yjruan@zju.edu.cn

I joined the Life Science Institute (LSI) at Zhejiang University (ZJU) since August 2022. The established intellectual depth and the breadth in biomedical research at LSI and ZJU represent an immense opportunity to broaden the spectrum of my research interests. Likewise, my innovative approaches in developing novel genomic technologies and providing comprehensive solutions to a wide range of biomedical questions would help the local research community to achieve their ambitious goals nationally and internationally. 

Looking back, the first decade of my academic research (2000-2010) was focused on developing innovative genomic technologies to analyze the functional and regulatory elements in the human genomes. The most impactful technologies developed in my lab include the paired-end-tag (PET) sequencing strategy for full-length transcriptome analysis (Wei et al., PNAS 2004; Ng et al., Nature Methods 2005) and genome structural variations (Hillmer et al., Genome Research 2011) analysis that had been widely adopted in today’s high-throughput DNA sequencing practice (Fullwood et al., Genome Research 2009). To study the mechanisms of gene transcription regulation, we developed ChIP-PET (Wei et al., Cell 2006) that was the first sequencing-based mapping approach for transcription factor (TF) binding genome-wide. After the realization that a large numbers of TF binding sites are distal to gene promoters, we developed a novel strategy to for chromatin interaction analysis by paired-end-tag sequencing (ChIA-PET) that was one of the first and widely used genome-wide approaches for mapping 3D genome architectures (Fullwood et al., Nature 2009). During the second decade of my research efforts (2010-2020), I had been advocating the genomic research community to establish an emerging field of 3D genome biology (Ruan, Science 2011), and through collaborations we have established some fundamental concepts in chromatin folding architecture and long-range mechanisms of gene transcription regulation (Fullwood et al., Nature 2009; Handoko et al., Nature Genetics 2011; Li et al., Cell 2012; Zhang et al., Nature 2013; Kieffer-Kwon et al., Cell 2013; Tang et al., Cell 2015; Kanno et al., Nature 2015). Within in the first phase of the NIH-organized 4D Nucleome project (2015-2020), we advanced the 3D genome mapping technology with the development of ChIA-Drop, a microfluidic-based and barcode-linked method to map multiplex chromatin interactions with single molecule precision in individual cells (Zheng et al., Nature 2019). In collaboration within the fourth phase of the ENCODE consortium project (ENCODE4), we have comprehensively generated large numbers of chromatin folding architecture datasets (ChIA-PET and Hi-C) over 100s of human cell lines and tissues with a focus on human primary T-cells and activated subtypes (https://www.encodeproject.org/about/data-access/). Our ongoing efforts for complete and integrated analyses of these unprecedented 3D genomic and epigenomic data will undoubtedly unravel the underlining roles how chromatin topological structures determine the mechanisms of gene transcription regulation and other nuclear functions. 

Going forward, my lab will continue to push novel technology development in genomics and further expand 3D genome biology in biomedical research. Our overall goal is to unravel the mechanistic insights how chromatin folding architectures structurally determine the functions of gene transcription. In addition, I will devote significant effort in trying to answer some of the long-standing and unresolved questions in biology. One such fundamental question and challenge inspiring me is centered around the genetic architecture of complex traits and elusive molecular mechanism for polygenic diseases. Despite significant progress in complex genetics over the past decade had been made largely by genome-wide association study (GWAS), our current theories for the genetic architectures of polygenic traits are still chiefly based on population analyses of genotype-to-phenotype associations, lacking structure-based realization of how polygenic elements would be mechanistically organized and coordinated to drive complex traits,  and thus could not elucidating how non-coding genetic variants may influence such functional interactions and eventually lead to phenotypic diversity of traits and diseases. I anticipate that the current and soon-to-be developed 3D genomic technologies including computational solutions will have significant impacts to help eventually uncover the molecular mechanisms of complex genetics in polygenic traits and diseases. Finally, our ultimate purpose is to extend the concepts and technologies developed in 3D genome biology into a wide-arrange of biomedical questions and diverse biological systems. We will actively engage with our medical research community through specific collaborations.  I am highly confident that not only my research program will be successful in the next decade, but more importantly my collaborative efforts will provide transformative impacts to many research programs across the overall research community at ZJU and national wide.