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Published ahead of print on October 8, 2009
Am. J. Respir. Crit. Care Med. 2009, doi:10.1164/rccm.200907-1063OC
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Submitted on July 14, 2009
Accepted on October 7, 2009

Transcriptomic Analysis of Human Lung Development

Alvin T Kho1, Soumyaroop Bhattacharya2, Kelan G Tantisira3, Vincent J Carey4, Roger Gaedigk5, J Steven Leeder5, Isaac S Kohane1, Scott T Weiss4, and Thomas J. Mariani2*

1 Children's Hospital Informatics Program, Harvard–MIT Division of Health Sciences and Technology, Boston, Massachusetts, United States, 2 Division of Neonatology and Center for Pediatric Biomedical Research, University of Rochester, Rochester, New York, United States, 3 Channing Laboratory, Brigham and Women’s Hospital, Boston, Massachusetts, United States, 4 Channing Laboratory, Brigham and Women's Hospital, Boston, Massachusetts, United States, 5 Division of Pediatric Pharmacology and Medical Toxicology, Department of Pediatrics, Children's Mercy Hospitals and Clinics, Kansas City, Missouri, United States

* To whom correspondence should be addressed. E-mail: tom_mariani{at}urmc.rochester.edu.

Rationale: Current understanding of the molecular regulation of lung development is limited and derives mostly from animal studies. Objectives: To define global patterns of gene expression during human lung development. Methods: Genome-wide expression profiling was used to measure the developing lung transcriptome in RNA samples derived from 38 normal human lung tissues at 53–154 days post conception. Principal component analysis was used to characterize global expression variation and identify genes and bio-ontologic attributes contributing to these variations. Individual gene expression patterns were verified by quantitative reverse transcriptase-polymerase chain reaction analysis. Measurements and Main Results: Gene expression analysis identified attributes not previously associated with lung development, such as chemokine–immunologic processes. Lung characteristics attributes (e.g., surfactant function) were observed at an earlier than anticipated age. We defined a 3,223–gene developing lung characteristic sub–transcriptome, capable of describing a majority of the process. In gene expression space, the samples formed a time-contiguous trajectory with transition points both correlating with histological stages and suggesting the existence of novel molecular sub-stages. Induction of surfactant gene expression characterized a pseudoglandular “molecular phase” transition. Individual gene expression patterns were independently validated. Further, we predicted the age of independent human lung transcriptome profiles with a median absolute error of 5 days, supporting the validity of the data and modeling approach. Conclusions: This study extends our knowledge of key gene expression patterns and bio–ontologic attributes underlying early human lung developmental processes. The data also suggest the existence of molecular phases of lung development.


Key words: Microarrays • Surfactant • Principal Component Analysis







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