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

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 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

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

Epigenetic Regulatory Factors in Neurodevelopmental Diseases:

Enzymes that directlymodulate chromatin structure

Van Bokhoven and Kramer Neurobiol. Dis. (2010)

Epigenetic Regulatory Factors in Neurodevelopmental Diseases:

Enzymes that indirectlymodulate chromatin structure

Van Bokhoven and Kramer Neurobiol. Dis. (2010)

Novel Epigenetic Mechanisms

Non-Protein-Coding RNAs

RNA Editing

J Exp Biol 210:1526, 2007

Explosive Growth of Non-Coding RNAs During

Eukaryotic Evolution

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

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

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

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

Nature 447, 932-940(21 June 2007)

Expansion Repeat Disorders

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