SummaryMesodiencephalic dopaminergic (mdDA) neurons are located in the ventral mesodiencephalon and are involved in psychiatric disorders and severely affected in neurodegenerative diseases such as Parkinson's disease. mdDA neuronal development has received much attention in the last 15 years and many transcription factors involved in mdDA specification have been discovered. More recently however, the impact of epigenetic regulation has come into focus, and it's emerging that the processes of histone modification and DNA methylation form the basis of genetic switches that operate during mdDA development. Here, we review the epigenetic control of mdDA development, maturation and maintenance. As we highlight, epigenetic mechanisms play a pivotal role in all of these processes and the knowledge gathered from studying epigenetics in these contexts may aid our understanding of mdDA-related pathologies. Key words: Brain, Development, Dopamine, Epigenetics, Gene regulation, Midbrain IntroductionIf you turn this page, both the decision you make and the action that you carry out are significantly influenced by the amount of dopamine (DA; see Glossary, Box 1) released from dopaminergic neurons within your brain. Mesodiencephalic dopaminergic (mdDA) neurons located in the substantia nigra pars compacta (SNc; see Glossary, Box 1), in particular, are essential for motor functions whereas mdDA neurons of the ventral tegmental area (VTA; see Glossary, Box 1) and the retrorubal field (RRF; see Glossary, Box 1) are involved in the regulation of emotions and reward . Notably, severe loss of SNc mdDA neurons is a pathological hallmark of Parkinson's disease (PD) (Sulzer, 2007). By contrast, mdDA neurons in the VTA and RRF, which remain intact in PD, are part of the mesocorticolimbic system (see Glossary, Box 1), in which defective DA neurotransmission has been implicated in the development of drug addiction, depression and schizophrenia (Nestler, 2000). Given their involvement in neurodegenerative diseases and psychiatric disorders, mdDA neurons have been studied intensively in recent years.In the last two decades, a variety of molecular approaches have revealed factors that are specific for mdDA neuronal subsets or that guide their spatial organization ; recently, a pathway that molecularly distinguishes SNc DA neurons from those located in the VTA was identified (Jacobs et al., 2011). In addition to molecular profiling of DA neurons, however, a second level of complexity has been added by the rapidly emerging field of epigenetics, which has provided new insights into the origin and maintenance of distinctive gene expression patterns in mdDA neurons. Current definitions of epigenetics often emphasize the heritability of changes in gene expression throughout cell divisions that are not due to alterations in DNA sequence. However, perhaps a more appropriate definition of epigenetics, especially when applying this term to mature neurons that cannot divide, is postulated by Adrian Bird: 'The structural adaptation of chromosomal regio...

Parkinson disease (PD) is a common neurodegenerative disorder that progresses with age, with an increasing number of symptoms. Some of the efforts to understand PD progression have been focusing on the regulation of epigenetic mechanisms, that generally include small molecular modifications to the DNA and histones that are essential for regulating gene activity. Here, we have pointed out difficulties to untangle genetic and epigenetic mechanisms, and reviewed several studies that have aimed for untangling. Some of those have enabled more solid claims on independent roles for epigenetic mechanisms. Hereby, evidence that specific DNA hydroxymethylation, global hyperacetylation, and histone deacetylase (HDAC) dependent regulation of SNCA , one of the hallmark genes involved in PD, have become more prominent from the current perspective, than mechanisms that directly involve DNA methylation. In the absence of current epigenetic clinical targets to counteract PD progression, we also hypothesize how several mechanisms may affect local and global epigenetics in PD neurons, including inflammation, oxidative stress, autophagy and DNA repair mechanisms which may lead to future therapeutic targets.

Methylation of histone 3 at lysine 79 (H3K79) and its catalyst, a disrupter of telomeric silencing (DOT1l), have been coupled to multiple forms of stress, such as bioenergetic and ER challenges. However, studies on H3K79 methylation and Dot1l in the (aging) brain and neurons are limited. This, together with the increasing evidence of a dynamic neuroepigenome, made us wonder if H3K79 methylation and its activator Dot1l could play important roles in brain aging and associated disorders. In aged humans, we found strong and consistent global hypermethylation of H3K79 in neurons. Specific in dopaminergic neurons, we found a strong increase in H3K79 methylation in lipofucsin positive neurons, which are linked to pathology. In animals, where we conditionally removed Dot1l, we found a rapid loss of H3K79 methylation. As a consequence, we found some decrease in specific dopaminergic genes, and surprisingly, a clear up-regulation of almost all genes belonging to the family of the respiratory chain. These data, in relation to the observed increase in global H3K79 methylation, suggest that there is an inverse relationship between H3K79 methylation and the capacity of energy metabolism in neuronal systems.

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