Transcriptional Regulation by Neuronal Activity: To the Nucleus and Back

Preface
Contents
About the Editors
Part I: Activity-Regulated Transcription: Getting to the Nucleus
	Fos/AP-1 as an Exemplar for the Study of Neuronal Activity-Dependent Gene Regulation
		1 Discovery of Fos and the Broader Neuronal Activity-Responsive Gene Program
		2 A Focus on Signal Transduction: Unraveling Stimulus-Transcription Coupling
			2.1 Poised Pre-bound Transcription Factors at the Fos Promoter: CREB and SRF
			2.2 Further Dissecting Synapse to Nucleus Signaling
			2.3 Expanding Beyond the Proximal Promoter
		3 Genomic Profiling-Based Insights into Fos/AP-1 Molecular Function
		4 Fos Induction as a Tool: Exploiting IEGs as Proxy Activity Labels
		5 Application of Fos-Based Reagents in the Study of Memory Engrams
		6 “Second Wave” Studies of AP-1 Cellular and Circuit Function
		7 Future Perspectives
		References
	Calcium Signaling to the Nucleus
		1 Introduction
		2 NFAT Transcription Factors
			2.1 NFAT-Dependent Genes
			2.2 NFAT Transcription Co-factors
		3 CREB Transcription Factor
			3.1 CREB Coactivators
			3.2 LTCC-Dependent CREB Activation and CaMKII Involvement
			3.3 ERK-Dependent CREB Activation
			3.4 CaMKIV-Dependent CREB Activation
			3.5 The Question of Nuclear Ca2+ Signaling
		4 MEF2 Family of Transcription Factors
			4.1 Regulation of MEF2 Transcriptional Activity
			4.2 Mechanisms of MEF2-Dependent Synapse Elimination
		5 Concluding Remarks
		References
	Protein Transport from Synapse-to-Nucleus and the Regulation of Gene Expression
		1 Introduction
		2 Synapto-Nuclear Protein Messengers
		3 The Dual Function of the Synapto-Nuclear Protein Messenger Jacob
		4 Presynapse-to-Nucleus Macromolecular Protein Transport
		5 Conclusions and Future Directions
		References
	Gene Regulation by Nuclear Calcium and Its Antagonism by NMDAR/TRPM4 Signaling
		1 Introduction
		2 Generation and Functional Consequences of Synaptic Activity-Evoked Calcium Signals
			2.1 Activity-Dependent Gene Transcription Is Required for Memory Consolidation
			2.2 Experimental Synaptic Activity Patterns Involved in Neuroplasticity
			2.3 Nuclear Calcium Signals Are Required for Synaptic Activity-Driven, CREB-Dependent Transcription and Long-Lasting Neuroadaptations
			2.4 Calcium Signals Evoked by Synaptic Activity
			2.5 Calcium Sources Contributing to the Nuclear Calcium Signal
			2.6 The Relay of Calcium Signals from the Somatic Cytosol to the Nucleus
			2.7 Measurement of Nuclear Calcium Signals
		3 Calcium-Dependent Signaling Mechanisms in Transcriptional Regulation
			3.1 Cytosolic Calcium Signaling
			3.2 Nuclear Calcium Signaling
			3.3 Synopsis of the Activity-Regulated Transcriptional Response
			3.4 Activity-Driven Transcription in Human Neurons
		4 Antagonism of Activity-Driven Transcription
			4.1 Activity-Dependent Acquired Neuroprotection and Extrasynaptic NMDAR-Mediated Neurotoxicity
			4.2 Deregulation of Transcriptional Control in Neuropathological Conditions with Excessive esNMDAR Activity
			4.3 Targeting the NMDAR/TRPM4 Complex to Impede esNMDARs-Mediated Signaling and Rescue Activity-Driven Gene Transcription
		5 Concluding Remarks
		References
	Chemo-electrical Signaling, Protein Translocation, and Neuronal Transcription
		1 Prescient Early Contributions to Excitation-Transcription Coupling
		2 Evidence That CNS Neurons Use Tandem Signaling by NMDARs and LTCC
		3 Dendritic Spines as the Nexus for AMPAR, NMDAR, and LTCC Signaling
		4 Local Signaling Downstream of LTCCs Involves CaMKII
		5 Cellular and Molecular Underpinnings of CaV1-CaMKII Signaling for E-T Coupling
		6 Ca2+/CaM Translocation as a Mechanism for Signaling to the Nucleus
		7 Scrutinizing the Ca2+/CaM Translocation Hypothesis in Light of Alternatives
		8 A Ca2+/CaM Shuttle: An Exemplar Synaptonuclear Relay Mechanism
		9 CaM Shuttling: Dynamics and Stoichiometry
		10 Behavioral Impact of γCaMKII-Based CaM Shuttling
		11 Implications for Neuropsychiatric Disease
		References
Part II: Activity-Regulated Transcription: Epigenetic Regulation
	Histone Variants in Neuronal Transcription and Behavioral Regulation
		1 Why Study Epigenetics in Behavioral Plasticity?
		2 Role of Canonical and Variant Histones in Chromatin
		3 Histone Variants Are Dynamically Regulated
			3.1 Relevance of Histone Variant Dynamics for Gene Expression
			3.2 Histone Variants Regulate Splicing
			3.3 Caveats to Links Between Activity-Mediated Changes in Chromatin and Transcription
			3.4 Transcriptional Changes in Response to Histone Variant Depletion
			3.5 Transcriptional Effects of Histone Variants Are Regulated by Histone Chaperones and Chromatin Remodeling Complexes
			3.6 Behavioral and Functional Effects of Histone Variants
			3.7 Effects of Histone Variants Depend on Sex and Prior Stress Exposure
			3.8 Role of Post-Translational Modifications on Histone Variants
			3.9 Conclusions
		References
	Genome and Epigenome Engineering Approaches to Studying Neuronal Activity-Dependent Transcriptional Enhancers
		1 Introduction
		2 An Embarrassment of Methods
			2.1 Enter the Genome Engineers and Cue the CRISPR Revolution
		3 CRISPRi and CRISPRa: Putting the FUN in Functional Genomics
		4 Written on the Genome and Revised by Epigenome Editors
		5 The Loop’s the Thing
		6 Can We Fix It? Enhancers in Diseases and as Therapeutic Targets
		7 Conclusions and Future Directions
		References
	Higher-Order Genome Organization in the Control of Neuronal Identity and Neural Circuit Plasticity
		1 Introduction: Genome Organization at Multiple Length Scales
		2 Local Genome Organization Within TADs
		3 Chromosome Organization by Specialized Subnuclear Structures
		4 Reorganization of TADs During Neuronal Maturation
		5 Repositioning of Chromosomes by Subnuclear Structures during Neuronal Maturation
			5.1 Developmental Regulation of Transcriptionally Repressive Subnuclear Structures
			5.2 Developmental Regulation of Transcriptionally Active Subnuclear Structures
		6 Extrinsic Cues and Neuronal Activity
		7 Dynamic Changes in Enhancer–Promoter Loops and TADs with Activity
		8 Stimulus-Dependent Control of Large Subnuclear Genome-Organizing Structures
		9 Higher-Order Genome Architecture in Neural Circuits and Animal Behavior
		10 Future Perspectives on Activity-Dependent Genome Organization
		References
	Chromatin Remodelers in Neuronal Gene Transcription
		1 An Introduction to Chromatin Remodeler Families
		2 Imitation Switch (ISWI) Complex
		3 Chromodomain Helicase DNA Binding (CHD) Complex
		4 Inositol Requiring 80 (INO80) Complex
		5 SWI/SNF, Aka, the BAF Complex
		6 Discovery
		7 BAF Complexes Exist in Three Different Configurations (Subtypes)
		8 Modular Assembly of the BAF Complex
		9 The BAF Complex in Gene Transcription
		10 The npBAF and the nBAF Complexes in Neurodevelopment
		11 Neuron-Specific Chromatin Remodeling During Neuronal Activity
		12 The nBAF Complex and Neurodevelopmental Disorders
		13 Latest Perspectives and Future Directions on nBAF
		References
Part III: Activity-Regulated Transcription: Role in Nervous System Function
	Nature and Nurture Converge in the Nucleus to Regulate Activity-Dependent Neuronal Development
		1 Introduction
		2 Neurite Development
			2.1 Overview
				2.1.1 Molecular Effectors of Activity-Dependent Neurite Development
			2.2 ADT Mechanisms of Neurite Development
				2.2.1 Somatosensory System
			2.3 Summary: ADT Mechanisms of Neurite Development
			2.4 Linking Neurite Growth and Synapse Development
		3 Synapse Formation
			3.1 Overview
				3.1.1 Molecular Effectors of Activity-Dependent Synapse Formation
			3.2 ADT Mechanisms of Synapse Formation
		4 Developmental Synaptic Plasticity
			4.1 Overview
				4.1.1 Molecular Effectors of Activity-Dependent Synaptic Plasticity
			4.2 ADT Mechanisms of Developmental Synaptic Plasticity: Regulating the Regulators
				4.2.1 Nr4a1
				4.2.2 Mef2
			4.3 ADT Mechanisms of Developmental Synaptic Plasticity: Synaptic Effectors
				4.3.1 Arc
				4.3.2 Ube3a
				4.3.3 SynGAP
				4.3.4 Homer1a
			4.4 Summary: ADT Mechanisms in Synapse Development
		5 Neurodevelopmental Disorders (NDDs)
			5.1 Overview
			5.2 ADT in Excitation/Inhibition Balance
			5.3 ADT in Autism Spectrum Disorders
			5.4 ADT in Monogenetic Disorders
				5.4.1 Rett Syndrome (MECP2)
				5.4.2 Angelman Syndrome (UBE3A)
				5.4.3 Fragile X (FMR1)
			5.5 Summary: ADT Mechanisms in NDDs
		6 Closing Remarks
		References
	Roles for the MEF2 Transcription Factors in Synapse and Circuit Development and Plasticity
		1 Overview of the MEF2 Transcription Factors
		2 MEF2 Genes Function in Activity-Dependent Suppression of Excitatory Synapses in Hippocampus and Cerebellum
		3 MEF2 in Activity-Dependent Suppression of Excitatory Synapse in Other Brain Regions: Cerebellum and Striatum
		4 MEF2C Mediates Input-Specific Development of Cortical Excitatory Connections
		References
	Activity-Related Transcription: Role in Addiction
		1 Introduction
		2 Immediate Early Gene (IEG) Expression: A View from the Field of Virology
		3 Drug-Dependent Induction of IEG Response
			3.1 Pharmacological Activity of Psychostimulants and Opioids
			3.2 Distribution of Drug-Responsive Receptors
			3.3 Establishing IEG Expression as a Measure of Drug-Responsive Activity
		4 Drug-Responsive IEG Regulation
			4.1 Signaling Mechanisms for IEG Induction
			4.2 Transcriptional Regulation of IEGs
		5 Downstream Effects of Drug-Induced IEGs
			5.1 Distinguishing Delayed Secondary Response Genes (DSRGs)
			5.2 DSRG-Mediated Alterations in Synaptic Structure and Function
			5.3 DSRG-Mediated Alterations in Transcription
		6 Technical Innovations in Transcriptomic Analysis
			6.1 RNA-Sequencing Technologies
			6.2 IEGs in Sc- and snRNA-Seq
			6.3 Spatial Transcriptomics
		7 Conclusion
		References
	Epigenetic Priming of Activity-Dependent Transcription in Drug Addiction
		1 Introduction
		2 Epigenetics in SUDs
		3 Epigenetic Priming in the NAc
		4 Investigating “Chromatin Scars”
		5 DNA Methylation in Addiction
		6 Histone PTMs in Addiction
		7 Epigenetic Regulation of Activity-Induced Transcription
		8 Sex-Differences in Drug-Responsive Epigenetics
		9 Targeted Epigenetic Therapies
		10 The Journey Continues
		References
	Molecular Intersection of Activity-Dependent Gene Expression and Behavior: The Transcriptomic Signature of Long-Term Memory
		1 Introduction
		2 Memory Consolidation and Retrieval Rely on Activity-Dependent Transcription
		3 Transcription Factor Families Implicated in Long-Term Memory and Synaptic Plasticity
			3.1 Extracellular Signal Activated TFs
				3.1.1 CREB and CREB-Dependent Transcription
				3.1.2 SRF
				3.1.3 ELK-1
				3.1.4 Retrograde Signaling via NFқB
				3.1.5 NR4A Family of Nuclear Hormone Receptors
			3.2 TFs Functioning as IEGs
				3.2.1 EGR1/ZIF-268
				3.2.2 AP-1 Transcription Factor Complex
				3.2.3 FOS
				3.2.4 C/EBP Family of IEGs
			3.3 Activity-Dependent Transcriptional Repressors
		4 The “Second” Wave of Transcriptional Response
		5 Epigenetic Control of Activity-Dependent Gene Expression Underlying Long-Term Memory Storage and Synaptic Plasticity
		6 Conclusion
		References
	Perturbations to Stimulus-Dependent Gene Activity Patterns in Neurodegenerative Disorders
		1 Introduction
		2 Activity-Dependent Synapse-to-Nucleus Communication in Neurons
		3 Synapse-to-Nucleus Signaling Is Altered in Neurodegenerative Diseases
		4 Epigenetic Control of Activity-Dependent Transcription and Its Links to Neurodegeneration
		5 Genome Integrity in Activity-Dependent Gene Transcription and Neurodegenerative Disorders
		6 Conclusions
		References
Part IV: New Tools to Study and Use Activity-Regulated Transcription
	Genome Editing Technologies for Investigation of Activity-Dependent Transcription
		1 Introduction
		2 Current Applications of CRISPR/Cas9-Based Systems
			2.1 Components of the CRISPR/Cas9 Machinery
			2.2 Genome Editing
				2.2.1 Gene Editing with CRISPR/Cas9
			2.3 Epigenome Editing
				2.3.1 Epigenetic Editing with CRISPR/dCas9
				2.3.2 Transcriptional Repression with CRISPR/dCas9
				2.3.3 dCas9 Fused to Transcriptional Repressors
				2.3.4 Interference Platforms Using Epigenetic Editors
				2.3.5 Multiplexed Targeting with Repressors
			2.4 Transcriptional Activation Strategies
				2.4.1 Activation Strategies with Artificial Transcription Factors
				2.4.2 Activation Strategies with Epigenetic Editors
				2.4.3 CRISPR Display
				2.4.4 CRISPRa Strategies for Multiplexed Manipulations
			2.5 Inducible CRISPR Systems
				2.5.1 Cre-Dependent CRISPR Systems
				2.5.2 Light-Inducible Systems
		3 Future Perspectives
			3.1 Improving Specificity for Editing in Discrete Cell Populations
				3.1.1 Cell-Type Specific CRISPR Strategies
				3.1.2 Projection- and Ensemble-Specific CRISPR Manipulations
			3.2 Improving Translational Relevance
				3.2.1 Remaining Challenges
		References
	Imaging Activity-Dependent Gene Expression in Neurons: RNA-Tagging Technologies
		1 Introduction
		2 Overview of Current RNA Imaging Technologies
			2.1 Stem Loop-Coat Protein System
			2.2 RNA Aptamers
			2.3 Imaging RNAs Without Sequence Engineering
		3 Imaging Transcription in Real Time: Kinetics and Models
			3.1 Monitoring IEG Expression Ex Vivo and In Vivo
		4 Probing Excitation–Transcription Coupling by Imaging IEG mRNAs
		5 Multiplexed Imaging of Transcription and Transcriptional Regulators
		6 Future Perspectives
		References
	Optogenetic Approaches to Study IEG Activation
		1 Specificity and Precision of Neuronal Stimulation
		2 Controlling Neuronal Spiking with the Channelrhodopsin ChrimsonR
		3 Using Photoactivatable Adenylyl Cyclase (PACmn) to Drive Fos Expression
		4 Advantage of Precision Stimulation for a Careful Dissection of IEG Activation Pathways
		References
	New Genome-Wide Technologies to Study Activity-Regulated Transcription
		1 Introduction
		2 Differential Expression Profiling in the Neurosciences: From Microarrays to RNA-Seq
		3 Technical Decisions and Experimental Design
		4 Different Types of RNA-Seq
		5 Different Waves of the Activity-Driven Transcriptome
		6 Activity-Driven Transcription Factor Binding in Neurons
		7 Noncoding Activity-Driven Transcriptome
		8 Exploring Activity-Driven Changes in Neuronal Chromatin
			8.1 Histone Posttranslational Modifications
			8.2 DNA Methylation
			8.3 Accessibility and Occupancy of Chromatin by Nucleosomes and TFs
			8.4 Chromatin Conformation
		9 Neuronal Activity in the Healthy and Diseased Brain: A Multiomics Task
		References
Index