Angel Barco, Instituto de Neurociencias de Alicante, Spain
Andre Fischer, German Center for Neurodegenerative Diseases (DZNE) Göttingen, Germany
Farah Lubin, Department of Neurobiology, University of Alabama, Birmingham, USA
Isabelle Mansuy, Brain Research Institute, ETH Zürich, Switzerland
Ian Maze, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, USA
Arturas Petronis, CAMH & Department of Psychiatry, University of Toronto, Canada.
Neuroepigenetics in the Human Brain
Many cellular constituents in the human brain permanently exit from the cell cycle during pre- or early postnatal development, but little is known about epigenetic regulation of neuronal and glial epigenomes during maturation and aging, including changes in mood and psychosis spectrum disorders and other cognitive or emotional disease. Normal brain development and function is dependent on highly regulated mechanisms governing DNA cytosine methylation and hydroxymethylation, and probably more than 100 residue-specific histone modifications associated with gene expression and silencing and various other functional chromatin states. Equally important is the 3-dimensional organization of the chromosomal material inside the cell nucleus, with chromosomal loopings potentially bypassing hundreds of kilobases on the linear genome to enable promoter-enhancer interactions and other mechanisms important for transcriptional regulation. Combined exploration of epigenomic and chromosomal conformation maps with the genetic risk maps of psychiatric disorders is likely to illuminate the role of regulatory non-coding sequences in the neurobiology of psychosis.
Genomic landscape of lysine acetylation in the adult hippocampus: Implications in neuronal plasticity and brain disorders
The acetylation of lysine residues at the histone tails is an epigenetic modification of the chromatin associated with active transcription. The process is regulated by the opposing activities of lysine acetyltransferase (KAT) and histone deacetylase (HDAC) enzymes and it is thought to play a relevant role in neuronal plasticity, learning and memory and diverse brain pathologies ranging from intellectual disability syndromes to neurodegenerative diseases. These enzymes also have hundreds of non-histone substrates including transcription and chromatin-remodeling factors and regulatory subunits of the RNA polymerase II complex. Understanding of the role of lysine acetylation in neuronal plasticity, memory and neuropsychiatric disorders will require a clear distinction between epigenetic and transcriptional mechanisms. Our lab uses genomic approaches to investigate the role of lysine acetylation in neuronal gene expression and the consequences of interfering with either KAT or HDAC activity.
Epigenetic Memory: From plasticity to dementia.
Recent data support the view that epigenetic processes play a role in memory consolidation and help to transmit acquired memories even across generations in a Lamarckian manner. Drugs that target the epigenetic machinery were found to enhance memory function in rodents and ameliorate disease phenotypes in models for brain diseases such as Alzheimer's disease, Chorea Huntington, Depression or Schizophrenia.
The field of neuroepigenetics is currently in a highly dynamic stage moving from merely describing phenomena to obtaining mechanistic insight.
In my talk I will give an overview on the current knowledge of epigenetic processes in memory function and brain disease with a focus on Alzheimer's disease and address the question if an epigenetic therapy could indeed be a suitable therapeutic avenue to treat brain diseases on a individual level and discuss the necessary steps that should help to take neuroepigenetic research to the next level. I will put a special emphasis on the tools that may help to decipher the epigenetic code underlying memory function and point to the necessary tools that allow the investigation of behavioral experiments in rodents, human disease phenotypes and the analysis of human tissue in the context of neuropsychiatric diseases including bioinfomratic analysis pipelines and systems medicine approaches based on next-generation sequencing data.
The epigenetics of the central nervous system: implications for cognition and cognitive disorders
It is well-established that environmental influences or experience-stimuli trigger long-lasting changes in gene transcription and protein synthesis in the brain, both of which are critical processes for the formation of long-term memory (LTM). Extensive research in adult brain chromatin biology has established the importance of epigenetic markings of DNA or its associated proteins in the encoding of LTM. We and others have observed that neurons have "highjacked" epigenetic processes such as DNA methylation to coordinate dynamic gene transcription changes in the hippocampus in response to learning, thus revealing an unexpected role for chromatin structure regulation in mature, non-dividing neurons during memory formation. These studies have given us hope in unraveling the causes of cognitive deficits and to develop treatment options. This presentation will address the idea that manipulation of chromatin is critically involved in regulating gene expression for the formation of LTM. Furthermore, the study of epigenetic gene regulation, in conjunction with transcription factor activation, can provide complementary lines of evidence to further understanding transcriptional mechanisms subserving memory storage. Such research offers novel concepts for understanding transcriptional mechanisms subserving adult cognition and mental health and promises novel avenues for therapeutic approach in the clinic. There will be specific discussion on epilepsy and associated memory deficits. Indeed, temporal lobe epilepsy (TLE) patients exhibit signs of memory impairments even when seizures are pharmacologically controlled. Surprisingly, the underlying molecular mechanisms involved in TLE-associated memory impairments remain elusive. Our studies suggest that we can manipulate aberrant epigenetic mechanisms in epilepsy to not only reduce interictal spike activity and improve theta rhythm power, but also to reverse memory deficits in epileptic animals.
Epigenetics and nervous system: The influence of environmental factors and their impact on mental health across generations
Epigenetic mechanisms are important regulators of gene activity in all organs and cells. In the nervous system, these mechanisms contribute to the control of genetic programs engaged during the development and the formation of neural circuits, and that are necessary for the activity and functions of the adult brain. Brain cells carry many epigenetic marks that greatly vary within cells and between individuals. These marks are dynamically regulated across life, and can be modulated by environmental factors. This lecture will discuss the importance of epigenetic marks in the brain and their involvement in cognitive functions and behavioral responses in the adult. The emphasis will be placed on epigenetic mechanisms shaped by environmental factors during early life, and their study in rodent (mouse/rat) experimental models. The course will describe the relation between the epigenetic make-up of each individual and interindividual differences in susceptibility to the environment such as stress. It will discuss experimental approaches that allow modifications of the epigenetic profile of an individual based on environmental conditions such as maternal care, early traumatic stress or environmental enrichment. It will also discuss the consequences of epigenetic alterations induced by the environment on individuals directly exposed but also on future generations, and will propose possible mechanisms for epigenetic heritability.
Harnessing the power of chromatin biochemistry to explore novel aspects of neuronal biology and disease.
Abstract: Over the past three decades, revolutionary advances in the field of chromatin biochemistry have greatly increased our understanding of human biology and disease; however, faithful application of such approaches to investigations of the nervous system remains inadequate. Although the field of 'neuroepigenomics' has blossomed in recent years, little coalescence between the fields of neuroscience of chromatin biology exists. Throughout this course, we will discuss the possibilities of exploring the interface of these two interrelated disciplines, with the hope of demonstrating the feasibility of approaching complicated neurobiological questions from very basic biochemical frameworks. In particular, we will discuss various methods required to address novel chromatin-related phenomena in brain including, but not limited to, the identification of novel chromatin 'reader' proteins, investigations of CNS enriched histone post-translational modifications, and studies of activity-dependent chromatin remodeling and histone variant exchange. Specific emphasis will be placed on the necessity of incorporating expertise from both disciplines to truly address fundamental aspects of neurological/psychiatric disease that may one day lead to more effective therapeutic interventions.
Epigenomics of major psychiatric disease: progress, problems and perspectives.
Understanding the origins of normal and pathological behavior is one of the most exciting opportunities in contemporary biomedical research. There is increasing evidence that, in addition to DNA sequence and the environment, epigenetic modifications of DNA and histone proteins may contribute to complex phenotypes. Inherited and/or acquired epigenetic factors are partially stable and have regulatory roles in numerous genetic and genomic activities, thus making epigenetics a promising research path in etiological studies of psychiatric disease. In this lecture, I will discuss methodological and technological aspects of epigenomic strategies in complex psychiatric disease. Second, I will review epigenetic DNA modification studies examining the brain and other tissues from individuals with schizophrenia, bipolar disorder, and major depression which have been performed in the lecturer's laboratory. Finally, I will highlight heuristic aspects of the epigenetic theory of psychiatric disease and present my personal view on the future directions of psychiatric epigenomics.