Suppressed expression of T-box transcription factors is involved in senescence in chronic obstructive pulmonary disease

George K. Acquaah-Mensah, Deepti Malhotra, Madhulika Vulimiri, Jason E. McDermott, Shyam Biswal

Research output: Contribution to journalArticle

Abstract

Chronic obstructive pulmonary disease (COPD) is a major global health problem. The etiology of COPD has been associated with apoptosis, oxidative stress, and inflammation. However, understanding of the molecular interactions that modulate COPD pathogenesis remains only partly resolved. We conducted an exploratory study on COPD etiology to identify the key molecular participants. We used information-theoretic algorithms including Context Likelihood of Relatedness (CLR), Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNE), and Inferelator. We captured direct functional associations among genes, given a compendium of gene expression profiles of human lung epithelial cells. A set of genes differentially expressed in COPD, as reported in a previous study were superposed with the resulting transcriptional regulatory networks. After factoring in the properties of the networks, an established COPD susceptibility locus and domain-domain interactions involving protein products of genes in the generated networks, several molecular candidates were predicted to be involved in the etiology of COPD. These include COL4A3, CFLAR, GULP1, PDCD1, CASP10, PAX3, BOK, HSPD1, PITX2, and PML. Furthermore, T-box (TBX) genes and cyclin-dependent kinase inhibitor 2A (CDKN2A), which are in a direct transcriptional regulatory relationship, emerged as preeminent participants in the etiology of COPD by means of senescence. Contrary to observations in neoplasms, our study reveals that the expression of genes and proteins in the lung samples from patients with COPD indicate an increased tendency towards cellular senescence. The expression of the anti-senescence mediators TBX transcription factors, chromatin modifiers histone deacetylases, and sirtuins was suppressed; while the expression of TBX-regulated cellular senescence markers such as CDKN2A, CDKN1A, and CAV1 was elevated in the peripheral lung tissue samples from patients with COPD. The critical balance between senescence and anti-senescence factors is disrupted towards senescence in COPD lungs.

Original languageEnglish (US)
Article numbere1002597
JournalPLoS Computational Biology
Volume8
Issue number7
DOIs
StatePublished - Jul 2012

Fingerprint

Senescence
Pulmonary diseases
Transcription factors
senescence
Transcription Factor
respiratory tract diseases
Chronic Obstructive Pulmonary Disease
Transcription Factors
transcription factors
etiology
Lung
Genes
Gene
lungs
gene
Cyclin-Dependent Kinase Inhibitor p16
cyclin-dependent kinase
Cell Aging
Inhibitor
inhibitor

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Ecology
  • Molecular Biology
  • Genetics
  • Ecology, Evolution, Behavior and Systematics
  • Modeling and Simulation
  • Computational Theory and Mathematics

Cite this

Suppressed expression of T-box transcription factors is involved in senescence in chronic obstructive pulmonary disease. / Acquaah-Mensah, George K.; Malhotra, Deepti; Vulimiri, Madhulika; McDermott, Jason E.; Biswal, Shyam.

In: PLoS Computational Biology, Vol. 8, No. 7, e1002597, 07.2012.

Research output: Contribution to journalArticle

Acquaah-Mensah, George K. ; Malhotra, Deepti ; Vulimiri, Madhulika ; McDermott, Jason E. ; Biswal, Shyam. / Suppressed expression of T-box transcription factors is involved in senescence in chronic obstructive pulmonary disease. In: PLoS Computational Biology. 2012 ; Vol. 8, No. 7.
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