Epigenetic Regulation

Epigenetic regulation is regulation of gene expression that does not involve alterations to the DNA sequence or any of its transcribed products. The most common forms of epigenetic regulation are DNA methylation, which suppresses gene expression, and modifications to the histone proteins, which affect the structure of DNA packaging. Epigenetic modifications are responsible for the conditions related to imprinting, including Prader–Willi and Angelman syndromes.

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Overview

Definition

Epigenetic modification are modifications to the DNA or DNA packaging that affect gene expression without altering the genetic code (i.e., sequence of DNA) itself.

These modifications:

  • Control which regions of DNA are available for transcription
  • Are typically reversible
  • Can be influenced by environmental factors
  • Are heritable (i.e., epigenetic patterns are preserved during cell division)

Overview of epigenetic regulation

  • Epigenetic factors:
    • Change phenotype without changing genotype
    • Can influence how genes are expressed at different ages
    • Contribute significantly to differential gene expression in different tissues
  • Epigenetic modifications include modifications:
    • Directly to the DNA (e.g., DNA methylation)
    • To the DNA-binding proteins (e.g., histone modification)
    • To higher-order chromatin structures
  • Epigenetic regulation plays a role in:
    • Cellular differentiation
    • X-chromosome inactivation in females
    • Disease processes:
      • Imprinted disorders: Prader-Willi syndrome (PWS), Angelman syndrome (AS)
      • Cancer
    • Adaptations to the environment, including:
      • Stress
      • Starvation or obesity
      • Exposures to toxins, pollution, and/or endocrine-disrupting chemicals

Review of DNA packaging in chromatin

The basic unit of DNA packaging is the nucleosome. DNA wraps 2¼ times around a core of 8 histone proteins, forming a nucleosome.

  • Nucleosomes:
    • The histone core is made up of 2 of each of the following histones: H2A, H2B, H3, and H4.
    • H1 is a 9th histone, and it sits just outside the nucleosome.
    • There are approximately 146 base pairs of DNA associated with each nucleosome.
    • There are approximately 20–60 base pairs of free DNA between nucleosomes. 
    • Nucleosomes appear like beads on a string of DNA.
  • Secondary structure of chromatin:
    • Solenoid model: a spiraling configuration of nucleosomes with 6 nucleosomes per turn
    • Zigzag model: a more irregular configuration of packed nucleosomes
  • Further compaction of chromatin:
    • Secondary structures coil, and these coils supercoil.
    • Chromatin condenses into full chromosomes during cell division.
  • Euchromatin versus heterochromatin:
    • Euchromatin: chromatin that is available for transcription (unwound, or loosely wound, DNA)
    • Heterochromatin: chromatin that is unavailable for transcription because it is too tightly wound
Dna packaging in nucleosomes

How DNA is packaged into nucleosomes and then chromosomes

Image by Lecturio.

Epigenetic Modifications

The most important forms of epigenetic modification include direct methylation of the DNA, modifications to the histone proteins, and other chromatin modifications. 

DNA methylation 

  • Methyl groups can be added to and removed from DNA.
  • Methylation typically occurs:
    • On cytosine bases in DNA
    • In promoter and enhancer regions of a gene
  • Methylation typically prevents transcription of a gene:
    • Regulatory proteins bind to the methylated cytosines → prevent access of the transcription machinery to the DNA → silence gene expression
    • Removing methyl groups → allows transcription → activates gene expression
  • Enzymes involved in methylation:
    • DNA methyltransferases: enzymes that methylate DNA 
    • Methylcytosine dioxygenases: enzymes that remove methyl groups from DNA

Histone modifications

  • How the DNA is wrapped around histone proteins affects which genes can be translated:
    • Tightly wrapped DNA is inaccessible to the transcriptional machinery.
    • Altering how genes are wrapped makes certain segments of DNA more or less accessible to transcriptional machinery.
  • Modifying the histones:
    • Alters the affinity of the histone proteins for the DNA
    • Can recruit other proteins that affect chromatin structure
  • The effect of the histone modifications (e.g., enhancing or suppressing transcription) depends on the specific combination of:
    • Which histone subunits were modified
    • Which amino acids within those subunits were modified
    • What the modifications were (e.g., methylation versus acetylation)
  • Histone modifications are a type of posttranslational modification to the histone proteins.

Types of histone modifications

  • Methylation:
    • In general, methylation is associated with inactive (i.e., nontranscribed) DNA.
    • Histone methyltransferases add methyl groups to lysines in the histone tail.
    • Histone demethylases remove the methyl groups.
  • Acetylation:
    • In general, acetylation “unpacks” DNA, allowing transcription.
    • Histone acetyltransferases (HATs) can add acetyl groups to lysines in the histone protein.
    • Histone deacetylases (HDACs) remove the acetyl groups.
    • These enzymes typically contain zinc.
  • Other types of histone modifications:
    • Ubiquitylation
    • Phosphorylation
    • Isomerization of proline
    • ADP-ribosylation of glutamic acids
Histone acetylation

Histone acetylation

Image by Lecturio.

Chromatin remodeling

Remodeling the chromatin and/or nucleosomes is another way the cell can regulate gene expression at the epigenetic level. Chromatin remodeling typically requires energy. Types of chromatin remodeling include:

  • Moving or sliding the nucleosome down the DNA strand
  • Remodeling the shape of the nucleosome
  • Temporarily removing the nucleosome
  • Replacing the histones
Nucleosome remodeling

Nucleosome remodeling:
Examples of changes to histones. Chromatin remodeling factors also alter chromatin structure. Chromatin uses energy from ATP.

Image by Lecturio.

Imprinting

Overview

Imprinting comprises the specific epigenetic modifications that occur in sex-specific gametes (i.e., the modifications occur in only sperm or ova).

  • Some genes are transcribed from the chromosomes of 1 parent but not the other. 
  • This transcription is due to DNA hypermethylation (epigenetic silencing) of that same gene in the opposite parent.
  • Clinical implication: Gene deletions in these areas cause different phenotypes in offspring depending on whether the mutation was inherited from the mother or the father.
  • The imprinted gene is the hypermethylated, silenced gene.
  • Classic examples of conditions related to imprinted genes: 
    • PWS
    • AS
  • The genes associated with PWS and AS are both located at chromosome 15q11-13, but they are not the exact same genes.
Normal state of gene expression

Normal gene expression in the 15q11-13 region

AS: Angelman syndrome
PWS: Prader–Willi syndrome

Image by Lecturio.

Prader-Willi syndrome

  • The Prader-Willi genetic region is:
    • Transcribed only from the paternal chromosome
    • Hypermethylated (i.e., silenced) on the maternal chromosome
  • Paternal deletions in this region result in PWS.
  • Clinical presentation: 
    • Hyperphagia with early-onset obesity
    • Hypogonadism
    • Mild developmental delay
    • Abnormal facial features
    • Short stature with generally small hands and feet
Gene expression in prader-willi

Gene expression in Prader–Willi syndrome:

AS: Angelman syndrome
PWS: Prader–Willi syndrome
Image by Lecturio.

Angelman syndrome

  • The Angelman genetic region is:
    • Transcribed only from the maternal chromosome
    • Hypermethylated (i.e., silenced) on the paternal chromosome
  • Maternal deletions in this region result in AS.
  • Clinical presentation: “the happy puppet”:
    • Microcephaly with seizures
    • Severe developmental delays
    • Minimal speech
Gene expression in angelman

Gene expression in Angelman syndrome

AS: Angelman syndrome
PWS: Prader–Willi syndrome

Image by Lecturio.

Clinical Relevance

  • Cancer: All cancers have abnormalities in their epigenetic regulation. Also, some common epigenetic “signatures” have been discovered in certain types of cancers. Examples of these signatures include global hypomethylation leading to the activation of oncogenes (e.g., RAS) and DNA methylation at promoter sequences silencing tumor suppressor genes. In addition, mutations can affect other histone modifications as well.
  • Histone deacetylase inhibitors: Histone acetylation activates gene expression and HDACs remove the acetyl groups; therefore, HDAC inhibitors end up increasing gene expression. Some examples include romidepsin, panobinostat, and vorinostat, which are used in the treatment of T-cell lymphomas. In addition, valproic acid (an antiepileptic drug) also demonstrates HDAC inhibitor activity and is being explored for applications beyond seizure control related to this HDAC inhibitor activity.
  • Alzheimer’s disease: neurodegenerative disease resulting in dementia. Alzheimer’s disease is thought to be the result of misfolded and/or abnormally modified proteins, including the β-amyloid peptide and tau proteins. Environmental and epigenetic factors are also implicated in its pathogenesis, though the exact mechanisms are still unknown. Patients present with progressive dementia.
  • Hutchinson–Gilford progeria syndrome (HGPS): premature aging syndrome related to a rare genetic defect in laminin A, which is critical in stabilizing the nuclear membrane. Without normal, functional laminin A, the heterochromatin becomes very disorganized and unstable, and gene transcription is dysregulated. Patients with HGPS manifest with multiple progeroid symptoms by 2 years of age, including failure to thrive and dermatologic, musculoskeletal, neurologic audiologic, ophthalmologic, and life-limiting cardiovascular abnormalities. 

References

  1. Jaenisch R, Bird A. (2003). Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nature genetics, 33(Suppl):245–254. https://doi.org/10.1038/ng1089
  2. Lee JH, Kim EW, Croteau DL, et al. (2020) Heterochromatin: an epigenetic point of view in aging. Exp Mol Med 52:1466–1474. https://doi.org/10.1038/s12276-020-00497-4
  3. Shahid Z, Simpson B, Miao KH, et al. Genetics, histone code. (2020). StatPearls. Retrieved April 21, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK538477/
  4. Simpson B, Hajira B. (2020). Genetics, DNA packaging. In Al Aboud N (Ed.), StatPearls. Retrieved April 21, 2021, from https://www.statpearls.com/articlelibrary/viewarticle/32591/ 
  5. Figueroa ME. (2021). Principles of epigenetics. In Tirnauer JS (Ed.), UpToDate. Retrieved April 21, 2021, from https://www.uptodate.com/contents/principles-of-epigenetics

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