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Gene & Protein in Disease Stress-induced epigenetics of the DRD2 gene

6. Effector moieties in SUD. Numerous associations and interventional studies
demonstrate that epigenetic mechanisms are responsible
The effector moieties are molecules that selectively bind for the complex regulation of dopamine homeostasis,
to proteins to modify their biological activities. These particularly concerning the expression of the DRD2
molecules, essentially ligands, can modify enzyme activity, gene. Epigenetic regulatory mechanisms (i.e., histone
genomic activity, cell signaling, and other protein functions. modifications, ncRNA, and DNA methylation) interact
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While identifying epigenetic-induced post-transcriptional in an orchestrated fashion to establish phenotypes
methylation or acetylation on chromosome histones is influenced by genetic background (e.g., the presence of
crucial, one of the first and most successful effector moieties mutations) and environmental factors (e.g., the presence
in editing transcriptional activator domains was VP64, of active compounds from drugs, alcohol, and tobacco).
which is derived from the herpes simplex virus. VP64 Importantly, these interactions occur in a tissue- and cell-
recruits RNA polymerase ll directly for gene-targeted specific manner. Hence, a detailed mapping of epigenetic
transcriptional activation. It is now understood that by modifications across various presentations of SUD
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targeting VP64 to the promoter region of a single gene will enable the understanding of the precise regulatory
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using DNA-binding domains such as ZFP, TALE, 150,151 mechanisms involved in each case and identify potential
or CRISPR/dCas9, laboratories can consistently induce targets for therapeutic interventions.
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transcription of targeted genes in vitro and even in vivo. 153,154
The utilization of effector moieties emerges as a promising
Furthermore, to attain bidirectional control over intervention. However, caution is warranted due to the
gene expression, the suppression of endogenous genes is pleiotropic effects of epigenetic modifiers (e.g., DNMTs,
typically achieved using KRAB effector moieties. KRAB HDACs, and HTAs), and systemic inactivation of these
represents a transcriptional repression domain present enzymes may lead to undesirable side effects, hindering
in human zinc finger transcription factors. It functions their clinical translation. Further research is needed to
by recruiting heterochromatin-forming complexes that elucidate mechanisms for cell-specific activation or delivery
subsequently deposit H3K9me3 repressive marks, resulting of the effector moieties to mitigate side effects. Moreover,
in transcriptional suppression. Similar to VP64, the given that prenatal SUD may impact offspring health,
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KRAB domain modifies the epigenome by enlisting the mechanistic and interventional studies are imperative to
secondary factors rather than utilizing enzymatic activity. determine and target epigenetic modifications, aiming to
In addition, promoter- or enhancer-targeted KRAB has mitigate the effects of prenatal SUD on fetal health.
been used in cell culture and in the brain. 156,157 In addition,
research has identified specific transcription factors and 8. Summary
epigenetic readers, erasers, and writers associated with the SUD often entails persistent behavioral abnormalities
addiction pathogenesis. More recently, a number of effector observed in susceptible individuals following repeated
moieties have been developed for neuroepigenetic editing. exposure to psychoactive drugs of abuse. The enduring
These effector moieties include DNA-modifying enzymes nature of these behavioral alterations suggests potential
such as DNMT3A (responsible for CpG methylation). 158,159 long-lasting changes in gene expression within specific
and TET1 (which catalyzes hydroxymethylation of brain regions, which may contribute to the addiction
CpG). 160,161 They also encompass proteins involved in phenotype. Advanced research over the past decade
regulating histone PTMs such as NFκB subunit p65 has revealed the pivotal involvement of epigenetic
(which recruits HATs to acetylate core histones). histone mechanisms in orchestrating lasting alterations, whether
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methyltransferase G9a (which catalyzes H3K9me2), 162,163 positive or negative, in gene expression across various
p300 HAT (which acetylates all four core histones), tissues, particularly in the brain. This understanding has
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Sin3-interaction domain (which recruits HDACs), 165,166 spurred investigations aimed at elucidating the impact of
lysine-specific demethylase 1 (which demethylates H3K4 epigenetic regulatory processes in mediating the enduring
and H3K9), PRDM9 (which methylates H3K4 and effects of psychoactive substances of abuse on the brain,
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H3K36), and DOT1L (which methylates H3K79). 169,170 predominantly using animal models of drug addiction.
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Furthermore, transcription factors such as CREB have However, more recently, human neuroepigenetic research
also been utilized, thus mimicking known mechanisms of has been rapidly emerging. Compelling evidence indicates
transcriptional regulation. 171 that repeated exposure to drugs of abuse induces alterations
7. Research outlook in epigenetics of SUD within the brain’s reward regions through three primary
modes of epigenetic regulation: Histone modifications
The evidence presented in this commentary strongly such as acetylation and methylation, DNA methylation,
indicates the significant role of epigenetic (mis) regulation and ncRNAs. In this commentary, our focus lies on

Volume 3 Issue 1 (2024) 11 https://doi.org/10.36922/gpd.1966