Epigenetic Principles and Mechanisms Underlying Nervous System Function in Health and Disease Mark F. Mehler MD, FAAN
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1 Epigenetic Principles and Mechanisms Underlying Nervous System Function in Health and Disease Mark F. Mehler MD, FAAN Institute for Brain Disorders and Neural Regeneration F.M. Kirby Program in Neural Repair and Protection Departments of Neurology, Neuroscience and Psychiatry and Behavioral Sciences Rose F. Kennedy Center for Research in Mental Retardation and Developmental Disabilities Einstein Cancer Center Albert Einstein College of Medicine
2 Unresolved Issues in Neuroscience Evolution of human brain form and function Limitations of bioenergetic reserve Basis of gene-environmental interactions Complexity of cellular identities and connectivity Plasticity/heritability of cognitive/behavioral traits Molecular genetics of neurological diseases
3 Cell Mol Life Sci 64:1531, 2007
4
5 The classical definition of epigenetics refers to modifications of gene expression and function not requiring primary changes in nucleotide sequence DNA methylation Histone code modifications Nucleosome positioning Higher-order chromatin remodeling
6 JAMA 299:1346, 2008 Organizational Structure of the Classical Epigenome I Higher-order chromatin remodeling Nucleosome positioning Post-translational histone tail modifications DNA methylation and methyl binding proteins
7 Epigenetic Regulatory Factors in Neurodevelopmental Diseases: Enzymes that directly modulate chromatin structure Van Bokhoven and Kramer Neurobiol. Dis. (2010)
8 Epigenetic Regulatory Factors in Neurodevelopmental Diseases: Enzymes that indirectly modulate chromatin structure Van Bokhoven and Kramer Neurobiol. Dis. (2010)
9 Novel Epigenetic Mechanisms Non-Protein-Coding RNAs RNA Editing
10 Explosive Growth of Non-Coding RNAs During Eukaryotic Evolution J Exp Biol 210:1526, 2007
11 Subclasses of Non-Coding RNAs (ncrnas) Signal recognition particle (SRP) RNAs Ribosomal RNAs (rrnas) Transfer RNAs (trnas) Transcription initiation RNAs (tirnas) Small nucleolar (spliceosomal) RNAs (snrnas) Small nucleolar RNAs (snornas) Sno-derived silencing RNAs (snirnas) Telomerase RNA MicroRNAs (mirnas) Small-interfering (cis-acting) RNAs (sirnas) Trans-acting antisense RNAs Tiny non-coding RNAs (tncrnas) Small modulatory double-stranded (dsrnas) RNAs (smrnas) Messenger RNA-like ncrnas Cytoplasmic ncrnas Heterogeneous nuclear RNAs (hnrnas) Genomic imprinting-related RNAs X-chromosome inactivation-related RNAs (rox RNAs) trna maturation-related RNAs (RNase P RNAs) MacroRNAs/long-expressed ncrnas (ENORs) Mehler & Mattick J. Physiol. 575:333, 2006
12 Non-Coding RNA Expression in Mammalian Brain PNAS 105:716, 2008
13 Non-Coding RNAs Associated with Neurological Genes PNAS 105:716, 2008 PNAS 105:716, 2008
14 RNA Editing Enzymes Recode Specific Base Pairs in Non-Coding and Coding RNAs to Fine-Tune Gene Expression and Function in Response to a Complex Environment RNA Biol 3:1, 2006
15
16 RNA Binding Proteins Regulate RNA Cellular Localization and Function Nat Rev Genet 8:533, 2007
17 The Role of RNA Binding Proteins in the Pathogenesis of Complex Diseases Nat Rev Genet 8:533, 2007
18 Short and Long Range Extracellular Trafficking of RNAs J Mol Endocrinol 40:151, 2007 Diverse RNA species may participate in signaling between adjacent neurons and across distributed neural networks RNAs may be transported to other organ systems through the systemic circulation RNAs may play a role in intergenerational inheritance through germline transmission
19 Expression of Receptors for Intercellular Transport of RNAs in Adult Brain J Mol Endocrinol 40:151, 2007
20 The New RNA Biology Science 319:1787, 2008
21 Towards Understanding and Treating Complex Neurological Diseases
22 Metabolic/homeostatic/environmental cues Genome regulation genomic imprinting gene dosage effect long-range gene modulation genomic stability epigenetic reprogramming -DNA/RNA/protein multigenerational heritability Essential cellular functions cell cycle regulation DNA replication/repair/recombination nuclear reorganization telomere maintenance gene transcription post-translational processing Neural development neural induction regional neural patterning stem cell self-renewal/maturation neuronal/glial subtype specification terminal differentiation synaptogenesis Adult brain functions neuronal homeostasis/plasticity neural network connectivity trans-neuronal signaling adult neurogenesis neural regeneration memory formation higher-order cognitive processing Ann Neurol. 64:602, 2008
23 Expansion Repeat Disorders Nature 447, (21 June 2007)
24 Ann Neurol. 64:602, 2008
25 Ann Neurol. 64:602, 2008
26 Ann Neurol. 64:602, 2008
27 Ann Neurol. 64:602, 2008
28 Ann Neurol. 64:602, 2008
29 Pharmacoepigenomics J Cell Physiol 212:330, 2007
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