ScienceDaily (May 3, 2010) — During embryonic development, proteins called Polycomb group complexes turn genes off when and where their activity must not be present, preventing specialised tissues and organs from forming in the wrong places. They also play an important role in processes like stem cell differentiation and cancer.
These microscopy images show the region of the embryo larva that will develop into the adult fruit fly’s wing. In cells genetically manipulated so that PR-DUB cannot remove the gene-silencing tag (left), a gene which would normally be silenced becomes turned on (red) - a situation which is corrected when PR-DUB’s activity is restored (right). (Credit: J.Mueller/EMBL)
Another Polycomb group complex was already known to silence genes by placing a chemical tag near them. Juerg Mueller and his group at EMBL found that the new Polycomb complex they discovered, PR-DUB, removes that same tag.
"Surprisingly, this new complex which takes the tag off seems to act in the same tissues and at the same developmental stages as the one that puts the tag on," says Mueller, "and both opposing activities must occur to keep the gene silenced in our model organism, the fruit flyDrosophila."
The reason for this unexpected behaviour is yet to be experimentally confirmed, but it may be a case of fine-tuning, with the newly-found complex ensuring that the chemical tagging is kept at its optimal level.
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Johanna C. Scheuermann1,3, Andrés Gaytán de Ayala Alonso1,3, Katarzyna Oktaba1, Nga Ly-Hartig1, Robert K. McGinty2, Sven Fraterman1, Matthias Wilm1, Tom W. Muir2 & Jürg Müller1
European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany
The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA
These authors contributed equally to this work.
Correspondence to: Jürg Müller1 Correspondence and requests for materials should be addressed to J.M. (Email: juerg.mueller@embl.de).
Abstract
Polycomb group (PcG) proteins are transcriptional repressors that control processes ranging from the maintenance of cell fate decisions and stem cell pluripotency in animals to the control of flowering time in plants1, 2, 3, 4, 5, 6. InDrosophila, genetic studies identified more than 15 different PcG proteins that are required to repress homeotic (HOX) and other developmental regulator genes in cells where they must stay inactive1, 7, 8. Biochemical analyses established that these PcG proteins exist in distinct multiprotein complexes that bind to and modify chromatin of target genes1, 2, 3, 4. Among those, Polycomb repressive complex 1 (PRC1) and the related dRing-associated factors (dRAF) complex contain an E3 ligase activity for monoubiquitination of histone H2A (refs 1–4). Here we show that the uncharacterized Drosophila PcG gene calypso encodes the ubiquitin carboxy-terminal hydrolase BAP1. Biochemically purified Calypso exists in a complex with the PcG protein ASX, and this complex, named Polycomb repressive deubiquitinase (PR-DUB), is bound at PcG target genes in Drosophila. Reconstituted recombinant Drosophila and human PR-DUB complexes remove monoubiquitin from H2A but not from H2B in nucleosomes.Drosophila mutants lacking PR-DUB show a strong increase in the levels of monoubiquitinated H2A. A mutation that disrupts the catalytic activity of Calypso, or absence of the ASX subunit abolishes H2A deubiquitination in vitro and HOX gene repressionin vivo. Polycomb gene silencing may thus entail a dynamic balance between H2A ubiquitination by PRC1 and dRAF, and H2A deubiquitination by PR-DUB.
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