Transcriptomic analysis of human lung development.
BACKGROUND
Current understanding of the molecular regulation of lung development is limited and derives mostly from animal studies.


OBJECTIVE
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 to 154 days post conception. Principal component analysis was used to characterize global expression variation and to identify genes and bioontologic attributes contributing to these variations. Individual gene expression patterns were verified by quantitative reverse transcriptase-polymerase chain reaction analysis.


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 subtranscriptome capable of describing a majority of the process. In gene expression space, the samples formed a time-contiguous trajectory with transition points correlating with histological stages and suggesting the existence of novel molecular substages. Induction of surfactant gene expression characterized a pseudoglandular "molecular phase" transition. Individual gene expression patterns were independently validated. 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 bioontologic attributes underlying early human lung developmental processes. The data also suggest the existence of molecular phases of lung development.
Kho
Alvin T
AT
Children's Hospital Informatics Program, Harvard-MIT Division of Health Sciences and Technology, Boston, Massachusetts, USA.
Bhattacharya
Soumyaroop
S
Tantisira
Kelan G
KG
Carey
Vincent J
VJ
Gaedigk
Roger
R
Leeder
J Steven
JS
Kohane
Isaac S
IS
Weiss
Scott T
ST
Mariani
Thomas J
TJ
D047109:Fetal Development / Q000235:genetics*; D020869:Gene Expression Profiling; D005865:Gestational Age; D006801:Humans; D008168:Lung / Q000196:embryology*; D020411:Oligonucleotide Array Sequence Analysis; D025341:Principal Component Analysis; D011663:Pulmonary Surfactants
D011663:Pulmonary Surfactants