GSTCD and INTS12 regulation and expression in the human lung.
Genome-Wide Association Study (GWAS) meta-analyses have identified a strong association signal for lung function, which maps to a region on 4q24 containing two oppositely transcribed genes: glutathione S-transferase, C-terminal domain containing (GSTCD) and integrator complex subunit 12 (INTS12). Both genes were found to be expressed in a range of human airway cell types. The promoter regions and transcription start sites were determined in mRNA from human lung and a novel splice variant was identified for each gene. We obtained the following evidence for GSTCD and INTS12 co-regulation and expression: (i) correlated mRNA expression was observed both via Q-PCR and in a lung expression quantitative trait loci (eQTL) study, (ii) induction of both GSTCD and INTS12 mRNA expression in human airway smooth muscle cells was seen in response to TGFβ1, (iii) a lung eQTL study revealed that both GSTCD and INTS12 mRNA levels positively correlate with percent predicted FEV1, and (iv) FEV1 GWAS associated SNPs in 4q24 were found to act as an eQTL for INTS12 in a number of tissues. In fixed sections of human lung tissue, GSTCD protein expression was ubiquitous, whereas INTS12 expression was predominantly in epithelial cells and pneumocytes. During human fetal lung development, GSTCD protein expression was observed to be highest at the earlier pseudoglandular stage (10-12 weeks) compared with the later canalicular stage (17-19 weeks), whereas INTS12 expression levels did not alter throughout these stages. Knowledge of the transcriptional and translational regulation and expression of GSTCD and INTS12 provides important insights into the potential role of these genes in determining lung function. Future work is warranted to fully define the functions of INTS12 and GSTCD.
Division of Respiratory Medicine, University of Nottingham, Queen's Medical Center, Nottingham, United Kingdom ; James Hogg Research Centre, Institute for Heart and Lung Health, University of British Columbia, Vancouver, British Columbia, Canada.
Ma'en
M
Obeidat
Suzanne
S
Miller
Kelly
K
Probert
Charlotte K
CK
Billington
Amanda P
AP
Henry
Emily
E
Hodge
Carl P
CP
Nelson
Ceri E
CE
Stewart
Caroline
C
Swan
Louise V
LV
Wain
María
M
Soler Artigas
Erik
E
Melén
Kevin
K
Ushey
Ke
K
Hao
Maxime
M
Lamontagne
Yohan
Y
Bossé
Dirkje S
DS
Postma
Martin D
MD
Tobin
Ian
I
Sayers
Ian P
IP
Hall
D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D005541:Forced Expiratory Volume / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D015321:Gene Rearrangement / Q000235:genetics; D056426:Genetic Loci / Q000235:genetics; D015894:Genome, Human / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008168:Lung / Q000166:cytology / Q000196:embryology / Q000378:metabolism* / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D059372:Nucleotide Motifs / Q000235:genetics; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D040641:Quantitative Trait Loci / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
D002352:Carrier Proteins; C000588764:GSTCD protein, human; C000588765:INTS12 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D005982:Glutathione Transferase