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Review
. 2014:2014:750459.
doi: 10.1155/2014/750459. Epub 2014 Mar 31.

The role of epigenetics in the fibrotic processes associated with glaucoma

Fiona McDonnell  1 , Colm O'Brien  2 , Deborah Wallace  2
Affiliations
Review

The role of epigenetics in the fibrotic processes associated with glaucoma

Fiona McDonnell et al. J Ophthalmol. 2014.

Abstract

Glaucoma is an optic neuropathy that affects 60 million people worldwide. The main risk factor for glaucoma is increased intraocular pressure (IOP), this is currently the only target for treatment of glaucoma. However, some patients show disease progression despite well-controlled IOP. Another possible therapeutic target is the extracellular matrix (ECM) changes in glaucoma. There is an accumulation of ECM in the lamina cribrosa (LC) and trabecular meshwork (TM) and upregulation of profibrotic factors such as transforming growth factor β (TGF β ), collagen1 α 1 (COL1A1), and α -smooth muscle actin ( α SMA). One method of regulating fibrosis is through epigenetics; the study of heritable changes in gene function caused by mechanisms other than changes in the underlying DNA sequence. Epigenetic mechanisms have been shown to drive renal and pulmonary fibrosis by upregulating profibrotic factors. Hypoxia alters epigenetic mechanisms through regulating the cell's response and there is a hypoxic environment in the LC and TM in glaucoma. This review looks at the role that hypoxia plays in inducing aberrant epigenetic mechanisms and the role these mechanisms play in inducing fibrosis. Evidence suggests that a hypoxic environment in glaucoma may induce aberrant epigenetic mechanisms that contribute to disease fibrosis. These may prove to be relevant therapeutic targets in glaucoma.

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Figures

Figure 1
Figure 1
Epigenetic mechanisms. DNA is wrapped around proteins called histones; this forms the core DNA package called the nucleosome. When the DNA is tightly wrapped, transcription factors cannot bind and transcription is repressed. When the DNA is more loosely wrapped, transcription is more active as transcription factors can bind. DNA methylation is when a methyl group is added to the DNA strand and is associated with transcriptional repression [58]. Histone acetylation is the addition of acetyl groups to the histone tails and this is associated with transcriptional activation. Histone deacetylation is the removal of acetyl groups which is associated with transcriptional repression [59].
Figure 2
Figure 2
The potential role of hypoxia and epigenetics in the fibrosis seen in glaucoma. The hypoxic environment in glaucoma [74] may cause the epigenetic profile of the cells to change bringing about a more fibrotic phenotype [61, 75].
Figure 3
Figure 3
Epigenetic regulation of the TGFβ pathway. TGFβ has been shown to upregulate the expression of DNMT1 which causes aberrant methylation [76] leading to a more fibrotic phenotype. Furthermore, TGFβ has been shown to decrease acetylation in corneal fibroblasts causing them to remain active and leading to fibrosis [77]. In contrast to its role in corneal fibroblasts, TGFβ enhances Smad 2/3 acetylation leading to increased activity of these Smads [78].
Figure 4
Figure 4
Hypoxia induces the expression of ECM remodelling genes in LC cells. It has been hypothesized that the increased IOP in glaucoma causes the blood flow to the eye to be altered, and this may be a cause of the hypoxic environment seen in glaucomatous eyes [–83]. In addition to the altered blood flow, our group has shown that glaucomatous LC cells have decreased antioxidant capacity [73]. We have also shown that hypoxia can induce increased expression of ECM remodelling genes such as insulin-like growth factor 2 receptor (IGFR2) and macrophage migration inhibitory factor 1 (MIF) in LC cells [84].
Figure 5
Figure 5
Epigenetic changes allow HIF binding to HIF response elements (HREs). A hypoxic environment within a cell can cause normal epigenetic mechanisms to be changed, altering the level of DNA methylation and/or modifying chromatin conformation allowing HIF1α to bind to the HRE on the gene [85]. The TGFβ1 promoter has been previously shown to contain a HRE [86], and so hypoxia can alter TGFβ1 expression through HIF1α.
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