Please describe the research questions of your lab.
My lab is interested in the interface of epigenetic modifications, transcription factor function, and lung disease.Why do some people with asthma have great control over basic therapies and others need injectable medications? One major research topic involves studying the molecular mechanisms of glucocorticoid receptor signaling, noting that corticosteroids, which bind to the glucocorticoid receptor (a transcription factor), are among the most widely used compounds to treat lung disease such as asthma. We are interested in determining specific mechanisms that underpin disease endotypes that are resistant to corticosteroids. To address this issue, we have conducted a series of experiments to better define our understanding of normal corticosteroid function, and we have discovered new pathways that we think form the basis for both steroid efficacy and resistance. We are currently interested in extending our research program to address other forms of lung inflammation, including determining molecular pathways that propagate airway dysfunction in COPD and determining the molecular effects of different forms of air pollution on the airway epithelium.What genetics/genomics techniques do you utilize in your lab?
My lab uses many genomics techniques related to gene regulation including ChIP-seq, ATAC-seq, RNA-seq, and PRO-seq.
Describe a key technique/assay/instrument utilized in your lab, and what novel insights does it bring to your research question?
We have used Precision-Run On sequencing or PRO-seq, a method that assays nascent transcription on a genome-wide basis. This allows for the identification of genes that are regulated at the transcriptional level but also identifies all ncRNAs, including enhancer RNAs. Enhancer RNAs or eRNAs are markers of active enhancers and also provide a readout on enhancer activity. PRO-seq, which quantifies eRNAs genome-wide, therefore, allows one to ask whether enhancer activity is different in different diseases or in response to diverse exposures, such as air pollution. Enhancer sequences can also be analyzed to define de novo regulatory pathways. PRO-seq also identifies specific sites of RNA polymerase II interactions with the genome, which can potentially be leveraged to identify functional SNPs. Although technically difficult, it is a very powerful technique that gives beautiful data.
At what point in your life did you decide you wanted to be a scientist/physician?
In college.
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?
It has to be the cloning and sequencing of the CF gene – this has formed the basis for designing drugs that truly change the trajectory of the disease. As a field, we can hope that key genetic findings using later techniques, such as GWAS-based identification of the IPF-associated MUC5B enhancer G-T transversion, will eventually lead to similar therapeutic successes.
Briefly describe your favorite publication involving genomics/omics that you were involved with.
When I first set up my lab at National Jewish Health, I was interested in studying why the glucocorticoid receptor (GR, a transcription factor) directly induces KLF15, which is also a transcription factor. The question was, “Why does one transcription factor turn on another transcription factor rather than directly activating all of the relevant downstream genes?” We applied MicroArray technology, which was prevalent at the time, to wild type mice and mice deficient for KLF15 to identify genes that depend on KLF15 for normal expression responses to corticosteroids. We found that GR and KLF15 form a specific type of regulatory circuit, known as the feedforward loop, which can be used to confer temporal control of gene expression to signaling responses. We reported ion this in MCB, PMID:23508109. In further collaboration with Mukesh Jain at Case Western, we went on the show that this GR-KLF15 feedforward pathway is important for conferring endurance exercise tolerance in mice through changing metabolic programming and that this may be part of the reason corticosteroids are effective in muscular dystrophy. The underlying molecular physiology is that a long pulse of corticosteroid allows for activation of KLF15 and downstream cooperation between GR and KLF15 regulates specific metabolic transcriptional sub-programs. In contrast, short pulses of cortisol do not activate this program. This elegant two-part system allows a single hormone to cause vary responses based on length of exposure. It turns out that feed-forward loop systems, such as the GR-KLF15 system, are very widely used in biology, and probably have a great deal to do with timing repair in lung injury and also terminating inflammatory responses.
What is your favorite aspect of ATS?
I love catching up with colleagues at ATS. I have formed key collaborations through attending ATS and developed a broad network of colleagues with similar interests. The Genetics and Genomics section is a special part of this, and I think is an ideal mechanism for researchers to interact with a cadre of scientists that share similar approaches to studying lung disease.
How could your research assist scientists and clinicians in other assemblies at ATS?
The tools we use to study transcription have broad applicability to critical care, environmental health, and cancer, among other topics. My lab is very collaborative and we have hosted other scientists to help them learn some of the techniques we use that are technically challenging.
