Chromatin Signaling and Neurological Disorders

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Translational Epigenetics Series
Chromatin Signaling and Neurological Disorders
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Contributors
Preface
	Chromatin and epigenetics
	Chromatin signaling and neurological diseases
	References
1. Chromatin and epigenetic signaling pathways
	1.1 Chromatin signaling and epigenetics
	1.2 Chromatin organization
	1.3 Histone posttranslational modifications and the histone code
	1.4 Functions of histone posttranslational modifications
	1.5 DNA methylation
	1.6 Writers, erasers, and readers
		1.6.1 Histone writers
		1.6.2 DNA writers
		1.6.3 Histone erasers
		1.6.4 DNA erasers
		1.6.5 Histone readers
		1.6.6 DNA readers
	1.7 Modification cross talk
	1.8 Effects of metabolism on histone and DNA modifications
	1.9 Epigenetic inheritance
	1.10 Summary
	References
Section 1: Neurodegenerative disorders
2. Into the unknown: chromatin signaling in spinal muscular atrophy
	2.1 Spinal muscular atrophy: prevalence, genetic basis, clinical features, and pathogenesis
	2.2 The survival motor neuron protein: localization, structure, and function
	2.3 Epigenetic landscape in spinal muscular atrophy pathogenesis
	2.4 Targeting epigenetic factors as potential therapeutics in spinal muscular atrophy
		2.4.1 Histone deacetylase inhibitors as regulators of the survival motor neuron gene
		2.4.2 The nonspecific effect of histone deacetylase inhibitors
		2.4.3 The potential protective effect of histone deacetylase inhibitors in the pathogenesis of spinal muscular atrophy
	2.5 Conclusion
	Acronyms and abbreviations
	Acknowledgments
	References
3. Charcot-Marie-Tooth disease
	3.1 Introduction
	3.2 Epigenetic regulation of Schwann cell development
	3.3 Epigenetic regulation of dosage-sensitive genes
	3.4 Epigenetic regulators targeted by CMT mutations
		3.4.1 DNMT1
		3.4.2 LMNA
		3.4.3 SYNE1
		3.4.4 MED25
		3.4.5 SETX
		3.4.6 MORC2
		3.4.7 PRDM12
	3.5 Novel mechanisms for CMT mutations
	3.6 Summary
	Acknowledgments
	References
4. Epigenetic mechanisms in Huntington's disease
	4.1 Introduction
	4.2 Huntington's disease
		4.2.1 Neuropathology of HD
	4.3 Transcriptional dysregulation in HD
	4.4 Altered epigenetic marks in HD
		4.4.1 Histone modifications
			4.4.1.1 Histone acetylation
			4.4.1.2 Histone acetylation alterations in HD
			4.4.1.3 Histone methylation
			4.4.1.4 Histone methylation changes in HD
			4.4.1.5 Histone phosphorylation
			4.4.1.6 Histone phosphorylation and HD
			4.4.1.7 Histone ubiquitination
			4.4.1.8 Altered histone ubiquitination in HD
		4.4.2 DNA methylation
		4.4.3 DNA methylation changes in HD
			4.4.3.1 Global DNA methylation changes
			4.4.3.2 Gene-specific DNA methylation changes
			4.4.3.3 Implicating DNA methylation enzymes
	4.5 Epigenetic-based therapies
		4.5.1 HDAC inhibitors as a treatment for HD
		4.5.2 Methylation-inhibiting drugs
	4.6 Concluding remarks
	4.7 Abbreviations
	References
5. The epigenetics of multiple sclerosis
	5.1 Multiple sclerosis, the knowns and the unknowns
		5.1.1 A chronic progressive disease of the central nervous system
		5.1.2 The genetics of MS
		5.1.3 Gender bias and parent-of-origin effect
		5.1.4 A role for environmental factors
		5.1.5 A viral component in MS
	5.2 MS as an epigenetic disorder
		5.2.1 Nongenetic causes of MS and their link to chromatin and transcription
			5.2.1.1 Vitamin D and the vitamin D receptor
			5.2.1.2 Reactivation of HERVs
		5.2.2 DNA and histone modifications are footprints of transcriptional regulation
	5.3 DNA and histone modifications linked to MS
		5.3.1 DNA methylation
			5.3.1.1 Imprinting
			5.3.1.2 Differential methylation in blood cells and in CNS
			5.3.1.3 Cytosine hydroxymethylation
		5.3.2 A possibly reduced efficiency of the H3K9me/HP1 axis of transcriptional repression in MS
			5.3.2.1 Reduced recruitment of HP1 at HERVs and proinflammatory genes in patients with MS
			5.3.2.2 Peptidylarginine deiminases interfere with the H3K9me/HP1 axis of transcriptional repression
			5.3.2.3 The H3K9me/HP1 axis: a central player in the onset of MS?
	5.4 Epigenetics beyond transcription
		5.4.1 Exosomal miRNA silencing
		5.4.2 Microbiota
		5.4.3 Environment: pollutants that may interfere with silencing machineries
	5.5 Conclusions
	Acknowledgments
	References
6. Alterations in epigenetic regulation contribute to neurodegeneration of ataxia-telangiectasia
	6.1 Decreased level of histone acetylation induced by nuclear accumulation of HDAC4 drives A-T neurodegeneration
	6.2 Dysfunction of polycomb repressive complex 2 involved in A-T neurodegeneration
	6.3 Selective loss of 5-hmC is associated with purkinje cell vulnerability in A-T brain
	6.4 TETs-mediated DNA oxidation regulates ATM/ATR-dependent DDR
	6.5 Conclusion
	6.6 Future perspective
	Acknowledgments
	References
7. Cockayne syndrome
	7.1 Clinical phenotypes
		7.1.1 Classical (moderate) type I cockayne syndrome
		7.1.2 Early-onset (severe) subtypes
		7.1.3 Late-onset subtypes
	7.2 Genetics
	7.3 CSA and CSB proteins
	7.4 Cellular and molecular aspects
	7.5 The molecular basis of neurodegeneration
	7.6 Concluding remarks
	References
8. Epigenetic processes in Alzheimer's disease
	8.1 Alzheimer's disease: a need for new drug targets
	8.2 Alzheimer's disease: the genomic era
	8.3 An additional layer of information: Alzheimer's disease from an epigenetic perspective
		8.3.1 DNA modifications
		8.3.2 Histone modifications
		8.3.3 Regulatory RNA–based mechanisms
		8.3.4 Epigenetic signatures as blood biomarkers
	8.4 Modeling Alzheimer's disease: mouse models as powerful tools
	8.5 Current challenges and future directions
	8.6 Final considerations
	References
Section 2: Neurodevelopmental disorders
9. Genetic and epigenetic influences on the phenotype of Rett syndrome
	9.1 Introduction
	9.2 The genetic cause of Rett syndrome
	9.3 The biology of MeCP2
		9.3.1 Neurobiology of MeCP2
		9.3.2 Molecular functioning of MeCP2
	9.4 The phenotype of Rett syndrome
		9.4.1 Early development and regression
		9.4.2 Diagnostic criteria
		9.4.3 Functional impairments
		9.4.4 Stereotypies
		9.4.5 Comorbidities
		9.4.6 Epidemiology
	9.5 Evidence for epigenetic mechanisms affecting MECP2 function and expression
		9.5.1 DNA methylation
		9.5.2 Histone modifications and nucleosome and higher-order chromatin remodeling
		9.5.3 Noncoding RNAs
		9.5.4 RNA splicing
	9.6 Epigenetic regulation of MeCP2 expression or phenotypes
		9.6.1 X chromosome inactivation
		9.6.2 IGF1/mTOR pathway
		9.6.3 Enriched environments
	9.7 Inclusion of epigenetic data collection in epidemiological studies
	9.8 Summary
	References
10. Sotos syndrome
	10.1 Introduction
	10.2 The genetic basis of Sotos syndrome
	10.3 Comparing Sotos syndrome with other single-gene overgrowth syndromes
	10.4 Neurological profile of Sotos syndrome
	10.5 The cognitive and behavioral profile of Sotos syndrome
		10.5.1 Cognition
			10.5.1.1 Intellectual ability
			10.5.1.2 Sotos syndrome cognitive profile
			10.5.1.3 Language
		10.5.2 Behavior
			10.5.2.1 Attention-deficit/hyperactivity disorder
			10.5.2.2 Anxiety
		10.5.3 Aggression and tantrums
	10.6 Sotos syndrome and autism spectrum disorder
	10.7 Nuclear receptor–binding SET domain methyltransferases modify histones and affect epigenetics
	10.8 Limitations and future research directions
	10.9 Summary and conclusions
	References
11. ATRX tames repetitive DNA within heterochromatin to promote normal brain development and regulate oncogenesis
	11.1 Introduction
	11.2 Biochemical and molecular functions of ATRX
		11.2.1 ATRX protein structure
		11.2.2 ATRX is a heterochromatin interacting protein
		11.2.3 Other critical interactions and functions of ATRX
		11.2.4 ATRX interactions with RNA
	11.3 Neurologic deficits and phenotypic variability in ATRX-associated syndromes
	11.4 Delineating a role for ATRX in cancer
		11.4.1 Cancer profiling identifies ATRX as a common mutation target
		11.4.2 Cancers with ATRX mutations are alternative lengthening of telomere positive
		11.4.3 Understanding the alternative lengthening of telomeres pathway
		11.4.4 ATRX is a suppressor of the alternative lengthening of telomeres pathway
	11.5 Conclusion
	List of abbreviations
	References
Section 3: Neuropsychiatric disorders
12. Epigenetic dysregulation in the fragile X-related disorders
	12.1 Introduction
	12.2 Clinical features of the FXDs
		12.2.1 Fragile X syndrome
		12.2.2 Fragile X-associated tremor/ataxia syndrome
		12.2.3 Fragile X-associated primary ovarian insufficiency
	12.3 Genetics of the FXDs
	12.4 The pathological basis of FXTAS
	12.5 The pathological basis of FXPOI
	12.6 The pathological basis of FXS
	12.7 Epigenetic abnormalities associated with the FXDs
	12.8 Resolving the repeat paradox
	12.9 Prospects and challenges for epigenetic therapies for the FXDs
	12.10 Concluding remarks
	Grant Sponsor
	References
13. The epigenetics of autism
	13.1 Autism
		13.1.1 Heritability and genetics
	13.2 Epigenetics of autism
		13.2.1 DNA methylation and hydroxymethylation in autism
			13.2.1.1 Candidate gene methylation studies in humans
			13.2.1.2 Methylome-wide association studies
		13.2.2 Histone modifications
			13.2.2.1 Histone methylation and acetylation
			13.2.2.2 Chromatin modifying and remodeling complexes
		13.2.3 Risk factors affecting the epigenetics of autism
			13.2.3.1 Hormones
	13.3 Discussion
	Acknowledgments
	References
14. Chromatin modification and remodeling in schizophrenia
	14.1 Introduction
	14.2 SZ GWAS implicate gene expression and chromatin regulation as a possible causal molecular mechanism
	14.3 SZ and DNA methylation
		14.3.1 Aberrant DNA methylation in SZ
		14.3.2 Genetic control of DNA methylation and its relevance to SZ
	14.4 SZ and histone modifications
		14.4.1 Histone acetylation
		14.4.2 Histone methylation
	14.5 SZ and 2D chromatin structure
	14.6 SZ and higher-order chromatin structure
	14.7 SZ genetic risk variants affect chromatin remodeling gene pathway
		14.7.1 Analysis of common SZ variants implicates the dysregulated chromatin-signaling pathway
		14.7.2 Rare SZ coding risk variants and chromatin remodeling
		14.7.3 SZ-associated CNVs and abnormal chromatin organization
	14.8 hiPSC model combined with CRISPR editing for studying SZ-relevant chromatin function
		14.8.1 hiPSC-derived neurons as a cellular model for neurodevelopmental disorder
		14.8.2 CRISPR-based approaches for genome/epigenome perturbation
		14.8.3 CRISPR-based 2D and 3D chromatin perturbation relevant to SZ in hiPSC models
	14.9 Therapeutic drugs that target chromatin structure and activity in SZ
	14.10 Conclusion and perspectives
	Acknowledgments
	References
15. Gilles de la Tourette syndrome
	15.1 Introduction: Gilles de la Tourette syndrome and other tic disorders
		15.1.1 Definition and diagnostic criteria of Gilles de la Tourette syndrome and other tic disorders
		15.1.2 Epidemiology
	15.2 Clinical presentation of tics
		15.2.1 Shared characteristics of tics
		15.2.2 Characteristics of motor tics
		15.2.3 Characteristics of vocal/phonic tics
		15.2.4 Characteristics of cognitive tics
	15.3 Tic-related behavioral symptoms and health-related quality of life
		15.3.1 Behavioral spectrum of Gilles de la Tourette syndrome
		15.3.2 Obsessive–compulsive disorder
		15.3.3 Attention-deficit and hyperactivity disorder
		15.3.4 Health-related quality of life
	15.4 Etiology and pathophysiology
		15.4.1 Genetic factors
		15.4.2 Environmental factors
		15.4.3 Role of dopamine and cortico-striato-thalamo-cortical pathways
		15.4.4 Possible role of chromatin regulation
	15.5 Treatment strategies
		15.5.1 Psychoeducation
		15.5.2 Behavioral therapy
		15.5.3 Pharmacotherapy
		15.5.4 Other approaches
	15.6 Conclusions: open questions and suggestions for future research
	Acknowledgments
	References
Index
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