August 19-26, 2017
Coordinator: Schahram Akbarian
Icahn School of Medicine at Mount Sinai, New York, USA
Tracy Bale, University of Pennsylvania, Philadelphia, USA
Farah Lubin, University of Alabama School of Medicine, Birmingham, USA
Angel Barco, Instituto de Neurociencias de Alicante, Spain
Art Petronis, Centre for Addiction and Mental Health, University of Toronto, Canada
Ian Maze, Icahn School of Medicine at Mount Sinai, New York, USA
Marcelo Wood, University of California at Irvine, USA
Schahram Akbarian, Icahn School of Medicine at Mount Sinai, New York, USA
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 cognitive and psychiatric 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, commonly referred to as the 3D Genome, 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 3D genome chromosomal conformation maps maps is likely to illuminate the role of regulatory non-coding sequences in neuropsychiatric disease.
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.
Transgenerational and intergenerational epigenetic mechanisms
Parental lifetime exposures to perturbations such as stress, infection, malnutrition, and advanced age have been linked with an increased risk for offspring disease, including a strong association with neurodevelopmental disorders. While maternal insults during pregnancy can directly impact somatic cells and fetal development, the mechanisms by which lifelong parental experiences can alter germ cell programming and affect offspring brain development are just beginning to be examined. Surprisingly few animal models have been developed to study mechanisms of preconception perturbations. This session will discuss the epidemiological and preclinical research that has begun to define the windows of vulnerability for both transgenerational and intergenerational programming and the epigenetic mechanisms involved. Specific studies examining paternal exposures related to the offspring brain have identified unique epigenetic changes in the sperm that directly affect embryonic development, including miRNA, tRNA, DNA methylation and histone post-translational modifications. Causal studies have confirmed the importance of sperm noncoding RNA populations in programming of long-term offspring outcomes. The course will also discuss evidence for how and where the environment alters parental germ cells to produce transgenerational vs intergenerational and offspring sex-specific neurodevelopmental changes.
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.
Marcelo A. Wood
A tale of two epigenetic mechanisms necessary for memory: histone deacetylation in the aging brain and nucleosome remodeling in the young brain
Long-term memory storage is an essential process to human life. Without long-term memory, we would not be able to remember our pasts, interpret our present, or predict our future. We would have little personal identity and functioning in a world that continues to grow in complexity would be impossible. It has long been known that transcription is required for a learning event to be encoded into long-term memory. Successful transcription of specific genes required for long-term memory processes involves the orchestrated effort of not only transcription factors, but also very specific enzymatic protein complexes that modify chromatin structure. Chromatin modification has been identified as a pivotal molecular mechanism underlying certain forms of synaptic plasticity and memory. The best-studied form of chromatin modification in the learning and memory field is histone acetylation, which is regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). This session will focus on new results from the field that test the general hypothesis that histone deacetylase function becomes dysfunctional in the aging brain, giving rise to age-related memory impairments. Furthermore, chromatin modification is known to work hand in hand with nucleosome remodeling, another major epigenetic mechanism of gene regulation. However, very little is known about the role of nucleosome remodeling in neuroscience in general, which is surprising given that several intellectual disability disorders may be caused by mutations in nucleosome remodeling genes. This session will also analyze the role of neuron-specific nucleosome remodeling mechanisms in neuronal differentiation, synaptic plasticity, and memory.
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.
The Genetics and Epigenetics of Intellectual Disability
Intellectual development disorders (IDDs) represent one of the biggest medical challenges in our society. Their cause includes the mutation of genes encoding epigenetic regulators of gene expression. IDD-linked epigenetic factors often interact with one another in complexes that regulate chromatin structure at genes important for neurodevelopment and/or neuroplasticity. After introducing the general role of epigenetic mechanisms in neurodevelopment and neuroplasticity, I will focus on our recent work on two of these IDDs: Rubinstein-Taybi syndrome, a rare autosomal dominant disorder caused by mutation in the genes encoding the lysine acetyltransferases CBP and p300 (aka KAT3A and KAT3B, respectively), and X-Linked Intellectual Disability, Claes-Jensen type which is caused by mutations in the lysine demethylase 5C gene (KDM5C). We aim to determine the role of these chromatin-modifying enzymes in neuronal gene expression and plasticity, to dissect the developmental and adult components of the syndromes, and to describe the epigenetic and transcriptional alterations that underlie ID through state-of-the-art genomic screens. These studies do not only contribute to the understanding and therapy of these rare IDDs, but also provide answer to fundamental questions in neurobiology.