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Mol Cell. 2016 Jul 21;63(2):318-328. doi: 10.1016/j.molcel.2016.06.018.

An Evolutionary Conserved Epigenetic Mark of Polycomb Response Elements Implemented by Trx/MLL/COMPASS.

Author information

1
Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, 320 E. Superior Street, Chicago, IL 60611, USA.
2
Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
3
Research Institute of Molecular Pathology (IMP), Vienna Biocenter VBC, Dr Bohr-Gasse 7, 1030 Vienna, Austria.
4
Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, 320 E. Superior Street, Chicago, IL 60611, USA; Robert H. Lurie NCI Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, 320 E. Superior Street, Chicago, IL 60611, USA. Electronic address: ash@northwestern.edu.

Abstract

Polycomb response elements (PREs) are specific DNA sequences that stably maintain the developmental pattern of gene expression. Drosophila PREs are well characterized, whereas the existence of PREs in mammals remains debated. Accumulating evidence supports a model in which CpG islands recruit Polycomb group (PcG) complexes; however, which subset of CGIs is selected to serve as PREs is unclear. Trithorax (Trx) positively regulates gene expression in Drosophila and co-occupies PREs to antagonize Polycomb-dependent silencing. Here we demonstrate that Trx-dependent H3K4 dimethylation (H3K4me2) marks Drosophila PREs and maintains the developmental expression pattern of nearby genes. Similarly, the mammalian Trx homolog, MLL1, deposits H3K4me2 at CpG-dense regions that could serve as PREs. In the absence of MLL1 and H3K4me2, H3K27me3 levels, a mark of Polycomb repressive complex 2 (PRC2), increase at these loci. By inhibiting PRC2-dependent H3K27me3 in the absence of MLL1, we can rescue expression of these loci, demonstrating a functional balance between MLL1 and PRC2 activities at these sites. Thus, our study provides rules for identifying cell-type-specific functional mammalian PREs within the human genome.

PMID:
27447986
PMCID:
PMC4996622
DOI:
10.1016/j.molcel.2016.06.018
[Indexed for MEDLINE]
Free PMC Article

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