Epithelial cells which line the airways of the lung play a central role in almost all essential pulmonary functions, including barrier protection, mucociliary clearance and respiratory gas-exchange. Moreover, functional decline in these cells underlies the development of most, if not all, respiratory diseases. Correct spatial and temporal patterns of gene expression in lung epithelial cells are essential for establishing a working lung that is not just ready for the first breath of life, but also can sustain respiration into the late stages of adulthood. However, aging, as well as various pulmonary insults, such as infections and environmental exposures, alter normal patterns of gene expression in the lung epithelium, leading to abnormal repair and regenerative mechanisms which drive the lung toward disease. To this end, my laboratory studies the genetic and epigenetic mechanisms that regulate lung epithelial gene expression patterns during prenatal, postnatal and various disease states. By studying the mechanisms that regulate gene expression in the lung epithelium we will better understand how diseases are initiated and will contribute to development of more effective therapies for both childhood and adult lung diseases.
Function of Novel Long Non-coding RNAs in Lung Epithelial Cell
More than 90% of the genome is transcribed into RNAs with no protein coding capabilities (ncRNAs). Among them, long ncRNAs (>200 nt, lncRNAs) are expressed in specific cells, and their expression fluctuates during development and disease. To date, the functions of most lncRNAs expressed in lung tissues are unknown. Intriguingly, a large number of lncRNAs originate by divergent transcription at promoters of genes encoding transcription factors and key developmental genes. Transcription factors that are critical for endoderm and lung epithelial cell differentiation in humans and mice have indeed been shown to have divergent lncRNA transcripts. Based on this, our working hypothesis is that these divergent lncRNAs play an essential role in regulating epithelial cell differentiation and that alterations in their expression may contribute to the development of disease (e.g. tumorigenesis). To study the functions of lncRNAs, we are currently using a novel in vitro model system of human induced pluripotent stem cells (iPSCs), which can be used to recapitulate the events that happen in normal and abnormal human lung development as well as lung homeostasis and disease.
Epigenetic Control of Lung Epithelial Cell Differentiation Through Lifespan and Disease
The lung epithelium plays an important role in the initiation of lung disease. In response to tissue injury, for example, the lung attempts to limit the damage and initiate repair. If the repair process aberrantly continues, it results in scarring and fibrosis. We are currently studying how epigenetic mechanisms contribute to the pathobiology of fibrotic lung disease. Specifically, we are studying how variations in the level of expression of different chromatin modification genes differentially modulate the response of cells to profibrotic factors. Our goal is to characterize the role of different chromatin modifying genes in management of tissue repair and regeneration and to understand how these mechanisms are altered or decline with age.
Transcription Factor Networks in Lung Epithelial Cell Differentiation
We have a long-standing interest in the transcriptional regulation of lung alveolar epithelial genes. We have studied transcription of the lung alveolar type I epithelial genes T1α(PDPN) and caveolin-1 and identified transcriptional and epigenetic mechanisms regulating the type II cell gene Sftpb. We have also identified cell-cell interaction genes regulated by GRHL2 in lung epithelial cells and have identified a novel positive transcriptional feed-back loop between Grhl2 and the homeobox transcription factor Nkx2-1 in the embryonic lung. The critical role of NKX2-1 in regulating epithelial cell proliferation, and differentiation led us to characterize the transcriptional program controlled by Nkx2-1 in early and late lung development, and in lung cancer including other transcription factors and microRNAs. We are currently evaluating the role of several transcription factors expressed at early time points in lung development, and whether these factors play a similar role during epithelial regeneration after alveolar injury.