epigenetic principles and mechanisms underlying nervous...
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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
Epigenetic Principles and Mechanisms Underlying
Nervous System Function in Health and Disease
Mark F. Mehler MD, FAAN
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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
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Cell Mol Life Sci 64:1531, 2007
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The classical definition of epigeneticsrefers 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
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DNA methylation and methyl binding proteins
Organizational Structure of the Classical Epigenome I
Post-translational histone tail modifications
Nucleosome positioning
Higher-order chromatin remodeling
JAMA 299:1346, 2008
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Epigenetic Regulatory Factors in Neurodevelopmental Diseases:
Enzymes that directlymodulate chromatin structure
Van Bokhoven and Kramer Neurobiol. Dis. (2010)
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Epigenetic Regulatory Factors in Neurodevelopmental Diseases:
Enzymes that indirectlymodulate chromatin structure
Van Bokhoven and Kramer Neurobiol. Dis. (2010)
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Novel Epigenetic Mechanisms
Non-Protein-Coding RNAs
RNA Editing
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J Exp Biol 210:1526, 2007
Explosive Growth of Non-Coding RNAs During
Eukaryotic Evolution
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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
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Non-Coding RNA Expression in Mammalian Brain
PNAS 105:716, 2008
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Non-Coding RNAs Associated with Neurological Genes
PNAS 105:716, 2008
PNAS 105:716, 2008
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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
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RNA Binding Proteins Regulate RNA Cellular
Localization and Function
Nat Rev Genet 8:533, 2007
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The Role of RNA Binding Proteins in the
Pathogenesis of Complex Diseases
Nat Rev Genet 8:533, 2007
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Short and Long Range Extracellular
Trafficking of RNAs
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
J Mol Endocrinol 40:151, 2007
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Expression of Receptors for
Intercellular Transport of RNAs in Adult Brain
J Mol Endocrinol 40:151, 2007
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The New RNA Biology
Science 319:1787, 2008
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Towards Understanding and
Treating Complex
Neurological Diseases
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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
Metabolic/homeostatic/environmental cues
Ann Neurol. 64:602, 2008
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Nature 447, 932-940(21 June 2007)
Expansion Repeat Disorders
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Ann Neurol. 64:602, 2008
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Ann Neurol. 64:602, 2008
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Ann Neurol. 64:602, 2008
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Ann Neurol. 64:602, 2008
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Ann Neurol. 64:602, 2008
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Pharmacoepigenomics
J Cell Physiol 212:330, 2007