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Home » Drug Development » Molecular Changes That Control Gene Activity: Epigenetic DNA Modifications

Molecular Changes That Control Gene Activity: Epigenetic DNA Modifications

by | Dec 2, 2023 | Drug Development

Epigenetic Modification of DNA:  Nature’s Undo Button

Epigenetics refers to the study of changes in gene activity that occur without altering the underlying DNA sequence. Epigenetic changes affect the layer of instruction that influences how genes turn on or off.

The Epigenetic Basics

Chemical alterations to DNA and histone proteins associated with DNA can reversibly change gene activity by controlling the accessibility of DNA to RNA. The role of RNA is to transcribe the “DNA code” into an “RNA code” and share that “RNA code” with cellular structures called ribosomes.  In turn, ribosomes read the “RNA code” and build proteins.

Zoom Out

Epigenetic DNA modifications encompass chemical alterations to DNA nucleotides (A, C, G, or T) or histones, proteins responsible for packaging DNA into chromosomes. These modifications are pivotal in regulating how genetic instructions are carried out. 

Why it Matters

Epigenetic changes affect how often a cell creates a protein from its DNA instructions. These gene expression modifications are mainly responsible for differentiating cells like neurons, muscle, and immune cells possessing the same genetic information.

Zoom In

DNA is epigenetically modified in three ways:

  1. Methylation adds a methyl (CH3) group to cytosine (C) nucleotides, reducing or blocking gene expression.
  2. Acetylation adds an acetyl group (CH3CO) to histones, loosening histone binding to DNA and increasing protein production.
  3. Deacetylation removes an acetyl group, increasing DNA binding around histones and decreasing protein production.

Disease can occur when cells make the wrong amount of critical proteins—too few or too many. Epigenetic medicine identifies disease-associated differences in epigenetic modifications and develops drugs that restore the proper amount of proteins produced.

Small Molecule Drug Discovery Primer 101

Applied Science

The following proteins regulate epigenetics and are the drug targets for epigenetic medications. 

  • Writers are proteins that methylate or acetylate DNA molecules or histones.
  • Erasers are proteins that remove chemical groups on DNA molecules or histones.
  • Readers are proteins that detect and alter the association of DNA with histone proteins.

Bench to Bedside

FDA-approved epigenetic medications fall into two categories: erasers and writers. The following drugs are FDA-approved for the treatment of cancer.



  • DNA-methyltransferase (DNMT) inhibitors add methyl groups to DNA, decreasing the protein of interest. 
  • Histone-methyltransferase (EZH2) inhibitors transfer methyl groups to histone proteins, decreasing the protein amount. 

The Epigenetic Medicine Horizon

“Bromodomain and Extra Terminal motif” (BET reader proteins) bind to specific histone acetyl groups. Inhibiting the interaction between “BET reader proteins” and histones may prevent “BET reader proteins” from binding to DNA it shouldn’t. Currently, no BET inhibitors (BBIs) are FDA-approved.

Cocktail Fodder

Researchers in the Netherlands discovered that adults developing in the womb during the Dutch Hunger Winter experienced higher incidences of obesity, diabetes, and schizophrenia and ten percent higher mortality after 68 years compared to adults who were not in utero during this time.  The team attributed the adverse health effects to epigenetic gene silencing that occurred in utero during the famine.

Getting Started

Learn how epigenetic medicines and other small molecule drugs get their start by enrolling in Biotech Primer’s Small Molecule Drug Discovery 101 Primer. From identifying potential drug targets to optimizing lead compounds, this 55-minute on-demand class demonstrates how scientists refine small molecule drugs before they undergo preclinical and clinical trials.

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