Please describe the research questions of your lab.
The goal of my laboratory is to decode the molecular mechanisms by which genetic variants identified by genome-wide association studies (GWAS) determine disease susceptibility to asthma and COPD. We have developed integrative approaches to identify regulatory DNA regions, localize functional variants, and evaluate the function of novel GWAS genes in vitro and in vivo in conventional and conditional knockout mice. Our earlier work identified intergenic functional variants at the COPD GWAS locus near HHIP (hedgehog interacting protein) by demonstrating a chromatin loop between the DNA region spanning the functional variant and the promoter of HHIP (HMG, 2012). This work pioneered post-GWAS functional studies in COPD.
What genetics/genomics techniques do you utilize in your lab?
We apply genetic perturbation targeting GWAS genes by CRISPR/Cas-9 based genome editing approach. We apply bulk RNA-Seq, single cell RNA-eq and mass-spectrometry to investigate the signaling pathways regulated by novel GWAS genes in asthma and COPD. We also apply MPRA, 4C-Seq, ChIP-Seq, ATAC-Seq and RNA-Seq in lung relevant cell types to identify regulatory regions residing in GWAS regions in lung cells and to connect non-coding GWAS regions and their regulated candidate genes.
Describe a key technique/assay/instrument utilized in your lab, and what novel insights does it bring to your research question?
We applied Massive Parallel Reporter assay in human bronchial epithelial cells to identify regulatory variants in the FAM3A COPD GWAS locus. This semi-high throughput method helps to identify multiple potential regulatory variants simultaneously. In combination CRISPR/Cas-9 based genome editing in the endogenous genomic and chromatin context, we will have stronger experimental evidence on these potential functional variants in the different GWAS loci. This method will greatly improve the throughput compared to traditional reporter assay to assess allelic effects.
At what point in your life did you decide you wanted to be a scientist/physician?
Curiosity was rooted in my mind from early on. So, I was interested in research since college. But it was until when I started to establish the functional genomics laboratory in 2009 in Channing Division at BWH/HMS, I found the research area that I would devote my career to: translating human genetic discoveries to disease pathogenesis and lung biology and provide a molecular basis for precision medicine in the future.
In your opinion, what is one of the most important discoveries in the field of respiratory illness/disease/function that was dependent on genomics or similar techniques?
Application of single cell RNA-Seq in lung diseases research have greatly increased the resolution in studying lung biology and lung diseases. Lung is a complex organ composed of 40+ cell types, so the genomic dissection at single cell levels is the most appropriate approach to address genomic questions in lungs. Recent application of this method in lungs has led to several important findings in human and murine model of lung diseases (Vaughan A et al, Nature, 2015; Xu Y et al, JCI Insight, 2016; Xi Y, et al, 2017 Nature Cell Biology; Xie T et al, Cell Report, 2018)
Briefly describe your favorite publication involving genomics/omics that you were involved with in general-audience terms.
The work in my group involves most cell biology and in vivo mouse model work to characterize function of GWAS genes in COPD and asthma. We utilize omics approaches mainly in cell or murine samples. For example, we have applied proteomics in cellular samples to identify interacting proteins of COPD GWAS genes. This shed mechanistic insights into the function of HHIP (PMID: 27444019) and FAM13A (PMID:26862784) in regulating oxidative-stress and beta-catenin/Wnt pathway respectively. HHIP (Hedgehog Interacting protein), is one of the most significant GWAS locus associated with COPD and has been replicated by many groups of researchers independently in last ten years. We demonstrated increased emphysema in Hhip heterozygous mice in response to chronic cigarette smoke exposure (PMID:25763110) or aging (PMID: 27444019). Through these two publications, our search suggested Hhip+/- mice, a suitable murine model for precision medicine studies targeting HHIP locus, because: 1) it has reduced expression of HHIP, similar to human subjects carrying COPD risk alleles at the HHIP locus; 2) Hhip+/- mice recapitulate COPD phenotypes: emphysema and lymphocytes infiltration in lungs.
What is your favorite aspect of ATS?
ATS is a great place to seek and meet potential collaborators and develop future long-term collaborations on either grant submission or manuscript generation with different interest groups.
How could your research assist scientists and clinicians in other assemblies at ATS?
Our research work of linking non-coding GWAS regions to coding genes will open a whole revenue for basic scientists in other assemblies at ATS who work on different lung diseases. Because most of genes have unclear function yet in diseases progression and some of genes with publications may lead new connection for translational potential and foundation for precision medicine based their association with COPD and asthma in human genetic studies.
Would you be open to collaborations with GG and/or non-GG scientists and clinicians? Do you have any potential lab openings currently or in the near future?
Yes. I am happy to collaborate with scientists with all diversified expertise, within GG or non-GG scientists. I have lab openings for motivated post-doctor, scientists and technicians at all levels.
