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
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
Cell Mol Life Sci 64:1531, 2007
The classical definition of epigenetics
refers to modifications of gene expression
and function not requiring primary
changes in nucleotide sequence
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DNA methylation
Histone code modifications
Nucleosome positioning
Higher-order chromatin remodeling
Organizational Structure of the Classical Epigenome I
Higher-order chromatin remodeling
Nucleosome positioning
Post-translational histone tail modifications
DNA methylation and methyl binding proteins
JAMA 299:1346, 2008
Epigenetic Regulatory Factors in Neurodevelopmental Diseases:
Enzymes that directly modulate chromatin structure
Van Bokhoven and Kramer Neurobiol. Dis. (2010)
Epigenetic Regulatory Factors in Neurodevelopmental Diseases:
Enzymes that indirectly modulate chromatin structure
Van Bokhoven and Kramer Neurobiol. Dis. (2010)
Novel Epigenetic Mechanisms
Non-Protein-Coding RNAs
RNA Editing
Explosive Growth of Non-Coding RNAs During
Eukaryotic Evolution
J Exp Biol 210:1526, 2007
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
Non-Coding RNA Expression in Mammalian Brain
PNAS 105:716, 2008
Non-Coding RNAs Associated with Neurological Genes
PNAS 105:716, 2008
PNAS 105:716, 2008
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
RNA Binding Proteins Regulate RNA Cellular
Localization and Function
Nat Rev Genet 8:533, 2007
The Role of RNA Binding Proteins in the
Pathogenesis of Complex Diseases
Nat Rev Genet 8:533, 2007
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
Expression of Receptors for
Intercellular Transport of RNAs in Adult Brain
J Mol Endocrinol 40:151, 2007
The New RNA Biology
Science 319:1787, 2008
Towards Understanding and
Treating Complex
Neurological Diseases
Metabolic/homeostatic/environmental cues
Genome regulation
• genomic imprinting
• gene dosage effect
• long-range gene modulation
• genomic stability
• epigenetic reprogramming
-DNA/RNA/protein
• multigenerational heritability
Neural development
• neural induction
• regional neural patterning
• stem cell self-renewal/maturation
• neuronal/glial subtype specification
• terminal differentiation
• synaptogenesis
Essential cellular functions
• cell cycle regulation
• DNA replication/repair/recombination
• nuclear reorganization
• telomere maintenance
• gene transcription
• post-translational processing
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
Expansion Repeat Disorders
Nature 447, 932-940(21 June 2007)
Ann Neurol. 64:602, 2008
Ann Neurol. 64:602, 2008
Ann Neurol. 64:602, 2008
Ann Neurol. 64:602, 2008
Ann Neurol. 64:602, 2008
Pharmacoepigenomics
J Cell Physiol 212:330, 2007