17 research outputs found
Neuronal Dot1l Activity Acts as a Mitochondrial Gene-Repressor Associated with Human Brain Aging via H3K79 Hypermethylation
Neuronal Dot1l Activity Acts as a Mitochondrial Gene-Repressor Associated with Human Brain Aging via H3K79 Hypermethylation
Double-Spin Asymmetry in the Cross Section for Exclusive rho^0 Production in Lepton-Proton Scattering
Evidence for a positive longitudinal double-spin asymmetry = 0.24
+-0.11 (stat) +-0.02 (syst) in the cross section for exclusive diffractive
rho^0(770) vector meson production in polarised lepton-proton scattering was
observed by the HERMES experiment. The longitudinally polarised 27.56 GeV HERA
positron beam was scattered off a longitudinally polarised pure hydrogen gas
target. The average invariant mass of the photon-proton system has a value of
= 4.9 GeV, while the average negative squared four-momentum of the virtual
photon is = 1.7 GeV^2. The ratio of the present result to the
corresponding spin asymmetry in inclusive deep-inelastic scattering is in
agreement with an early theoretical prediction based on the generalised vector
meson dominance model.Comment: 10 pages, 4 embedded figures, LaTe
Gene-regulation & epigenetics in dopaminergic neurons: New roles for Dot1l and Af9 in balanced synaptic versus mitochondrial neuronal gene regulation
The research described in this dissertation offers insights into various forms of neuronal gene regulation, especially in dopamine (DA) neurons. During the progression of Parkinson's Disease, DA neurons are among the most vulnerable neurons to degenerate. Mitochondria are widely appreciated to be involved in DA neurodegeneration. Moreover, transcripts encoding mitochondrial respiratory chain components are down-regulated in (early) PD neurons. Whereas mitochondrial genes are down-regulated in PD, we showed that down-regulation of the gene-regulator Dot1l has the opposite effect in DA neurons, increasing mitochondrial respiratory chain genes broadly. In addition, we have found genes involved in anti-oxidation, mitophagy, and ribosomes consistently up-regulated. Since Dot1l regulates the activity of genes via methylation at the histone subunit H3, lysine 79 (H3K79me), we have also studied the levels of H3K79me2 in mouse DA neurons and postmortem brains of aged and diseased individuals. Firstly, we found signs of a fast turnover of H3K79me in mouse DA neurons. Secondly, we have found that high levels of H3K79me associate with lipofuscin in the old brain. Lipofuscin consists of slow / undegradable protein aggregates that accumulate during aging. Thirdly, levels of H3K79me2 were also up-regulated in DA neurons from Parkinson's Disease patients, though, more restricted. Our research suggests that more research on the role of Dot1l in regulating neuronal mitochondria could be very rewarding as it may further reveal the roles of Dot1l in neuronal regulation of mitochondira, aging and PD, and perhaps as a future therapeutic target
Epigenetic mechanisms in the development and maintenance of dopaminergic neurons
Mesodiencephalic 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
Neuronal Dot1l Activity Acts as a Mitochondrial Gene-Repressor Associated with Human Brain Aging via H3K79 Hypermethylation
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