American Thoracic Society
Society for Developmental Biology

We are currently studying novel genetic and epigenetic mechanisms of gene regulation that drive the differentiation of distinct epithelial cell lineages during lung development, and the potential alteration of these mechanisms in lung disease. During embryo development, these mechanisms control the precise spatial and temporal patterns of gene expression that are critical for organogenesis of a functional lung ready for the first breath at birth. In adults, patterns of gene expression also have to be maintained to preserve a healthy lung. Understanding these basic mechanisms in development will in the long term provide the basis to find improvements of fetal lung maturation and to understand altered cell phenotypes in lung disease.

We particularly focus on the regulation of lung epithelial genes by tissue specific transcription factors, non-coding RNAs and chromatin modifications. Although most chromatin modifying protein complexes are ubiquitously expressed, they modify the chromatin within a cell in a timely and gene specific manner. How these complexes acquire specificity to bind to specific regulatory regions in the chromatin is becoming to be elucidated. Recent studies suggest that non-coding RNAs, which comprise more than 90% of the mammalian transcriptome, may provide specificity to chromatin modifying complexes by recruiting them to specific loci to induce or maintain key cellular states such as pluripotency or particular cell lineages. Our goal is to elucidate how these complexes acquire their specificity in lung gene regulation by interacting with long non-coding RNAs (lncRNAs) and the role of this process in lung lineage specification and differentiation.

The functions of most of the lncRNAs identified in the lung are uncharacterized.  Intriguingly, a large number of lncRNAs originate by divergent transcription at promoters of genes encoding transcription factors and developmental genes. Transcription factors that are critical for endoderm and lung epithelial cell differentiation in humans and mice have indeed divergent lncRNA transcripts. We hypothesize that these divergent lncRNAs have essential roles in lung development by regulating epithelial cell differentiation. To study their functions, we are using a unique in vitro system of human induced pluripotent stem cells (iPSCs) that recapitulates the early stages of human or mouse endoderm and lung development. This system allows producing a high number of human cells representing definitive endoderm, lung epithelial progenitors and more mature lung epithelial cells for functional and molecular studies that usually require a high number of cells.