title: Haploinsufficiency of Hedgehog interacting protein causes increased emphysema induced by cigarette smoke through network rewiring.
abstract: BACKGROUND
  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. However, little is known about how HHIP contributes to COPD pathogenesis.
  
  
  METHODS
  We 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.
  
  
  RESULTS
  We 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.
  
  
  CONCLUSIONS
  In 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.
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA USA.
authors.forename: Taotao
authors.initials: T
authors.lastname: Lao
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA USA ; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA USA ; Department of Biostatistics, Harvard School of Public Health, Boston, MA USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Glass
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA USA.
authors.forename: Weiliang
authors.initials: W
authors.lastname: Qiu
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA USA ; The Lovelace Respiratory Research Institute, Albuquerque, NM USA ; Pulmonary Department, University of Parma, Parma, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Polverino
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA USA.
authors.forename: Kushagra
authors.initials: K
authors.lastname: Gupta
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA USA.
authors.forename: Jarrett
authors.initials: J
authors.lastname: Morrow
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA USA.
authors.forename: John Dominic
authors.initials: JD
authors.lastname: Mancini
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA USA.
authors.forename: Linh
authors.initials: L
authors.lastname: Vuong
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA USA ; Pediatric Newborn Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Perrella
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA USA ; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA USA.
authors.forename: Craig P
authors.initials: CP
authors.lastname: Hersh
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA USA ; The Lovelace Respiratory Research Institute, Albuquerque, NM USA.
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Owen
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA USA ; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA USA ; Department of Biostatistics, Harvard School of Public Health, Boston, MA USA.
authors.forename: John
authors.initials: J
authors.lastname: Quackenbush
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA USA ; Department of Biostatistics, Harvard School of Public Health, Boston, MA USA.
authors.forename: Guo-Cheng
authors.initials: GC
authors.lastname: Yuan
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA USA ; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA USA.
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA USA ; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA USA.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Zhou