Epigenetic Principles and Mechanisms Underlying Nervous System - - PowerPoint PPT Presentation

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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

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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 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

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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 directly modulate chromatin structure

Van Bokhoven and Kramer Neurobiol. Dis. (2010)

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Epigenetic Regulatory Factors in Neurodevelopmental Diseases: Enzymes that indirectly modulate 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