Brain-specific expression of N-acetylglucosaminyltransferase IX (GnT-IX) is regulated by epigenetic histone...

It is well known that biosynthesis of glycans takes place in organ- and tissue-specific manners and glycan expression is controlled by various factors including glycosyltransferases. The expression mechanism of glycosyltransferases, however, is poorly understood. Here we investigated the expression mechanism of a brain-specific glycosyltransferase, GnT-IX (N-acetylglucosaminyltransferase IX, also designated as GnT-Vb), which synthesizes branched O-mannose glycan. Using an epigenetic approach, we revealed that the genomic region around the transcriptional start site of the GnT-IX gene was highly associated with active chromatin histone marks in a neural cell-specific manner, indicating that brain-specific GnT-IX expression is under control of an epigenetic "histone code." By EMSA and ChIP analyses we identified two regulatory proteins, NeuroD1 and CTCF that bind to and activate the GnT-IX promoter. We also revealed that GnT-IX expression was suppressed in CTCF- and NeuroD1-depleted cells, indicating that a NeuroD1- and CTCF-dependent epigenetic mechanism governs brain-specific GnT-IX expression. Several other neural glycosyltransferase genes are also found to be regulated by epigenetic histone modifications. This is the first report demonstrating a molecular mechanism at the chromatin level underlying tissue-specific glycan expression.