RUNX transcription factors: association with pediatric asthma and modulated by maternal smoking

Haley, Kathleen J.; Lasky‐Su, Jessica; Manoli, Sara E.; Smith, Lacey; Shahsafaei, Aliakbar; Weiss, Scott T.; Tantisira, Kelan G.

doi:10.1152/ajplung.00348.2010

Cited by 54 publications

(60 citation statements)

References 77 publications

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“…Most notably, seven loci residing within the intronic and promoter regions of the RUNX3 gene displayed differential methylation patterns that were significantly associated with maternal smoking during pregnancy (Table 2). The RUNX3 gene has been associated with airway hyper-responsiveness and asthma and these conditions are also associated with maternal smoking [41-52], and as our analysis was focused on identifying CpG loci of potential biological relevance to maternal smoking during pregnancy, these loci within the RUNX3 gene were chosen for further analysis, as well as follow-up bisulfite pyrosequencing.…”

Section: Resultsmentioning

confidence: 99%

“…A growing body of literature suggests that RUNX3 plays an important role in normal immune system development [56,57], susceptibility to early life disease as a result of in utero exposures [41], and many cancers [58-68]. RUNX3 is important for normal cellular differentiation and development, including T-cell differentiation [56,57,66,69], macrophage differentiation [70], neuronal cell development [71] and cell-cycle progression [63], and is known to negatively regulate dendritic cell maturation [72].…”

Section: Discussionmentioning

confidence: 99%

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Placental DNA Methylation Alterations Associated with Maternal Tobacco Smoking at the RUNX3 Gene are also Associated with Gestational Age

et al. 2013

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Aims The developmental origins of health and disease hypothesis states that later-life disease may be influenced by the quality of the in utero environment. Environmental toxicants can have detrimental effects on fetal development, potentially through effects on placental development and function. Maternal smoking during pregnancy is associated with low birth weight, preterm birth and other complications, and exposure to cigarette smoke in utero has been linked to gross pathologic and molecular changes to the placenta, including differential DNA methylation in placental tissue. The aim of this study was to investigate the relationship between maternal smoking during pregnancy, methylation changes in the placenta and gestational age. Materials & methods We used Illumina®’s (CA, USA) Human Methylation27 BeadChip technology platform to investigate the methylation status of 21,551 autosomal, non-SNP-associated CpG loci in DNA extracted from 206 human placentas and examined loci whose variation in methylation was associated with maternal smoking during pregnancy. Results We found that methylation patterns of a number of loci within the RUNX3 gene were significantly associated with smoking during pregnancy, and one of these loci was associated with decreased gestational age (p = 0.04). Conclusion Our findings, demonstrating maternal smoking-induced changes in DNA methylation at specific loci, suggest a mechanism by which in utero tobacco smoke exposure could exert its detrimental effects upon the health of the fetus.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Placental DNA Methylation Alterations Associated with Maternal Tobacco Smoking at the RUNX3 Gene are also Associated with Gestational Age

et al. 2013

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“…Gestational SS decreases miR-130a that targets the anti-angiogenic factor GAX and the proapoptotic factor RUNX3 (37, Lee et al, 2015); both GAX and RUNX3 are increased in F1 and F2 lungs from gestationally SS-exposed mice. Furthermore, RUNX transcription factors have been implicated in predicting asthma associated with maternal smoking (55). miR-130a also promotes VEGF synthesis indirectly by targeting VEGF inhibitor Hoxa5.…”

Section: Discussionmentioning

confidence: 99%

Gestational Exposure to Sidestream (Secondhand) Cigarette Smoke Promotes Transgenerational Epigenetic Transmission of Exacerbated Allergic Asthma and Bronchopulmonary Dysplasia

Singh

Chand

Langley

et al. 2017

The Journal of Immunology

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Embryonic development is highly sensitive to xenobiotic toxicity and in utero exposure to environmental toxins affects physiological responses of the progeny. In the US, the prevalace of allergic asthma is inexplicably rising and in utero exposure to cigarette smoke (CS) increases the risk of allergic asthma (AA) and bronchopulmonary dysplasia (BPD) in children and animal models. We reported that gestational exposure to sidestream (secondhand) CS (SS) promoted nicotinic acetylcholine receptor-dependent exacerbation of AA and BPD in mice. Recently, perinatal nicotine injections in rats were reported to induce peroxisome proliferator-activated receptor gamma (PPARγ)-dependent transgenerational transmission of asthma. Herein, we show that F1 and F2 progeny from gestationally SS-exposed mice exhibit exacerbated AA and BPD that is not dependent on the decrease in PPARγ levels. Lungs from these mice show strong eosinophilic infiltration, excessive Th2 polarization, marked airway hyperresponsiveness, alveolar simplification, decreased lung compliance, and decreased lung angiogenesis. At the molecular level, these changes are associated with increased RUNX3 expression, alveolar cell apoptosis, and the antiangiogenic factor GAX, and decreased expression of HIF-1α and pro-angiogenic factors NF-κB and VEGFR2 in the 7-day F1 and F2 lungs. Moreover, the lungs from these mice exhibit lower levels of micro-RNA (miR)-130a and increased levels of miR-16 and miR-221. These miRs regulate HIF-1α-regulated apoptotic, angiogenic, and immune pathways. Thus the intergenerational effects of gestational SS involve epigenetic regulation of HIF-1α through specific miRs contributing to increased incidence of AA and BPD in the progenies.

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“…Human promoter SNPs also have been reported as autoimmune risk variants for systemic lupus erythematosus (96,97), systemic sclerosis (98), inflammatory bowel disease (99), and rheumatoid arthritis (100). RUNX2-mediated SPP1 promoter activity can be inhibited by histone deacetylase 1 (101), and RUNX transcription factors have been associated with increased risk of asthma in children with in utero smoke exposure (102,103).…”

Section: Discussionmentioning

confidence: 99%

Secreted Phosphoprotein 1 Is a Determinant of Lung Function Development in Mice

Ganguly

Martin

Concel

et al. 2014

Am J Respir Cell Mol Biol

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Secreted phosphoprotein 1 (Spp1) is located within quantitative trait loci associated with lung function that was previously identified by contrasting C3H/HeJ and JF1/Msf mouse strains that have extremely divergent lung function. JF1/Msf mice with diminished lung function had reduced lung SPP1 transcript and protein during the peak stage of alveologenesis (postnatal day [P]14-P28) as compared with C3H/ HeJ mice. In addition to a previously identified genetic variant that altered runt-related transcription factor 2 (RUNX2) binding in the Spp1 promoter, we identified another promoter variant in a putative RUNX2 binding site that increased the DNA protein binding. SPP1 induced dose-dependent mouse lung epithelial-15 cell proliferation. Spp1(2/2) mice have decreased specific total lung capacity/body weight, higher specific compliance, and increased mean airspace chord length (L m ) compared with Spp1(1/1) mice. Microarray analysis revealed enriched gene ontogeny categories, with numerous genes associated with lung development and/or respiratory disease. Insulin-like growth factor 1, Hedgehog-interacting protein, winglessrelated mouse mammary tumor virus integration site 5A, and NOTCH1 transcripts decreased in the lung of P14 Spp1 (2/2) mice as determined by quantitative RT-PCR analysis. SPP1 promotes pneumocyte growth, and mice lacking SPP1 have smaller, more compliant lungs with enlarged airspace (i.e., increased L m ). Microarray analysis suggests a dysregulation of key lung developmental transcripts in gene-targeted Spp1 (2/2) mice, particularly during the peak phase of alveologenesis. In addition to its known roles in lung disease, this study supports SPP1 as a determinant of lung development in mice.

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RUNX transcription factors: association with pediatric asthma and modulated by maternal smoking

Cited by 54 publications

References 77 publications

Placental DNA Methylation Alterations Associated with Maternal Tobacco Smoking at the RUNX3 Gene are also Associated with Gestational Age

Placental DNA Methylation Alterations Associated with Maternal Tobacco Smoking at the RUNX3 Gene are also Associated with Gestational Age

Gestational Exposure to Sidestream (Secondhand) Cigarette Smoke Promotes Transgenerational Epigenetic Transmission of Exacerbated Allergic Asthma and Bronchopulmonary Dysplasia

Secreted Phosphoprotein 1 Is a Determinant of Lung Function Development in Mice

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