Psip1/Ledgf p75 restrains<i>Hox</i>gene expression by recruiting both trithorax and polycomb group proteins

Trithorax and polycomb group proteins are generally thought to antagonize one another. The trithorax familymember MLL (myeloid/lymphoid or mixedlineage leukemia) is presumed to activate Hox expression, counteracting polycomb-mediated repression. PC4 and SF2 interacting protein 1 (PSIP1)/p75, also known as LEDGF, whose PWWP domain binds to H3K36me3, interacts with MLL and tethers MLL fusion proteins toHOXA9 in leukaemias. Here we show, unexpectedly, that Psip1/p75 regulates homeotic genes by recruiting not only MLL complexes, but also the polycomb group protein Bmi1. In Psip1-/- cells binding of Mll1/2, Bmi1 and the co-repressor Ctbp1 at Hox loci are all abrogated and Hoxa and Hoxd mRNA expression increased. Our data not only reveal a potential mechanism of action for Psip1 in the regulation of Hox genes but also suggest an unexpected interplay between proteins usually considered as transcriptional activators and repressors. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.