Histone methyltransferase

Histone Methyltransferase, front view.tiff

Histone Methyltransferase, back view.tiff

Histone Methyltransferase, SAM and Lysine residue.tiff

Histone methyltransferase (HMT) is an enzyme responsible for the methylation of histone proteins, a process that is critical for the regulation of gene expression and chromatin structure. Methylation of histones can either activate or repress gene expression, depending on the specific amino acids in the histones that are methylated and the number of methyl groups added. Histone methyltransferases are thus key players in the epigenetic control of gene function, influencing diverse biological processes such as cell cycle regulation, DNA repair, and development.

Types of Histone Methyltransferases

Histone methyltransferases can be broadly classified into two categories based on the specific lysine residue they target on histone proteins: lysine methyltransferases (KMTs) and arginine methyltransferases (PRMTs). KMTs catalyze the transfer of methyl groups to the lysine residues of histones, while PRMTs target arginine residues.

Lysine Methyltransferases (KMTs)

KMTs are further divided into two groups based on their SET domain, a conserved region involved in the enzymatic activity of these proteins. The SET domain-containing methyltransferases are the largest group and include enzymes such as EZH2, a component of the Polycomb repressive complex 2 (PRC2) that methylates histone H3 on lysine 27 (H3K27me3), contributing to transcriptional repression. Non-SET domain KMTs also exist and include DOT1L, the only known enzyme capable of methylating lysine 79 of histone H3.

Protein Arginine Methyltransferases (PRMTs)

PRMTs are responsible for the methylation of arginine residues on histones. This modification can lead to either transcriptional activation or repression, depending on the specific arginine residue methylated. PRMTs are categorized into Type I and Type II, based on the final methylation product they produce (mono-methyl arginine and symmetric or asymmetric di-methyl arginine, respectively).

Function and Mechanism

Histone methyltransferases transfer one, two, or three methyl groups from the donor molecule S-adenosylmethionine (SAM) to the amino acid residues on histone tails. This modification alters the interaction between histones and DNA, affecting the accessibility of the DNA to transcription factors and other DNA-binding proteins. The specific outcome of histone methylation (activation or repression of transcription) depends on the site of methylation and the number of methyl groups added.

Role in Disease

Aberrant activity of histone methyltransferases has been linked to the development of various diseases, particularly cancer. For example, mutations or overexpression of EZH2 have been implicated in the progression of several types of cancer, including lymphoma, prostate cancer, and breast cancer. As such, histone methyltransferases are considered potential targets for therapeutic intervention.

Research and Therapeutic Applications

The study of histone methyltransferases has led to the development of inhibitors targeting specific enzymes, such as EZH2 inhibitors, which are currently being tested in clinical trials for cancer treatment. These inhibitors represent a new class of epigenetic therapies that have the potential to modulate gene expression patterns aberrantly controlled in diseases.

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