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. 2012 Dec 27;6(1):1-24.
doi: 10.3390/ph6010001.

Strategies to modulate heritable epigenetic defects in cellular machinery: lessons from nature

Ganesh N Pandian  1 , Hiroshi Sugiyama
Affiliations

Strategies to modulate heritable epigenetic defects in cellular machinery: lessons from nature

Ganesh N Pandian et al. Pharmaceuticals (Basel). .

Abstract

Natural epigenetic processes precisely orchestrate the intricate gene network by expressing and suppressing genes at the right place and time, thereby playing an essential role in maintaining the cellular homeostasis. Environment-mediated alteration of this natural epigenomic pattern causes abnormal cell behavior and shifts the cell from the normal to a diseased state, leading to certain cancers and neurodegenerative disorders. Unlike heritable diseases that are caused by the irreversible mutations in DNA, epigenetic errors can be reversed. Inheritance of epigenetic memory is also a major concern in the clinical translation of the Nobel Prize-winning discovery of induced pluripotent stem cell technology. Consequently, there is an increasing interest in the development of novel epigenetic switch-based therapeutic strategies that could potentially restore the heritable changes in epigenetically inherited disorders. Here we give a comprehensive overview of epigenetic inheritance and suggest the prospects of therapeutic gene modulation using epigenetic-based drugs, in particular histone deacetylase inhibitors. This review suggests that there is a need to develop therapeutic strategies that effectively mimic the natural environment and include the ways to modulate the gene expression at both the genetic and epigenetic levels. The development of tailor-made small molecules that could epigenetically alter DNA in a sequence-specific manner is a promising approach for restoring defects in an altered epigenome and may offer a sustainable solution to some unresolved clinical issues.

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Figures

Figure 1
Figure 1
Transgenerational inheritance of epigenetic marks that leads to transcriptional dysregulation. Disadvantageous external stimuli (indicated in cream box) could cause aberrant regulation of the epigenome. The acquired epigenetic disorder (indicated in the red box) can be transmitted across generations from grand parents to their offspring. Epigenetic-based therapeutic approach may pave the way to restore this acquired transcriptional dysregulation even in the later generations (Restored transcriptional regulation is shown in green box).
Figure 2
Figure 2
Colorful language of histone modifications and their precise coordination are suggested to constitute a code. Components of the core histones (H2A and B, H3 and H4) and their modifications are indicated in different colors. Together, these dynamic modifications are thought to comprise an imaginary code termed, the “histone code”, which is depicted as binary digits in the background.
Figure 3
Figure 3
HDAC classes, their cellular localization, and inhibitory activities of certain HDAC inhibitors. A total of 18 HDACs belonging to four major classes of HDACs and their localization in cells are illustrated. HDACs that can localize to the cytoplasm and nucleus are indicated in both locations. Some notable HDAC inhibitors (HDACi) like trichostatin A, SAHA, NVP-LAQ824, valproic acid (VPA), MS-275 and their target HDACs on which they exhibit potent activity are also indicated.
Figure 4
Figure 4
Site-specific histone modifications using SAHA-PIP. SAHA-PIP encompasses chemical moieties that could access both epigenetic and genetic environments, and can be tuned to specific DNA sequences for inducing site-specific histone modifications.
Figure 5
Figure 5
Proposed strategy to modulate transgenerational epigenetic inheritance A) Epigenetic alterations could switch the cellular transcriptional machinery (Illustrated as diodes) from the normal (Orange) to the dysregulated (Blue) state. B) SAHA-PIP that was previously shown to induce multiple genes pertaining to single network [95] could potentially activate the pre-silenced gene network indicated as coordinated machine wheel that is critical for resetting the transcriptional dysregulation. This epigenetic-switch based approach alone may be insufficient to revert back the diseased cell to the normal state but when combined with gene-based approach, it may serve as the sustainable solution to some unresolved clinical issues.
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