• Development
• Diagnosis
• Gastrointestinal cancer
• Regulation
• Sine oculis homeobox homolog
• Therapeutics
• Transcription factor

• dna methylation
• embryonic stem cells

• Humans
• Myotonic Dystrophy/genetics
• Heterochromatin/genetics
• Cell Differentiation/genetics
• DNA Methylation
• Epigenesis, Genetic

• Israel Science Foundation (244/23 to R.E.) Ministry of Science and Technology (MOST) Israel (3-17372 to R.E.) Abrasba Foundation (Gindi family to R.E.)
• National Fish and Wildlife Foundation (NFWF)
• The Austrian Science Fund (FWF I 4768-B)
• ZonMw (TOP grant NL91212009) Prinses Beatrix Spierfonds (W.OR16-09)

• fuchs endothelial corneal dystrophy
• cancer
• odds ratio

• Aged
• Endothelium, Corneal/pathology
• Follow-Up Studies
• Fuchs' Endothelial Dystrophy/diagnosis
• Humans
• Male
• Medicare
• Melanoma/pathology
• Skin Neoplasms/pathology
• United States/epidemiology

• R01 EY021727 NEI NIH HHS
• R01 EY026490 NEI NIH HHS

Hearing impairment (HI) is a heterogeneous condition that affects many individuals globally with different age groups. HI is a genetically and phenotypically heterogeneous disorder. Over the last several years, many genes/loci causing rare autosomal recessive and dominant forms of hearing impairments have been identified, involved in various aspects of ear development. In the current study, two affected individuals of a consanguineous family exhibiting autosomal recessive nonsyndromic hearing impairment (AR-NSHI) were clinically and genetically characterized. The single affected individual (IV-2) of the family was subjected to whole-exome sequencing (WES) accompanied by traditional Sanger sequencing. Clinical examinations using air conduction audiograms of both the affected individuals showed profound hearing loss across all frequencies. WES revealed a homozygous missense variant (c.44G>C) in the SIX5 gene located on chromosome 19q13.32. We report the first case of autosomal recessive NSHI due to a biallelic missense variant in the SIX5 gene. This report further supports the evidence that the SIX5 variant might cause profound HI and supports its vital role in auditory function. Identification of novel candidate genes might help in application of future gene therapy strategies that may be implemented for NSHI, such as gene replacement using cDNA, gene silencing using RNA interference, and gene editing using the CRISPR/Cas9 system.

• Deafness/genetics
• Genes, Recessive
• Hearing Loss/genetics
• Hearing Loss, Sensorineural/genetics
• Homozygote
• Humans
• Mutation
• Mutation, Missense
• Pedigree

Repeat diseases, such as fragile X syndrome, myotonic dystrophy, Friedreich ataxia, Huntington disease, spinocerebellar ataxias, and some forms of amyotrophic lateral sclerosis, are caused by repetitive DNA sequences that are expanded in affected individuals. The age at which an individual begins to experience symptoms, and the severity of disease, are partially determined by the size of the repeat. However, the epigenetic state of the area in and around the repeat also plays an important role in determining the age of disease onset and the rate of disease progression. Many repeat diseases share a common epigenetic pattern of increased methylation at CpG islands near the repeat region. CpG islands are CG-rich sequences that are tightly regulated by methylation and are often found at gene enhancer or insulator elements in the genome. Methylation of CpG islands can inhibit binding of the transcriptional regulator CTCF, resulting in a closed chromatin state and gene down regulation. The downregulation of these genes leads to some disease-specific symptoms. Additionally, a genetic and epigenetic interplay is suggested by an effect of methylation on repeat instability, a hallmark of large repeat expansions that leads to increasing disease severity in successive generations. In this review, we will discuss the common epigenetic patterns shared across repeat diseases, how the genetics and epigenetics interact, and how this could be involved in disease manifestation. We also discuss the currently available stem cell and mouse models, which frequently do not recapitulate epigenetic patterns observed in human disease, and propose alternative strategies to study the role of epigenetics in repeat diseases.

• U.S. Department of Defense
• National Institutes of Health
• CHDI Foundation

• DM1 mice
• antisense oligonucleotides
• gene editing
• molecular therapy
• myotonic dystrophy
• trinucleotide-expansion disease

• CTG repeat expansion
• DM1 phenotype
• DM1 prediction and therapeutic targets
• DNA methylation and chromatin
• myotonic dystrophy type 1 (DM1)

• Alleles
• Biomarkers
• Epigenesis, Genetic
• Humans
• Myotonic Dystrophy/genetics
• Trinucleotide Repeat Expansion

CRISPR/Cas9-mediated therapeutic gene editing is a promising technology for durable treatment of incurable monogenic diseases such as myotonic dystrophies. Gene-editing approaches have been recently applied to in vitro and in vivo models of myotonic dystrophy type 1 (DM1) to delete the pathogenic CTG-repeat expansion located in the 3′ untranslated region of the DMPK gene. In DM1-patient-derived cells removal of the expanded repeats induced beneficial effects on major hallmarks of the disease with reduction in DMPK transcript-containing ribonuclear foci and reversal of aberrant splicing patterns. Here, we set out to excise the triplet expansion in a time-restricted and cell-specific fashion to minimize the potential occurrence of unintended events in off-target genomic loci and select for the target cell type. To this aim, we employed either a ubiquitous promoter-driven or a muscle-specific promoter-driven Cas9 nuclease and tetracycline repressor-based guide RNAs. A dual-vector approach was used to deliver the CRISPR/Cas9 components into DM1 patient-derived cells and in skeletal muscle of a DM1 mouse model. In this way, we obtained efficient and inducible gene editing both in proliferating cells and differentiated post-mitotic myocytes in vitro as well as in skeletal muscle tissue in vivo.

• CRISPR/Cas9
• CTG repeats
• DM1
• DMSXL mouse model
• gene editing
• gene therapy
• myotonic dystrophy
• skeletal muscle

• Alternative splicing
• Brain development
• CELF
• Congenital myotonic dystrophy
• DMPK
• MBNL
• Methylation
• Myotonic dystrophy type 1

The sine oculis (SIX) family of transcription factors are key regulators of developmental processes during embryogenesis. Members of this family control gene expression to promote self-renewal of progenitor cell populations and govern mechanisms of cell differentiation. When the function of SIX genes becomes disrupted, distinct congenital defects develops both in animal models and humans. In addition to the embryonic setting, members of the SIX family have been found to be critical regulators of tumorigenesis, promoting cell proliferation, epithelial-to-mesenchymal transition, and metastasis. Research in both the fields of developmental biology and cancer research have provided an extensive understanding of SIX family transcription factor functions. Here we review recent progress in elucidating the role of SIX family genes in congenital disease as well as in the promotion of cancer. Common themes arise when comparing SIX transcription factor function during embryonic and cancer development. We highlight the complementary nature of these two fields and how knowledge in one area can open new aspects of experimentation in the other.

• SIX genes
• cancer
• congenital disease
• developmental biology
• transcription factor

Epimutations refer to mistakes in the setting or maintenance of epigenetic marks in the chromatin. They lead to mis-expression of genes and are often secondary to germline transmitted mutations. As such, they are the cause for a considerable number of genetically inherited conditions in humans. The correction of these types of epigenetic defects constitutes a good paradigm to probe the fundamental mechanisms underlying the development of these diseases, and the molecular basis for the establishment, maintenance and regulation of epigenetic modifications in general. Here, we review the data to date, which is limited to repetitive elements, that relates to the applications of key editing tools for addressing the epigenetic aspects of various epigenetically regulated diseases. For each approach we summarize the efforts conducted to date, highlight their contribution to a better understanding of the molecular basis of epigenetic mechanisms, describe the limitations of each approach and suggest perspectives for further exploration in this field.

• DNA methylation
• epigenetic editing
• genetic editing
• histone modifications
• repeat associated diseases
• secondary epimutations
• transcriptional editing

• Chromatin/genetics
• Epigenesis, Genetic/genetics
• Gene Editing
• Genetic Diseases, Inborn/genetics
• Genetic Diseases, Inborn/prevention & control
• Germ-Line Mutation/genetics
• Humans

• genetic carrier screening
• genetic counselling
• genetics
• medical
• neurodegenerative diseases
• neurology

• AAV
• CRISPR
• Cas9
• DM1
• gene editing
• myotonic dystrophy

• Animals
• CRISPR-Associated Protein 9/genetics
• CRISPR-Cas Systems
• Clustered Regularly Interspaced Short Palindromic Repeats/genetics
• Dependovirus/genetics
• Disease Models, Animal
• Gene Editing/methods
• Genetic Therapy/methods
• Genetic Vectors/administration & dosage
• Humans
• Mice
• Myotonic Dystrophy/genetics
• Myotonic Dystrophy/therapy
• Myotonin-Protein Kinase/genetics
• RNA, Guide, CRISPR-Cas Systems/genetics
• Treatment Outcome
• Trinucleotide Repeat Expansion/genetics

• MR/P01741X/1 Medical Research Council

• RNA foci
• nuclear inclusions
• splicing misregulation
• trinucleotide repeats

• Animals
• DNA Repeat Expansion
• Disease Models, Animal
• Drosophila melanogaster/genetics
• Forecasting
• Gene Expression Regulation/genetics
• Humans
• Introns/genetics
• Mice
• Mice, Knockout
• Molecular Targeted Therapy
• Mutagenesis, Insertional
• Neurodegenerative Diseases/genetics
• Neuromuscular Diseases/genetics
• Peptides/genetics
• Poly A/genetics
• RNA Interference
• RNA Splicing/genetics
• RNA, Antisense/biosynthesis
• RNA, Antisense/genetics
• Spinocerebellar Ataxias/genetics
• Transcription, Genetic
• Trinucleotide Repeat Expansion

• CRISPR/Cas9
• DMPK
• SaCas9
• SpCas9 nickase
• genome editing
• induced pluripotent stem cell
• myotonic dystrophy
• nucleotide repeat expansion
• polyadenylation
• stem cell

• 3' Untranslated Regions
• CRISPR-Cas Systems/genetics
• Cell Differentiation/genetics
• Gene Editing/methods
• Genetic Therapy/methods
• HEK293 Cells
• Humans
• Muscle, Skeletal/growth & development
• Myocytes, Cardiac/physiology
• Myotonic Dystrophy/genetics
• Myotonic Dystrophy/pathology
• Myotonic Dystrophy/therapy
• Myotonin-Protein Kinase/genetics
• Neural Stem Cells/physiology
• Neurons/physiology
• RNA 3' Polyadenylation Signals/genetics
• RNA, Guide, CRISPR-Cas Systems
• Transfection
• Trinucleotide Repeat Expansion/genetics

• K08 AR064836 NIAMS NIH HHS

• Myotonic dystrophy
• biomarker
• myopathies
• splicing
• therapeutic.

• Animals
• Disease Management
• Humans
• Mutation/genetics
• Myotonic Dystrophy/complications
• Myotonic Dystrophy/therapy
• Myotonin-Protein Kinase/genetics
• RNA-Binding Proteins/genetics

• Ohio State University College of Medicine Roessler Research Scholarship

• RNA toxicity
• mesoangioblast
• muscle stem cell
• myoblast
• myogenesis
• myotonic dystrophy
• pericyte
• proteotoxicity

• Animals
• Gene Expression Regulation, Developmental
• Humans
• Muscle Development/genetics
• Muscle, Skeletal/pathology
• Mutation
• Myotonic Dystrophy/diagnosis
• Myotonic Dystrophy/genetics
• Myotonic Dystrophy/pathology
• Myotonic Dystrophy/physiopathology
• Pedigree
• RNA-Binding Proteins/genetics

• P01 NS058901 NINDS NIH HHS
• R01 AR046799 NIAMS NIH HHS
• R01 NS098819 NINDS NIH HHS
• RF1 NS098819 NINDS NIH HHS

• Alternative splicing and polyadenylation
• Microsatellite repeat expansions
• Post-transcriptional gene regulation
• RNA toxicity
• RNA-binding proteins

• CTCF
• ER stress
• IL-6
• NF-κB
• cytokine
• muscular dystrophy
• splicing
• trinucleotide

• Alternative Splicing
• Ataxin-7/genetics
• Ataxin-7/metabolism
• Binding Sites
• CCCTC-Binding Factor/genetics
• CCCTC-Binding Factor/metabolism
• CpG Islands
• DNA Methylation
• Humans
• Infant
• Interleukin-6/metabolism
• Muscle Proteins/genetics
• Muscle Proteins/metabolism
• Muscles/metabolism
• Myotonic Dystrophy/genetics
• Myotonic Dystrophy/metabolism
• Myotonic Dystrophy/pathology
• Myotonin-Protein Kinase/genetics
• Protein Binding
• RNA-Binding Proteins/genetics
• RNA-Binding Proteins/metabolism
• STAT3 Transcription Factor/metabolism
• Signal Transduction/physiology
• Transcription, Genetic
• Trinucleotide Repeat Expansion
• Up-Regulation

• DP5 OD017865 NIH HHS
• P01 NS058901 NINDS NIH HHS
• R01 NS098819 NINDS NIH HHS
• RF1 NS098819 NINDS NIH HHS

CTG repeat expansions in DMPK cause myotonic dystrophy (DM1) with a continuum of severity and ages of onset. Congenital DM1 (CDM1), the most severe form, presents distinct clinical features, large expansions, and almost exclusive maternal transmission. The correlation between CDM1 and expansion size is not absolute, suggesting contributions of other factors. We determined CpG methylation flanking the CTG repeat in 79 blood samples from 20 CDM1-affected individuals; 21, 27, and 11 individuals with DM1 but not CDM1 (henceforth non-CDM1) with maternal, paternal, and unknown inheritance; and collections of maternally and paternally derived chorionic villus samples (7 CVSs) and human embryonic stem cells (4 hESCs). All but two CDM1-affected individuals showed high levels of methylation upstream and downstream of the repeat, greater than non-CDM1 individuals (p = 7.04958 × 10⁻¹²). Most non-CDM1 individuals were devoid of methylation, where one in six showed downstream methylation. Only two non-CDM1 individuals showed upstream methylation, and these were maternally derived childhood onset, suggesting a continuum of methylation with age of onset. Only maternally derived hESCs and CVSs showed upstream methylation. In contrast, paternally derived samples (27 blood samples, 3 CVSs, and 2 hESCs) never showed upstream methylation. CTG tract length did not strictly correlate with CDM1 or methylation. Thus, methylation patterns flanking the CTG repeat are stronger indicators of CDM1 than repeat size. Spermatogonia with upstream methylation may not survive due to methylation-induced reduced expression of the adjacent SIX5, thereby protecting DM1-affected fathers from having CDM1-affected children. Thus, DMPK methylation may account for the maternal bias for CDM1 transmission, larger maternal CTG expansions, age of onset, and clinical continuum, and may serve as a diagnostic indicator.

• DMPK
• DNA/CpG methylation
• SIX5/DMAHP
• congenital myotonic dystrophy
• epigenetics
• maternal transmission/maternal inheritance
• myotonic dystrophy
• parent-of-origin effect(s)
• pre-natal diagnosis
• trinucleotide instability

• dystrophia myotonica protein kinase
• epigenetics
• myotonic dystrophy type 1
• triplet interruptions

• (CTG⋅CAG)n repeat
• CRISPR/Cas9
• DM1 myoblasts
• NHEJ
• dsDNA break repair
• myotonic dystrophy
• somatic cell therapy
• therapeutic genome editing
• trinucleotide instability

• Animals
• Bacterial Proteins/genetics
• Base Sequence
• CRISPR-Associated Protein 9
• CRISPR-Cas Systems
• Clustered Regularly Interspaced Short Palindromic Repeats
• Codon
• Disease Models, Animal
• Endonucleases/genetics
• Fibroblasts/metabolism
• Gene Editing
• Gene Expression
• Gene Order
• Genetic Loci
• Genomic Instability
• Humans
• Mice
• Myotonic Dystrophy/genetics
• Myotonin-Protein Kinase/genetics
• RNA, Guide, CRISPR-Cas Systems
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• Sequence Deletion
• Trinucleotide Repeat Expansion
• Trinucleotide Repeats

• DMPK
• High resolution melting
• Methylation
• Myotonic dystrophy type 1
• SIX5
• Variant expansions

CTG repeat expansion in DMPK, the cause of myotonic dystrophy type 1 (DM1), frequently results in hypermethylation and reduced SIX5 expression. The contribution of hypermethylation to disease pathogenesis and the precise mechanism by which SIX5 expression is reduced are unknown. Using 14 different DM1-affected human embryonic stem cell (hESC) lines, we characterized a differentially methylated region (DMR) near the CTGs. This DMR undergoes hypermethylation as a function of expansion size in a way that is specific to undifferentiated cells and is associated with reduced SIX5 expression. Using functional assays, we provide evidence for regulatory activity of the DMR, which is lost by hypermethylation and may contribute to DM1 pathogenesis by causing SIX5 haplo-insufficiency. This study highlights the power of hESCs in disease modeling and describes a DMR that functions both as an exon coding sequence and as a regulatory element whose activity is epigenetically hampered by a heritable mutation.

•

We identify a disease-associated, differentially methylated region in DM1 hESCs

Myotonic dystrophy type 1 (DM1 or Steinert’s disease) and type 2 (DM2) are multisystem disorders of genetic origin. Progressive muscular weakness, atrophy and myotonia are the most prominent neuromuscular features of these diseases, while other clinical manifestations such as cardiomyopathy, insulin resistance and cataracts are also common. From a clinical perspective, most DM symptoms are interpreted as a result of an accelerated aging (cataracts, muscular weakness and atrophy, cognitive decline, metabolic dysfunction, etc.), including an increased risk of developing tumors. From this point of view, DM1 could be described as a progeroid syndrome since a notable age-dependent dysfunction of all systems occurs. The underlying molecular disorder in DM1 consists of the existence of a pathological (CTG) triplet expansion in the 3′ untranslated region (UTR) of the Dystrophia Myotonica Protein Kinase (DMPK) gene, whereas (CCTG)n repeats in the first intron of the Cellular Nucleic acid Binding Protein/Zinc Finger Protein 9(CNBP/ZNF9) gene cause DM2. The expansions are transcribed into (CUG)n and (CCUG)n-containing RNA, respectively, which form secondary structures and sequester RNA-binding proteins, such as the splicing factor muscleblind-like protein (MBNL), forming nuclear aggregates known as foci. Other splicing factors, such as CUGBP, are also disrupted, leading to a spliceopathy of a large number of downstream genes linked to the clinical features of these diseases. Skeletal muscle regeneration relies on muscle progenitor cells, known as satellite cells, which are activated after muscle damage, and which proliferate and differentiate to muscle cells, thus regenerating the damaged tissue. Satellite cell dysfunction seems to be a common feature of both age-dependent muscle degeneration (sarcopenia) and muscle wasting in DM and other muscle degenerative diseases. This review aims to describe the cellular, molecular and macrostructural processes involved in the muscular degeneration seen in DM patients, highlighting the similarities found with muscle aging.

• aging
• muscle wasting
• myotonic dystrophy
• sarcopenia
• satellite cells

• Alleles
• Cell Line
• Gene Expression
• Gene Order
• Gene Silencing
• Genetic Loci
• Humans
• Iron-Binding Proteins/genetics
• Iron-Binding Proteins/metabolism
• Nuclear Lamina/metabolism
• Protein Transport
• RNA, Messenger/genetics
• Single-Cell Analysis
• Transcription Initiation Site
• Transcription Initiation, Genetic
• Transcription, Genetic
• Trinucleotide Repeat Expansion
• Frataxin

• MC_PC_14131 Medical Research Council
• MC_UU_12009/1 Medical Research Council
• MR/M00919X/1 Medical Research Council
• 091911 Wellcome Trust

• RNA toxicity
• alternative splicing
• antisense oligonucleotides
• developmental reprogramming
• myotonic dystrophy

Myotonic dystrophy (DM) of type 1 and 2 (DM1 and DM2) are inherited autosomal dominant diseases caused by dynamic and unstable expanded microsatellite sequences (CTG and CCTG, respectively) in the non-coding regions of the genes DMPK and ZNF9, respectively. These mutations result in the intranuclear accumulation of mutated transcripts and the mis-splicing of numerous transcripts. This so-called RNA gain of toxic function is the main feature of an emerging group of pathologies known as RNAopathies. Interestingly, in addition to these RNA inclusions, called foci, the presence of neurofibrillary tangles (NFT) in patient brains also distinguishes DM as a tauopathy. Tauopathies are a group of nearly 30 neurodegenerative diseases that are characterized by intraneuronal protein aggregates of the microtubule-associated protein Tau (MAPT) in patient brains. Furthermore, a number of neurodegenerative diseases involve the dysregulation of splicing regulating factors and have been characterized as spliceopathies. Thus, myotonic dystrophies are pathologies resulting from the interplay among RNAopathy, spliceopathy, and tauopathy. This review will describe how these processes contribute to neurodegeneration. We will first focus on the tauopathy associated with DM1, including clinical symptoms, brain histology, and molecular mechanisms. We will also discuss the features of DM1 that are shared by other tauopathies and, consequently, might participate in the development of a tauopathy. Moreover, we will discuss the determinants common to both RNAopathies and spliceopathies that could interfere with tau-related neurodegeneration.

• Alzheimer's disease
• RNAopathy
• myotonic dystrophy
• splicing
• tauopathy

• Cytoskeleton/genetics
• Cytoskeleton/metabolism
• Fibroblasts/metabolism
• Friedreich Ataxia/enzymology
• Friedreich Ataxia/genetics
• Friedreich Ataxia/metabolism
• Gene Silencing
• Humans
• Iron-Binding Proteins/genetics
• Iron-Binding Proteins/metabolism
• Lymphocytes/metabolism
• Phosphatidylinositol 4,5-Diphosphate/metabolism
• Phosphatidylinositol Phosphates/metabolism
• Phosphotransferases (Alcohol Group Acceptor)/genetics
• Phosphotransferases (Alcohol Group Acceptor)/metabolism
• Trinucleotide Repeat Expansion
• Frataxin

• Aged
• Amyotrophic Lateral Sclerosis/genetics
• Base Sequence
• Case-Control Studies
• CpG Islands
• DNA Methylation
• DNA Repeat Expansion
• Genetic Association Studies
• Heterozygote
• Humans
• Linear Models
• Membrane Proteins/genetics
• Middle Aged
• Molecular Sequence Data
• Pedigree
• Sequence Analysis, DNA
• Tumor Suppressor Proteins/genetics

Assess triplet repeat expansion (CTG)_n at the ‘dystrophia-myotonica protein kinase’ (DMPK) locus in muscular myopathies to elucidate its role in myopathic symptoms and enable genetic counseling and prenatal diagnosis in families.

Individuals with symptoms of myopathy, hypotonia and controls selected randomly from the population were evaluated for triplet repeat expansion of (CTG)_n repeats in the 3’untranslated region (UTR) of DMPK gene, the causative mutation in myotonic dystrophy (DM). DNA was isolated from peripheral blood of 40 individuals; they presented symptoms of muscle myopathy (n = 11), muscle hypotonia (n = 4), members of their families (n = 5) and control individuals from random population (n = 20). Molecular analysis of genomic DNA by polymerase chain reaction (PCR) using primers specific for the DMPK gene encompassing the triplet repeat expansion, showed that all controls (n = 20) gave a 2.1 kb band indicating normal triplet repeat number. Three out of 11 cases (two clinically diagnosed DM and one muscular dystrophy) had an expansion of the (CTG)_n repeat in the range of 1000-2100 repeats corresponding to the repeat number in cases of severe DM. Other two of these 11 cases, showed a mild expansion of ~ 66 repeats. Three samples, which included two cases of hypotonia and the father of a subject with muscular dystrophy, also gave a similar repeat expansion (~66 repeats).

Results suggest a role of (CTG)_n expansion at the DMPK locus in unexplained hypotonias and muscular myopathies other than DM. This calls for screening of the triplet repeat expansion at the DMPK locus in cases of idiopathic myopathies and hypotonia.

• Myopathies
• myotonic dystrophy
• triplet repeat expansion

• Bidirectional transcription
• Mouse models
• Neurodegenerative diseases
• RAN translation
• RNA foci
• RNA processing

• Adolescent
• Adult
• Age Factors
• Aged
• Child
• Child, Preschool
• Comorbidity
• Denmark/epidemiology
• Female
• Humans
• Infant
• Male
• Middle Aged
• Myotonic Dystrophy/epidemiology
• Neoplasms/epidemiology
• Patient Discharge/statistics & numerical data
• Registries/statistics & numerical data
• Risk
• Sex Factors
• Sweden/epidemiology
• Young Adult

• N02CP31003-3 NCI NIH HHS
• N01-AR-50-227450 NIAMS NIH HHS
• U54/NS048843 NINDS NIH HHS
• UL1 RR024160 NCRR NIH HHS
• U54 NS048843 NINDS NIH HHS
• ZIA CP010144-13 Intramural NIH HHS
• N02CP31003 NCI NIH HHS

Epigenetic marks are well recognized as heritable chemical modifications of DNA and chromatin that induce chromatin structural changes thereby affecting gene activity. A lesser-known phenomenon is the pervasive effects these marks have on genomic integrity. Remarkably, epigenetic marks and the enzymes that establish them are involved in multiple aspects of maintaining genetic content. These aspects include preserving nucleotide sequences such as repetitive elements, preventing DNA damage, functioning in DNA repair mechanisms and chromatin restoration, and defining chromosomal organization through effects on structural elements such as the centromere. This review discusses these functional aspects of epigenetic marks and their effects on human health and disease.