Genetic and Epigenetic Regulation of Pulmonary Function

To identify the genetic background to lung function decline with age, several thousands of people have participated in various gene association studies [11, 12] that aimed to find correlations amongst gene locations, and specific genetic predisposition to senile emphysema as well as a closely associated disease: COPD. The result of such studies finally identified a locus on chromosome 4q31 that was associated with the percent of expected FEV1/FVC (as forced expiratory volume in 1 s [FEV1] and forced vital capacity [FVC]) ratio [11]. The locus was located in an intergenic region upstream of hedgehog interacting protein (HHIP), a hedgehog pathway gene with a known role in development. Additionally, six new genetic loci were identified that appeared to be associated with pulmonary function. These were located on chromosomes 2, 4, 5, 6 and 15 near genes including Tensin1 (TSN1) (2q35), encoding an actin-filament binding protein, four additional genes including Glutathione S-Transferase, C-terminal Domain (GSTCD) (4q24), Human Serotonin Receptor (HTR4) (5q32-33) a serotonin pathway gene, immune function genes Advanced Glycosylation End Product-Specific Receptor (AGER) and Palmitoyl-Protein Thioesterase 2 (PPT2) (6p21), a G-protein coupled receptor GPR126 (6q24.1) as well as Thrombospondin type 1 domain containing 4 gene (THSD4) (15q33) in the thrombospondin gene family [11]. Currently, it is not entirely clear how the elderly will directly benefit from the results of genome wide association studies. Certainly, further work is needed to identify the precise relevance to ageing and potential targets that could prolong pulmonary function.

In addition to specific genes, pulmonary senescence is also regulated by heritable modifications in gene expression that is not coded in the DNA sequence itself, but is rather governed by post-translational modifications in histone proteins and DNA. These modifications include chromatin remodeling (histone acetylation, meth- ylation, ubiquitination, phosphorylation, and sumoylation) and DNA methylation. One of the most investigated epigenetic modulators of the ageing process are class I histone deacetylases [13]. Apart from various other cellular functions, for example, histone deacetylase 2 (HDAC2) regulates glucocorticoid function in inhibiting inflammatory responses and protects against DNA damage and cellular senescence as well as premature ageing in response to oxidative stress. Unfortunately, in ageing COPD patients HDAC2 is post-translationally modified by cigarette smoke leading to its reduction via an ubiquitination-proteasome dependent degradation process rendering glucocorticoid containing anti-inflammatory drugs ineffective during their treatment

[14]. Recently, NAD+-dependent deacetylases known as sirtuins (SIRT1-SIRT7) have also been widely investigated for their role in the regulation of the ageing process [15]. The best characterized is SIRT1 and although its function in prolonging lifespan is currently under debate, it has been shown that through deacetylation of many transcriptional factors, SIRT1 modulates key events in ageing [16] including the oxidative stress response, endothelial dysfunction, and inflammation [17, 18]. Whether sirtuins modulate lung function is currently under investigation.

Age-associated alterations in gene expression are also intensively investigated at the level of small “non-coding” micro-RNAs (miRNAs) that post-transcriptionally regulate gene expression. Several miRNAs have already been reported to regulate the expression of SIRT1 including miR-217 [19] in endothelial cells, a downstream target of p53 microRNA, miR34a [20, 21], as well as miR-199a and miR-132 that mediate the regulation of chemokine production [22] or HIF-1a function [23]. Recently, some miRNAs including miR-1, miR-122 and miR-375, miR-21, miR- 206, miR-30a that regulate conserved pathways of ageing, including insulin/IGF signalling (IIS), DAF-12 signalling and mTOR signalling, have been linked to human age-related disorders such as heart-, muscle- and neurodegenerative diseases [24]. Whether they are also involved in pulmonary senescence is currently unknown. The constantly present low level inflammation characteristic of ageing is also regulated by microRNAs e.g. miR-146a and thus could contribute to lung functional decline, this microRNA is also an important regulator of toll-like receptor dependent signalling pathways and therefore epithelial cell dependent immune responses [25].

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