Histondemethylasen

Histondemethylasen, or histone demethylases, are enzymes that remove methyl groups from lysine residues on histone proteins. By altering the methylation state of histones, they influence chromatin structure and the accessibility of DNA to transcriptional machinery, thereby modulating gene expression. They constitute a key component of epigenetic regulation and help coordinate development, differentiation, and cellular responses to stimuli.

Two major families govern histone demethylation. The LSD family (LSD1/KDM1A and LSD2/KDM1B) is FAD-dependent and acts as a mono- or di-methyllysine demethylase in concert with partner proteins. The JmjC domain-containing family (KDM2–KDM7) requires Fe(II) and α-ketoglutarate and can demethylate a broader set of lysine residues, including H3K4, H3K9, H3K27, and H3K36, among others. Substrate preference and regulation vary across individual enzymes, leading to diverse effects on transcriptional programs.

Biological roles of histone demethylases are wide-ranging. They participate in development and differentiation, control stem cell fate, influence DNA damage responses, and impact metabolic pathways. Misregulation of histone demethylases has been linked to cancer, neurological disorders, and aging, making them subjects of intensive research.

Therapeutic targeting is an active area of study. Researchers have developed inhibitors for LSD1, such as certain clinical- and preclinical-stage compounds, and for JmjC demethylases, including JMJD3/UTX inhibitors like GSK-J4. These agents are explored for cancer and other diseases, with ongoing work to improve selectivity and pharmacological properties.

Discovery and naming progressed from the identification of LSD1 in the early 2000s to the broader characterization of JmjC-domain demethylases in subsequent years, revealing a complex and evolving landscape of histone demethylation.