title: An Evolutionary Conserved Epigenetic Mark of Polycomb Response Elements Implemented by Trx/MLL/COMPASS.
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.
authors.affiliation: Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, 320 E. Superior Street, Chicago, IL 60611, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Rickels
authors.affiliation: Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, 320 E. Superior Street, Chicago, IL 60611, USA.
authors.forename: Deqing
authors.initials: D
authors.lastname: Hu
authors.affiliation: Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, 320 E. Superior Street, Chicago, IL 60611, USA.
authors.forename: Clayton K
authors.initials: CK
authors.lastname: Collings
authors.affiliation: Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, 320 E. Superior Street, Chicago, IL 60611, USA.
authors.forename: Ashley R
authors.initials: AR
authors.lastname: Woodfin
authors.affiliation: Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, 320 E. Superior Street, Chicago, IL 60611, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Piunti
authors.affiliation: Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
authors.forename: Man
authors.initials: M
authors.lastname: Mohan
authors.affiliation: Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
authors.forename: Hans-Martin
authors.initials: HM
authors.lastname: Herz
authors.affiliation: Research Institute of Molecular Pathology (IMP), Vienna Biocenter VBC, Dr Bohr-Gasse 7, 1030 Vienna, Austria.
authors.forename: Evgeny
authors.initials: E
authors.lastname: Kvon
authors.affiliation: 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.
authors.forename: Ali
authors.initials: A
authors.lastname: Shilatifard
mesh_terms: D000818:Animals; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics* / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018899:CpG Islands; D019175:DNA Methylation; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics* / Q000378:metabolism; D019143:Evolution, Molecular; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics* / Q000378:metabolism; D063151:Polycomb Repressive Complex 2 / Q000235:genetics* / Q000378:metabolism*; D034622:RNA Interference; D020218:Response Elements; D013045:Species Specificity; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D029721:Drosophila Proteins; D006657:Histones; C497422:KMT2A protein, human; C512571:trx protein, Drosophila; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2