Et Tu, Methyl Group? Epigenetic Betrayal of NSD1

February 1, 2010 Sometimes your best friend can become your worst enemy. Take the case of the methyl group and the histone methyltransferase enzyme NSD1: The methyl is NSD1’s little buddy through countless histone methyltransferase reactions, when suddenly the backstabbing little –CH3 teams up with a DNA methyltransferase to silence NSD1 expression. This tale of intrigue was told in a recent PNAS paper by Manuel Esteller and collaborators in Spain, France, the US, and the UK.

Until now, not much was known about the epigenetic regulation of NSD1, except that silencing of NSD1 by mutation or deletion has serious cellular consequences. NSD1 gene disruption causes Sotos syndrome, a disease characterized by accelerated growth during the first years of life and an increased cancer risk.

Strengthening the link between NSD1 inactivation and tumorigenesis, the researchers showed that silencing of NSD1 by promoter hypermethylation contributes to some sporadic malignancies:

• NSD1 hypermethylation is common in neuroblastomas and gliomas and is a predictor of poor outcome in high-risk neuroblastoma
• NSD1 epigenetic inactivation reduces global trimethylation of histone residues H3-K36 and H4-K20
• NSD1 silencing increases expression of the oncogene MEIS1, a major target of NSD1 methyltransferase activity

“It’s always interesting to find epigenetic inactivation of an epigenetic gene,” says Esteller. “It’s a double twist: promoter CpG island hypermethylation-associated silencing of a histone methyltransferase.” This story has more twists than a Shakespearean tragedy, so to keep it all straight visit: PNAS, December 2009