UHRF1 in RB development was first described in a study where genetic disruption of E2f1 or E2f3 in a murine RB model was found to abrogate tumor development, and searching for the candidate genes responsible for this phenotype rescue led to the identification of Hells and Uhrf1 as potential epigenetic factors involved in RB tumor progression (Benavente et al., 2014). Here, HELLS is linked to retinoblastoma.