WDR76 promotes MLL-rearranged leukemia via highly-selective binding of 5-hydroxymethylcytosine in DNA

Although rare, the distribution of the 5-hydroxymethylcytosine (hmC) modification in mammalian DNA is tissue- and gene-specific, yet distinct from its repressive methylcytosine (mC) precursor, suggesting unique functions. To examine this possibility, we fractionated mammalian brain extracts to discover binding partners specific for oxidized states of mC. We demonstrate that one such factor, WDR76, is a highly hmC-specific binding protein that modulates gene expression within chromosomal regions enriched in hmC where it binds. In human cell lines and mouse models, WDR76 recruitment by hmC is critical for the initiation and maintenance of MLL-rearranged leukemias. Beyond its canonical role as an intermediate in mC remediation, we show that hmC can be an epigenetic mark whose recognition drives leukemogenesis, portending analogous signaling pathways for other rare DNA modifications. ChiP-seq of epitope tagged WDR76 and RNA-seq of Wdr76 knockout in mouse embyrionic stem cells