Our bodies contain countless cells, each with the same DNA blueprint, yet performing different jobs. This diversity is managed by epigenetics, a system controlling gene activity without altering the DNA sequence. Epigenetic modifications act like molecular switches, determining which genes are active in a cell at a specific time. One such mark, found on proteins that package DNA, is known as H3K36me3.
Understanding H3K36me3
To understand H3K36me3, we first need to look at how DNA is organized inside our cells. Our DNA strands are precisely wound around spool-like proteins called histones, forming nucleosomes. These nucleosomes, along with other proteins, compact the DNA into chromatin. This packaging is not static; it can be adjusted to allow or restrict access to genetic information.
Histones, specifically the H3 family, are subject to chemical modifications on their protruding “tails.” These modifications can influence how tightly DNA is wound and whether genes are accessible for expression. H3K36me3 refers to a modification on histone H3.
The “K” stands for lysine, which is a specific amino acid building block found in proteins. The “36” indicates that this lysine is located at the 36th position along the H3 histone protein’s tail, counting from its beginning. The “me3” portion of the name signifies “trimethylation,” meaning three methyl groups are added to that specific lysine residue. This addition changes the histone tail’s chemical properties, creating a unique signal recognized by other proteins. This trimethylation mark on H3K36 plays a role in regulating gene expression and maintaining genetic material stability.
The Role of H3K36me3 in Cellular Processes
The H3K36me3 mark is predominantly found on the main bodies of genes that are actively being transcribed, meaning their genetic information is being copied into RNA. As RNA polymerase II moves along the DNA to create an RNA copy, it helps deposit this mark. This association with active transcription ensures accurate RNA production.
H3K36me3 contributes to maintaining chromatin structure during gene expression. It recruits protein complexes, such as histone deacetylases (HDACs), to gene bodies. These enzymes remove acetyl groups from histones, which helps prevent unwanted transcription within a gene’s coding region. This ensures gene expression starts and ends at correct locations, preserving the genetic message.
H3K36me3 also participates in DNA repair mechanisms, which are essential for safeguarding the genome from damage. It is involved in DNA mismatch repair (MMR), a system that corrects errors during DNA replication. H3K36me3 helps recruit mismatch recognition proteins to DNA damage sites.
Its presence at DNA double-strand breaks influences the choice of repair pathway. The mark can facilitate homologous recombination (HR), a precise repair mechanism. This dual function in transcription and DNA repair influences genome stability and cellular function.
H3K36me3 in Health and Disease
The precise regulation of H3K36me3 is important for normal development and the differentiation of cells into their specialized types. Levels of H3K36me3 increase in differentiating cells, such as those involved in germ cell development. This suggests its involvement in guiding cells towards their mature identities and maintaining those differentiated states. Disruptions in H3K36 methylation can lead to cells becoming less specialized or even taking on characteristics of other cell types.
Dysregulation of H3K36me3, meaning too much or too little of this mark, has been linked to various human diseases, with a notable focus on cancer. In many cancers, the enzymes responsible for adding or removing H3K36me3 are often mutated or their activity is altered. For example, loss of H3K36me3 has been observed in renal cell carcinoma, while increased levels have been reported in some prostate and breast cancers.
Mutations in the H3K36 histone itself, such as changes to methionine (H3K36M), have been identified in human tumors, including chondroblastomas and sarcomas. These “oncohistone” mutations can disrupt the normal deposition and function of H3K36me3, leading to widespread epigenetic changes that promote tumor development. Such alterations can affect the expression of genes involved in cell growth and DNA repair, contributing to uncontrolled cell division and genomic instability characteristic of cancer.
Understanding how H3K36me3 is regulated and how its dysregulation contributes to disease offers avenues for new diagnostic tools and therapeutic strategies. Targeting the enzymes that modify H3K36 or pathways influenced by its altered levels represents a promising area of research in cancer treatment.