Epigenetics modifications poster

Introduction to epigenetic modifications

Epigenetic modifications are heritable changes that affect how genes work without altering the DNA sequence. The two main categories of epigenetic modifications are histone and DNA modifications. 

What are histone modifications?

Histone proteins play a central role in chromatin compaction and regulation of gene expression. The modification of histone proteins leads to changes in chromatin architecture, altering the accessibility of the genome to regulatory proteins and transcriptional machinery. 

Histone modifications are reversible, covalent, post-translational modifications (PTMs) of histone proteins. Three types of enzymes mediate these epigenetic modifications: "writers" introduce chemical modifications, "readers" identify and interpret modifications, and "erasers" remove modifications.

At least nine types of histone modifications have been discovered, of which acetylation, methylation, phosphorylation, and ubiquitylation are the best understood. GlcNAcylation, citrullination, crotonylation, SUMOylation, and isomerization are more recent discoveries.

Together, these modifications make up what is known as the histone code, which dictates the transcriptional state of the local genomic region. Examining histone modifications at a particular region or across the genome can reveal gene activation states and the locations of promoters, enhancers, and other gene regulatory elements.

Epigenetic histone modifications in human health and disease

Histone modifications are essential in many cellular events, including gene expression, DNA replication and repair, chromatin compaction, and cell-cycle control^1,2. As well as affecting chromatin structure, histone modifications provide binding platforms for transcription factors, including chromatin re-modelers, histone chaperones, and DNA/histone-modifying enzymes.

Aberrant histone modifications are associated with a variety of human diseases. They are of particular interest in cancer research and drug development because dysregulation of these modifications alters chromatin structure and induces abnormal gene expression. Find out more about epigenetics in disease here.

Five key histone modifications 

γ-H2A.X (phospho S139)

H2A.X is a variant of the core histone H2A. Phosphorylation of histone H2A.X at serine 139, γ-H2A.X, is an early response to double-strand DNA breaks (DSB), leading to structural changes and repair³. In addition to being a cause of cancer, DSB induction is sometimes an effective cancer treatment, with therapeutic agents acting by introducing DSBs into cancer cells to activate cell death pathways⁴. For this reason, there are many possible clinical roles for γH2AX detection. 

Using γH2AX detection to determine the extent of DSB induction may help detect precancerous cells, stage cancers, monitor the effectiveness of cancer therapies, and develop novel anti-cancer drugs.

H3K4me3 

Histone H3K4me3 is an activator associated with the transcriptional start sites of actively transcribed genes⁵. The H3K4me3 modification is created by a lysine-specific histone methyltransferase (HMT) transferring three methyl groups to histone H3. 

Although H3K4me3 is one of the least abundant histone modifications, it is highly enriched at active promoters near transcription start sites (TSS)⁶ and positively correlated with transcription.  Some reports show H3K4me3 involved in liver⁷ and kidney⁸ cancers.

H3S10p 

H3 serine 10 phosphorylation to form H3S10p is an activation step required for normal chromosome dynamics^9–11. It plays a key role in mitosis, transcription, chromatin condensation, and UVB response¹². Many kinases, such as members of the Aurora kinase family and MSK1/2, mediate the generation of the H3S10p epigenetic mark. 

H2S10p is an important player in the initiation and propagation of cancer. Many enzymes catalyzing H3S10 phosphorylation and dephosphorylation are oncogenic factors that were traditionally thought to affect gene expression through the modulation of signaling pathways and the activity of transcription factors. 

H3K27me3 

H3K27me3 is a repressive mark associated with inactive gene promoters.  A polycomb repressive complex, PRC2, mediates the tri-methylation of histone 3 on lysine 27 through histone methyl transferase activity¹³.

H3K27me3 has been implicated in many different cancer types, including liver¹⁴, kidney¹⁵, stomach¹⁶, and prostate¹⁷ cancer.

H3K27ac

H3K27ac, an acetylated form of histone H3, is an activator associated with higher transcription levels. It is enriched in the regulatory regions of genes implicated in Alzheimer's disease, including those in tau and amyloid neuropathology¹⁸. 

The H3K27ac and H3K27me3 modifications are at the same location on the histone tail, so they antagonize each other¹⁹. 

Download our Epigenetics modification poster that covers:

• Histone and DNA modifications
• Histone modifier enzymes
• Histone modification binding proteins

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