Epigenetics

Overview – Epigenetics

• Changes in gene expression caused by mechanisms other than changes in actual DNA sequence
• Examples
  • X-inactivation
  • imprinting
  • histone modification
• see Chromatin structure topic

X-inactivation 

• Overview
  • normalizes the genetic amount of males and females (lyonization)
  • inactivates # of X chromosomes – 1 in a Barr body
    • triploid X will have 2 Barr bodies
• Mechanism
  • mediated by XIST gene
  • inactivation through methylation
  • occurs at blastocyst stage in female embryos
  • X copy chosen for inactivation is random
    • after choosing every subsequent cell will have the same X copy inactivated
• Clinical relevance
  • mosaicism
    • non-homogenous X inactivation
• some cells express paternal X and some cells express maternal X

Imprinting

• Overview
  • describes differences in transcriptional activity based on whether the chromosome is of maternal or paternal origin
  • at a single locus
    • 1 allele is active
    • 1 allele is inactive
  • creates a hemizygous state
• Mechanism
  • inactive (“imprinted”) allele is methylated during gametogenesis
    • creates transcriptional inactivity
  • is maternal/paternal specific
    • gene at one locus always methylated on a specific copy
  • all cells of an individual have same imprinting level
  • during gametogenesis of the individual the methylation state is erased
    • reset to be either maternal or paternal depending on the sex
• Clinical importance
  • Prader-Willi syndrome
    • cause
      • deletion or mutation of normally active paternal allele on 15q
      • remember: Prader = paternal deletion
    • presentation
      • mental retardation
      • hyperphagia → obesity
      • hypogonadism
      • neonatal hypotonia
      • behavior problems
    • affects both male and females
  • Angelman’s syndrome 
    • cause
      • disruption of the maternally expressed and paternally imprinted gene UBE3A, which encodes an E3 ubiquitin ligase 
      • typically results from deletion of the normally active maternal allele on chromosome 15q
        • same region of the genome as Prader-Willi syndrome deletion but opposite chromosome (not the same gene)
    • presentation
      • severe cognitive disability
      • frequent seizures
      • ataxia
      • speech impairment
      • hyperactivity
      • inappropriate laughter
        • “happy puppet”
• affects both male and females

Introduction

Epigenetics refers to the study of changes in gene expression that do not involve alterations to the underlying DNA sequence. These changes can be heritable, meaning that they can be passed down from one generation to the next, and can be influenced by a range of factors, including environmental exposures, lifestyle factors, and aging.

Epigenetic modifications can occur at various levels, including DNA methylation, histone modifications, and non-coding RNA expression. These modifications can alter the way that genes are expressed, either by promoting or repressing transcription, and can have significant impacts on cellular processes, including development, differentiation, and disease.

One of the key features of epigenetic modifications is their dynamic nature. Unlike changes to the underlying DNA sequence, which are relatively stable, epigenetic modifications can be influenced by a range of factors and can change over time. This plasticity means that epigenetic modifications may represent a potential target for therapeutic interventions, as they can be modulated by drugs or other interventions.

Types of Epigenetics

There are several types of epigenetic modifications that have been identified, each of which can impact gene expression in different ways. Here are some of the most common types of epigenetic modifications:

1. DNA methylation: This involves the addition of a methyl group to cytosine bases in DNA, typically in CpG dinucleotides. DNA methylation is generally associated with gene silencing, as it can inhibit the binding of transcription factors to DNA and recruit repressive chromatin modifiers.
2. Histone modifications: Histones are proteins that package DNA into chromatin, and their modification can have significant impacts on gene expression. These modifications can include the addition or removal of various chemical groups, such as acetyl, methyl, and phosphate groups, which can either promote or repress transcription.
3. Non-coding RNA expression: Non-coding RNAs are RNA molecules that do not code for proteins but can have important regulatory functions. These RNAs can interact with DNA, RNA, or proteins to modulate gene expression at various levels.
4. Chromatin remodeling: Chromatin structure can be modified through the action of chromatin remodeling complexes, which can alter the accessibility of DNA to transcription factors and other regulatory proteins.
5. RNA editing: RNA molecules can also be modified through the addition, deletion, or substitution of nucleotides, a process known as RNA editing. This can impact the stability and function of RNA molecules and can have important consequences for gene expression.

These are just a few examples of the diverse range of epigenetic modifications that have been identified. Each type of modification can impact gene expression in different ways and can be influenced by a range of environmental, lifestyle, and genetic factors.

Studies – Epigenetics

Epigenetics has been the subject of extensive research in various fields, including genetics, molecular biology, developmental biology, and medicine. Here are some examples of key findings from epigenetic research:

1. Development and differentiation: Epigenetic modifications play a critical role in regulating gene expression during development and differentiation. For example, DNA methylation and histone modifications are involved in the silencing of pluripotency genes in differentiated cells, while the activation of lineage-specific genes is often associated with changes in histone modifications.
2. Environmental exposures: Epigenetic modifications can be influenced by environmental exposures, such as diet, toxins, and stress. For example, studies have shown that maternal diet during pregnancy can impact DNA methylation patterns in offspring, while exposure to environmental toxins can lead to changes in histone modifications and DNA methylation in affected individuals.
3. Disease: Epigenetic modifications have been implicated in a range of human diseases, including cancer, cardiovascular disease, and neurological disorders. For example, DNA methylation changes are often associated with the development of cancer, while histone modifications can play a role in the regulation of cardiovascular disease-related genes.
4. Aging: Epigenetic modifications have been shown to change with age, and these changes have been linked to age-related diseases and declines in cellular function. For example, changes in DNA methylation patterns have been associated with age-related cognitive decline, while alterations in histone modifications have been linked to declines in immune function.
5. Therapeutic interventions: Epigenetic modifications represent a potential target for therapeutic interventions, as they can be modulated by drugs or other interventions. For example, DNA methylation inhibitors are used in the treatment of certain cancers, while histone deacetylase inhibitors are being investigated as potential treatments for a range of diseases.

Overall, the study of epigenetics has provided important insights into the regulation of gene expression and has led to the development of new approaches for the diagnosis, treatment, and prevention of a range of human diseases.

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