Abstract
BackgroundThe HHIP gene, encoding Hedgehog interacting protein, has been implicated in chronic obstructive pulmonary disease (COPD) by genome-wide association studies (GWAS), and our subsequent studies identified a functional upstream genetic variant that decreased HHIP transcription. However, little is known about how HHIP contributes to COPD pathogenesis.MethodsWe exposed Hhip haploinsufficient mice (Hhip+/-) to cigarette smoke (CS) for 6 months to model the biological consequences caused by CS in human COPD risk-allele carriers at the HHIP locus. Gene expression profiling in murine lungs was performed followed by an integrative network inference analysis, PANDA (Passing Attributes between Networks for Data Assimilation) analysis.ResultsWe detected more severe airspace enlargement in Hhip+/- mice vs. wild-type littermates (Hhip+/+) exposed to CS. Gene expression profiling in murine lungs suggested enhanced lymphocyte activation pathways in CS-exposed Hhip+/- vs. Hhip+/+ mice, which was supported by increased numbers of lymphoid aggregates and enhanced activation of CD8+ T cells after CS-exposure in the lungs of Hhip+/-mice compared to Hhip+/+ mice. Mechanistically, results from PANDA network analysis suggested a rewired and dampened Klf4 signaling network in Hhip+/- mice after CS exposure.ConclusionsIn summary, HHIP haploinsufficiency exaggerated CS-induced airspace enlargement, which models CS-induced emphysema in human smokers carrying COPD risk alleles at the HHIP locus. Network modeling suggested rewired lymphocyte activation signaling circuits in the HHIP haploinsufficiency state.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-015-0137-3) contains supplementary material, which is available to authorized users.
Highlights
The hedgehog interacting protein (HHIP) gene, encoding Hedgehog interacting protein, has been implicated in chronic obstructive pulmonary disease (COPD) by genome-wide association studies (GWAS), and our subsequent studies identified a functional upstream genetic variant that decreased HHIP transcription
Hhip+/- mice demonstrated more severe airspace enlargement induced by cigarette smoke compared with wild-type littermate control mice Previously, we detected approximately 32% reduced gene expression of HHIP in human COPD lung tissues compared with ex-smoker controls with normal lung function [7]
HHIP haploinsufficiency led to activation of CD8+ T cells Consistent with increased expression of genes involved in lymphocyte activation in Hhip+/- mice exposed to cigarette smoke (CS), we observed significantly increased numbers of lymphoid aggregates in Hhip+/- mice exposed to CS chronically (Figure 3A, B)
Summary
The HHIP gene, encoding Hedgehog interacting protein, has been implicated in chronic obstructive pulmonary disease (COPD) by genome-wide association studies (GWAS), and our subsequent studies identified a functional upstream genetic variant that decreased HHIP transcription. Chronic obstructive pulmonary disease (COPD), the third leading cause of death in the US [1], is a complex disease strongly influenced by cigarette smoke (CS) and genetic predisposition [2,3]. While the cause of emphysematous destruction of the alveoli is likely due to a Recently, progress in genome-wide association studies (GWAS) has provided compelling evidence for several COPD susceptibility loci, including an intergenic region on chromosome 4q31 [5,6]. Subsequent work by our group confirmed hedgehog interacting protein (HHIP) as the causative gene for this locus and identified a potential functional variant [7].
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