNAS, 2019b). We identified and validated the exRNA of PHGDH as a biomarker for early detection of Alzheimer's disease (Current Biology, 2020; Cell Metabolism, 2022). We demonstrated exRNA in human IVF culture media predicts embryo quality (Cell Genomics, 2024).

We contributed to discovering the nuclear-encoded RNAs that are stably attached to the cell surface and exposed to the extracellular space, called membrane-associated extracellular RNAs (maxRNAs). maxRNAs are functional components of the cell surface and mediate cell-cell interactions (Genome Biology, 2020).

We contributed to discovering that the earliest cell fate decision in mouse is made sooner than the commonly thought 8-cell stage (Genome Res, 2014). Our Rainbow-seq technology combined tracing of cell division history and single-cell RNA sequencing into one experiment (iScience 2018b).

We contributed to revealing that transposons are indispensable regulatory sequences in the mammalian genomes. Species-specific transposons are required for preimplantation embryonic development in humans and other mammals (Genome Res, 2010). Nature highlighted this discovery as "Hidden Differences," reporting that "transposons or 'jumping genes' had hopped in front of the genes, changing their regulation" (Nature, 2010). We contributed to establishing the proof-of-principle that cis-regulatory sequences can be annotated by cross-species epigenomic comparison (Cell, 2012).

See more from our YouTube channel. Watch KPBS News about our Alzheimer's research.

PUBLICATIONS

Complete list of publications on Google Scholar, NCBI

Selected papers (please choose a category)

    Genome architecture

  • Single-cell multiplex chromatin and RNA interactions in ageing human brain. Xingzhao Wen, Zhifei Luo, Wenxin Zhao, Riccardo Calandrelli, Tri C. Nguyen, Xueyi Wan, John Lalith Charles Richard, Sheng Zhong.
    Nature, 2024, 628:648-656. Text, Table S2: Linkers, adaptors, and barcodes.
  • Perspective: Spatial and temporal organization of the genome: current state and future aims of the 4D Nucleome Project. Job Dekker, Frank Alber, Sarah Aufmkolk, Brian J. Beliveau, Benoit G. Bruneau, Andrew Belmont, Lacramioara Bintu, Alistair Boettiger, Riccardo Calandrelli, Christine Disteche, David M. Gilbert, Thomas Gregor, Anders S. Hansen, Bo Huang, Danwei Huangfu, Reza Kalhor, Christina Leslie, Wenbo Li, Yun Li, Jian Ma, William S. Noble, Peter J. Park, Jennifer E. Phillips-Cremins, Katherine S. Pollard, Susanne Rafelski, Bing Ren, Yijun Ruan, Yaron Shav-Tal, Yin Shen, Jay Shendure, Xiaokun Shu, Caterina Strambio-De-Castillia, Anastassiia Vertii, Huaiying Zhang, Sheng Zhong.
    Molecular Cell, 2023, Text.
  • Perspective: The 4D nucleome project. Job Dekker, Andrew S. Belmont, Mitchell Guttman, Victor O. Leshyk, John T. Lis, Stavros Lomvardas, Leonid A. Mirny, Clodagh C. O’Shea, Peter J. Park, Bing Ren, Joan C. Ritland Politz, Jay Shendure, Sheng Zhong & the 4D Nucleome Network.
    Nature, 2017, 549:219–226. Text, Artwork,

    • RNA-chromatin and RNA-RNA interactions

  • Genome-wide identification of stable RNA-chromatin interactions. Xingzhao Wen, Sheng Zhong.
    eLife, 2024, to appear, bioRxiv
  • Regulation of nuclear transcription by mitochondrial RNA. Kiran Sriram, Zhijie Qi, Dongqiang Yuan, Naseeb K. Malhi, Xuejing Liu, Riccardo Calandrelli, Yingjun Luo, Shengyan Jin, Ji Shi, Martha Salas, Ruirui Dang, Brian Armstrong, Ping Wang, Jiayu Liao, Rama Natarajan, Sheng Zhong, Zhen B. Chen.
    eLife, 2024, Text
  • Spotlight: Alu transposable elements rewire enhancer-promoter network through RNA pairing. Xingzhao Wen, Sheng Zhong.
    Molecular Cell, 2023, 83:3234-3235. Text
  • Genome-wide analysis of the interplay between chromatin-associated RNA and 3D genome organization in human cells. Riccardo Calandrelli, Xingzhao Wen, Tri C. Nguyen, Chien-Ju Chen, Zhijie Qi, Weizhong Chen, Zhangming Yan, Weixin Wu, Kathia Zaleta-Rivera, Rong Hu, Miao Yu, Yuchuan Wang, Jian Ma, Bing Ren, Sheng Zhong.
    Nature Communications, 2023, 14:6519. Text
  • Stress-induced RNA-chromatin interactions promote endothelial dysfunction. Riccardo Calandrelli, Lixia Xu, Yingjun Luo, Weixin Wu, Xiaochen Fan, Tri Nguyen, Chien-Ju Chen, Kiran Sriram, Xiaofang Tang, Andrew Burns, Rama Natarajan, Zhen Chen, Sheng Zhong.
    Nature Communications, 2020, 11:5211. Text, YouTube.
  • Mapping RNA-chromatin interactions by sequencing with iMARGI. Weixin Wu, Zhangming Yan, Tri C. Nguyen, Zhen Chen, Shu Chien, Sheng Zhong.
    Nature Protocols, 2019, 14:3243–3272. Text, Protocol, Software,
  • Genome-wide co-localization of RNA-DNA interactions and fusion RNA pairs. Zhangming Yan, Norman Huang, Weixin Wu, Weizhogn Chen, Yiqun Jiang, Jingyao Chen, Xuerui Huang, Xingzhao Wen, Jie Xu, Qiushi Jin, Kang Zhang, Zhen Chen, Shu Chien, Sheng Zhong.
    PNAS, 2019, 116 (8) 3328-3337. Text, YouTube,
  • RNA, action through interactions. Tri C. Nguyen, Kathia Zaleta-Rivera, Xuerui Huang, Xiaofeng Dai, Sheng Zhong.
    Trends in Genetics, 2018, 34:867-882. Text
  • RNAs as proximity labeling media for identifying nuclear speckle positions relative to the genome. Weizhong Chen, Zhangming Yan, Simin Li, Norman Huang, Xuerui Huang, Jin Zhang, Sheng Zhong.
    iScience, 2018, 4:204-215. Text, Cover proposal
  • Systematic mapping of RNA-chromatin interactions in vivo. Bharat Sridhar, Marcelo Rivas-Astroza, Tri C. Nguyen, Weizhong Chen, Zhangming Yan, Xiaoyi Cao, Lucie Hebert, Sheng Zhong.
    Current Biology, 2017, 27(4): 602–609. Text, Data, Protocols, Bioinformatic pipeline, F1000Prime
  • Mapping RNA-RNA interactome and RNA structure in vivo by MARIO. Tri C. Nguyen, Xiaoyi Cao, Pengfei Yu, Shu Xiao, Jia Lu, Fernando H. Biase, Bharat Sridhar, Norman Huang, Kang Zhang, Sheng Zhong.
    Nature Communications, 2016, 7:12023. Text, Software, Data

    Cell Surface RNA

  • Natural display of nuclear-encoded RNA on the cell surface and its impact on cell interaction. Norman Huang, Xiaochen Fan, Kathia Zaleta-Rivera, Tri C. Nguyen, Jiarong Zhou, Yingjun Luo, Jie Gao, Ronnie H. Fang, Zhangming Yan, Zhen Bouman Chen, Liangfang Zhang, Sheng Zhong.
    Genome Biology, 2020, 21:225. Text, Antisense probes for Figure 4, YouTube, A 2-minute introduction.

    • Extracellular RNA

  • A temporal extracellular transcriptome atlas of human pre-implantation development. Qiuyang Wu, Zixu Zhou, Zhangming Yan, Megan Connel, Gabriel Garzo, Analisa Yeo, Wei Zhang, H. Irene Su, Sheng Zhong.
    Cell Genomics, 2024, 4:100464, Text, Preview.
  • Presymptomatic Increase of an Extracellular RNA in Blood Plasma Associates with the Development of Alzheimer’s Disease. Zhangming Yan, Zixu Zhou, Qiuyang Wu, Zhen Bouman Chen, Edward H. Koo, Sheng Zhong.
    Current Biology, 2020, 30:1771–1782. Text, Seminar for the Extracellular RNA Communication (ERCC) consortium, SILVER-seq flowchart, exRNA sequencing service at Genemo, Presentation in Chinese.
  • Extracellular RNA in a single droplet of human serum reflects physiologic and disease states. Zixu Zhou, Qiuyang Wu, Zhangming Yan, Haizi Zheng, Chien-Ju Chen, Yuan Liu, Zhijie Qi, Riccardo Calandrelli, Zhen Chen, Shu Chien, H. Irene Su, Sheng Zhong.
    PNAS, 2019, 116:19200–19208. Text, SILVER-seq flowchart, Mapping by exceRpt software, SILVER-seq service at Genemo, The POISE trial @ ClinicalTrials.gov.

    • Alzheimer's disease

  • PHGDH expression increases with progression of Alzheimer’s disease pathology and symptoms. Xu Chen, Riccardo Calandrelli, John Girardini, Zhangming Yan, Zhiqun Tan, Xiangmin Xu, Annie Hiniker, Sheng Zhong.
    Cell Metabolism, 2022, 34:651-653. Text, bioRxiv, KPBS News.
  • Cross-species microarray analysis with the OSCAR system suggests an INSR-Pax6-NQO1 neuro-protective pathway in ageing and Alzheimer's disease. Yue Lu, Xin He, Sheng Zhong.
    Nucleic Acids Research, 2007, 35: W105-W114. TEXT.

    • Blood Brain Barrier

  • Modeling the Blood-Brain Barrier Formation and Cerebral Cavernous Malformations in Human PSCs-and Primary Tissue-Derived Organoids. Lan Dao, Lu Lu, Zhen You, Tianyang Xu, Hui Zhu, Miao Liu, Riccardo Calandrelli, George Yoshida, Pei Lin, Yifei Miao, Sarah Mierke, Srijan Kalva, Mingxia Gu, Sudhakar Vadivelu, Sheng Zhong*, Lei Huang*, Ziyuan Guo*.
    Cell Stem Cell, 2024. Online access, Research Highlight, Nature 2024

    • Metabolism

  • Long noncoding RNA LEENE promotes angiogenesis and ischemic recovery in diabetes models. Xiaofang Tang, Yingjun Luo, Dongqiang Yuan, Riccardo Calandrelli, Naseeb Kaur Malhi, Kiran Sriram, Yifei Miao, Chih-Hong Lou, Walter Tsark, Alonso Tapia, Aleysha T. Chen, Guangyu Zhang, Daniel Roeth, Markus Kalkum, Zhao V. Wang, Shu Chien, Rama Natarajan, John P. Cooke, Sheng Zhong, and Zhen Bouman Chen
    J Clin Invest, 2023, 133(3):e161759. Article, Commentary: Endothelial cells LEENE on noncoding RNAs in diabetic vasculopathy.
  • Suppression of endothelial AGO1 promotes adipose tissue browning and improves metabolic dysfunction. Xiaofang Tang, Yifei Miao, Yingjun Luo, Kiran Sriram, Zhijie Qi, Feng-Mao Lin, Kendall Van Keuren-Jensen, Patrick Fueger, Gene W. Yeo, Rama Natarajan, Sheng Zhong, Zhen Bouman Chen
    Circulation, 2020, 142:365–379. Article, Editorial: Endotheliopathy of Obesity.
  • Genomic analysis of hepatic farnesoid X receptor binding sites reveals altered binding in obesity and direct gene repression by farnesoid X receptor in mice. Jiyoung Lee, Sunmi Seok, Pengfei Yu, Kyungsu Kim, Zachary Smith, Marcelo Rivas‐Astroza, Sheng Zhong, Jongsook Kim Kemper
    Hepatology, 2012, 56(1):108-117. Article.

    Chromatin

  • SMARCAD1 contributes to regulation of naïve pluripotency by interacting with histone citrullination. Shu Xiao, Jia Lu, Bharat Sridhar, Xiaoyi Cao, Pengfei Yu, Chieh-Chun Chen, Darina McDee, Laura Sloofman, Yang Wang, Marcelo Rivas-Astroza, Bhanu Prakash V.L. Telugu, Dana Levasseur, Kang Zhang, Han Liang, Jing Crystal Zhao, Tetsuya S. Tanaka, Gary Stormo, Sheng Zhong.
    Cell Reports, 2017, 18:3117-3128. Text, Raw images, Cover proposal
  • Spatiotemporal clustering of epigenome reveals rules of dynamic gene regulation. Pengfei Yu, Shu Xiao, Xiaoyun Xin, Chun-Xiao Song, Wei Huang, Darina McDee, Tetsuya Tanaka, Ting Wang, Chuan He, Sheng Zhong.
    Genome Research, 2013, 23:352-384. Cover article, Abstract, Software, Data; Review
  • Understanding variation in transcription factor binding by modeling transcription factor genome-epigenome interactions. Chieh-Chun Chen, Shu Xiao, Dan Xie, Xiaoyi Cao, Chun-Xiao Song, Ting Wang, Chuan He, Sheng Zhong.
    PLoS Computational Biology, 2013, 9(12): e1003367. Text, Software, Supplementary Figures
  • Comparative epigenomic annotation of regulatory DNA. Shu Xiao, Dan Xie, Xiaoyi Cao, Pengfei Yu, Xiaoyun Xing, Chieh-Chun Chen, Meagan Musselman, Mingchao Xie, Franklin D. West, Harris A. Lewin, Ting Wang, Sheng Zhong.
    Cell, 2012, 49: 1381-1391. Abstract, Data, Comparative Epigenome Browser.
    Reviewed by: J Stem Cell Res Ther, 2012, S10:007. SCIENCE CHINA Life Sciences, 2013, 56(3): 213-219. WIREs Systems Biol Med, 2012, 4(6): 525-545.
  • The p23 molecular chaperone and GCN5 acetylase jointly modulate protein-DNA dynamics and open chromatin status. Elena Zelin, Yang Zhang, Oyetunji A Toogun, Sheng Zhong, Brian C Freeman.
    Molecular Cell, 2012, 48(3):459-470. Text.
  • 3D Genome: from technologies to visualization. [ISBN: 987-1-17325643-0-5]. eBook published by eScholarship. Textbook for BENG183.

    • Embryogenesis

  • Rainbow-seq: combining cell lineage tracing with single-cell RNA sequencing in preimplantation embryos. Fernando H. Biase, Qiuyang Wu, Riccardo Calandrelli, Marcelo Rivas-Astroza, Shuigeng Zhou, Zhen Chen, Sheng Zhong.
    iScience, 2018, 7:16-29. Text
  • Cell fate inclination within 2-cell and 4-cell mouse embryos revealed by single-cell RNA sequencing. Fernando H. Biase, Xiaoyi Cao, Sheng Zhong.
    Genome Research, 2014, 24:1787-1796. Cover Article, Abstract, single-cell RNA-seq data, single-cell genome browser, single-cell Fluidigm qPCR data, in situ images
  • Rewirable gene regulatory networks in the preimplantation embryonic development of three mammalian species. Dan Xie, Chieh-Chun Chen, Leon M Ptaszek, Shu Xiao, Xiaoyi Cao, Fang Fang, Huck H Ng, Harris A Lewin, Chad Cowan, Sheng Zhong.
    Genome Research, 2010 20:804-815. Cover Article, Abstract, Embryo data, Mtf2 knockdown data.
    Research Highlight: Hidden differences. Nature 464: 1248.
  • A core Klf circuitry regulates self-renewal of embryonic stem cells. DJianming Jiang, Yun-Shen Chan, Yuin-Han Loh, Jun Cai, Guo-Qing Tong, Ching-Aeng Lim, Paul Robson, Sheng Zhong, Huck-Hui Ng.
    Nature cell biology, 2008, 10:353-360. Abstract.

    Machine Learning, AI

  • Molecule Design by Latent Prompt Transformer. Deqian Kong, Yuhao Huang, Jianwen Xie, Edouardo Honig, Ming Xu, Shuanghong Xue, Pei Lin, Sanping Zhou, Sheng Zhong, Nanning Zheng, Ying Nian Wu.
    NeurIPS, 2024, to appear. Conference
  • Time-variant clustering model for understanding cell fate decisions. Wei Huang, Xiaoyi Cao, Fernando H. Biase, Pengfei Yu, Sheng Zhong.
    PNAS, 2014, 111(44):E4797-E4806. Abstract
  • Network based comparison of temporal gene expression patterns. Wei Huang, Xiaoyi Cao, Sheng Zhong.
    Bioinformatics, 2010, 26(23): 2944-2951. Abstract, Software
  • Dissecting early differentially expressed genes in a mixture of differentiating embryonic stem cells. Feng Hong, Fang Fang, Xuming He, Xiaoyi Cao, Hiram Chipperfield, Dan Xie, Wing H. Wong, Huck H. Ng, Sheng Zhong.
    PLoS Computational Biology, 2009, 5(12): e1000607. Text, Data
  • Reproducibility Probability Score - incorporating measurement variability across laboratories for gene selection. Guixian Lin, Xuming He, Hanlee Ji, Leming Shi, Ronald Davis, Sheng Zhong.
    Nature Biotechnology, 2007, 24(12): 1476-1477. Text, Software, Supplementary Material. The article has been reviewed by: Pharmacogenomics, 2007, 8(8): 1037-1049. European Journal of Cancer, 2007, 5(5): 97-104. Current Opinion in Biotechnology Systems Biomedicine: Concepts and Perspectives, Edison Liu, Douglas Lauffenburger (editors), Elsevier, 2009, p.172. WIREs Systems Biol Med, 2012, 4(1): 39-49. WIREs Systems Biol Med, 2012, 4(6): 525-545.

    • Gene Regulatory Networks

  • Revealing protein-protein interactions at the transcriptome scale by sequencing. Kara L. Johnson, Zhijie Qi, Zhangming Yan, Xingzhao Wen, Tri C.Nguyen, Kathia Zaleta-Rivera, Chien-Ju Chen, Xiaochen Fan, Kiran Sriram, Xueyi Wan, Zhen Bouman Chen, Sheng Zhong.
    Molecular Cell, 2021, 81:4091-4103. Text, PROPER database, PROPERTools software, Corrections, YouTube.
  • EpiAlignment: alignment with both DNA sequence and epigenomic data. Jia Lu, Xiaoyi Cao, Sheng Zhong.
    Nucleic Acids Research, 2019, 47(W1):W11-W19. Text, Software.
  • A likelihood approach to testing hypotheses on the co-evolution of epigenome and genome. Jia Lu, Xiaoyi Cao, Sheng Zhong.
    PLoS Computational Biology, 2018, 14(12):e1006673. Text
  • Towards an evolutionary model of transcription networks. Dan Xie, Chieh-Chun Chen, Xin He, Xiaoyi Cao, Sheng Zhong.
    PLoS Computational Biology, 2011, 7(6): e1002064. Text. Website.
  • Modeling co-expression across species for complex traits: insights to the difference of human and mouse embryonic stem cells. Jun Cai, Dan Xie, Zhewen Fan, John Marden, Wing H. Wong, Sheng Zhong.
    PLoS Computational Biology, 2010, 6(3): e1000707. Text, Data, Software
  • Cross-species de novo identification of cis-regulatory modules with GibbsModule: application to gene regulation in embryonic stem cells. Dan Xie, Jun Cai, Na-Yu Chia, Huck H. Ng, Sheng Zhong.
    Genome Research, 2008, 18:1325-1335. Text. Software

    • Visualization and Personal Genome APP

  • GITAR: An Open Source Tool for Analysis and Visualization of Hi-C Data. Riccardo Calandrelli, Qiuyang Wu, Jihong Guan, Sheng Zhong.
    Genomics, Proteomics & Bioinformatics, 2018, 16(5):365-372. Text, Software.
  • GIVE: portable genome browsers for personal websites. Xiaoyi Cao, Zhangming Yan, Qiuyang Wu, Alvin Zheng, Sheng Zhong.
    Genome Biology, 2018, 19:92. Text, Software, News & Comments: Nature 549:117, Research Highlight: Genome Biology 19:93 , Technical feature: Nature 576:171-172.
  • GeNemo: a search engine for web-based functional genomic data. Yongqing Zhang, Xiaoyi Cao, Sheng Zhong.
    Nucleic Acids Research, 2016, 44: W122-W127. Text, Software
    News coverage: HIT Consultant, Science Daily, MediaPost, HealthDataManagement
  • Enabling interspecies epigenomic comparison with CEpBrowser. Xiaoyi Cao, Sheng Zhong.
    Bioinformatics, 2013, 29(9):1223–1225. Text. Software
  • Mapping personal functional data to personal genomes. Marcelo Rivas-Astroza, Dan Xie, Xiaoyi Cao, Sheng Zhong.
    Bioinformatics, 2011, 27(24):3427-3429. Text. Software

Software

Complete software list

GIVE

Build your own genome browser website.

GeNemo

Internet search for genomic big data.

MARIO Tools

Analyze RNA interaction data.

CEpBrowser

Comparative Epigenome Browser.

perEditor

Sequence mapping on personal genome.

GATE

Genome annotation using temporal epigenomic data.

4D Nucleome web portal

4D Nucleome Portal

Entry to NIH 4D Nucleome network.





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