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

Madapura M. Pradeepa,Wendy A. Bickmore,Heidi G. Sutherland,Graeme R. Grimes,Gillian C.A. Taylor

doi:10.1093/nar/gku647

Madapura M. Pradeepa, Wendy A. Bickmore + Show 3 more

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https://doi.org/10.1093/nar/gku647

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Abstract

Trithorax and polycomb group proteins are generally thought to antagonize one another. The trithorax family member MLL (myeloid/lymphoid or mixed-lineage 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 to HOXA9 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.

Highlights

The Homeotic (Hox) gene family encodes transcription factors essential for patterning the anterior–posterior body axis
The preference for p75 occupancy over Hox A and D clusters does not reflect an intrinsic property of the DNA sequence there: Chromatin immunoprecipitation (ChIP) in independent primary mouse embryonic fibroblasts (MEFs) derived in our laboratory [28] showed specific occupancy of p75 over Hoxa, b and c genes which are expressed in those cells, suggesting that PC4 and SF2 interacting protein 1 (Psip1)/p75 generally binds to expressed Hox genes
We have demonstrated that Psip1/p75 is required to retain Mll1/2 and Bmi1/Ctbp1 at HoxA and HoxD loci (Figures 1 and 2), with the net result of dampened gene expression

Summary

Introduction

The Homeotic (Hox) gene family encodes transcription factors essential for patterning the anterior–posterior body axis. Trithorax (Trx) proteins (MLL proteins in mammals) of the COMPASS-like family have histone H3 lysine 4 (H3K4) methyl transferase activity and are generally thought to maintain the active expression level of Hox genes [4,5], and may function as anti-repressors to prevent the repressive function of polycomb [6,7,8]. Six mammalian COMPASS-like complexes have been identified, each with a SET domain-containing HMT subunit including; Set1A/KMT2F, Set1B/KMT2G and four MLL-family proteins––MLL1/KMT2A, Mll2/KMT2B, MLL3/KMT2C, MLL4/KMT2D [9,10]. Each of these complexes associates with proteins that can modulate target site selection and enzymatic activity. Set1A/B are associated with Wdr82 [11,12], Mll and Mll are associated with Menin [5], Mll and Mll with PTIP [13]

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