Epigenetic Regulatory Dynamics in Models of Methamphetamine-Use Disorder

Abstract

Methamphetamine (METH)-use disorder (MUD) is a very serious, potentially lethal, biopsychosocial disease. Exposure to METH causes long-term changes to brain regions involved in reward processing and motivation, leading vulnerable individuals to engage in pathological drug-seeking and drug-taking behavior that can remain a lifelong struggle. It is crucial to elucidate underlying mechanisms by which exposure to METH leads to molecular neuroadaptive changes at transcriptional and translational levels. Changes in gene expression are controlled by post-translational modifications via chromatin remodeling. This review article focuses on the brain-region specific combinatorial or distinct epigenetic modifications that lead to METH-induced changes in gene expression.

Keywords: DNA methylation; HDAC inhibitors; addiction; epigenetics; histone acetylation; histone methylation; methamphetamine.

Figure 1

Illustration of aberrant alterations in METH-induced epigenetic modifications and effectors represented by “writers”, “readers”, and “erasers”. Epigenetic writers include histone acetyl-transferases (HATs: p300/CBP; PCAF; GCN5; TAF/Kat4; Tip60/Kat5), histone methyl-transferases (HMTs: PRMT5; MLL1/KMT2a; SUV39H1), DNA methyltransferases (DNMT: DNMT1; DNMT3b), ten-eleven translocase (TET: TET1, 2 and 3), readers include, corepressor for the RE1-silencing transcription factor (CoREST), methyl-binding protein (MBP: MeCP2) and erasers include, histone demethylase (HDM: Kdm5c), histone deacetylases (HDACs). The green arrow represents transcriptional activation and red block-head arrow represents transcriptional repression. The red circle on DNA strand (DNA methylation) indicate methyl-cytosine; yellow pentagon on the DNA strand (DNA hydroxymethylation) indicates hydroxymethyl-cytosine. ac: acetylation; me: methylation.