Functional analysis of AEBP2, a PRC2 Polycomb protein, reveals a Trithorax phenotype in embryonic development and in ESCs.
The Polycomb repressive complexes PRC1 and PRC2 are key mediators of heritable gene silencing in multicellular organisms. Here, we characterise AEBP2, a known PRC2 co-factor which, in vitro, has been shown to stimulate PRC2 activity. We show that AEBP2 localises specifically to PRC2 target loci, including the inactive X chromosome. Proteomic analysis confirms that AEBP2 associates exclusively with PRC2 complexes. However, analysis of embryos homozygous for a targeted mutation of Aebp2 unexpectedly revealed a Trithorax phenotype, normally linked to antagonism of Polycomb function. Consistent with this, we observe elevated levels of PRC2-mediated histone H3K27 methylation at target loci in Aebp2 mutant embryonic stem cells (ESCs). We further demonstrate that mutant ESCs assemble atypical hybrid PRC2 subcomplexes, potentially accounting for enhancement of Polycomb activity, and suggesting that AEBP2 normally plays a role in defining the mutually exclusive composition of PRC2 subcomplexes.
Developmental Epigenetics, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.
Anne
A
Grijzenhout
Developmental Epigenetics, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.
Jonathan
J
Godwin
Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro, Tsurumi-ku, Yokohama 230-0045, Japan.
Haruhiko
H
Koseki
Developmental Epigenetics, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.
Michal Ryszard
MR
Gdula
Department of Cardiovascular Medicine and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
Dorota
D
Szumska
TDI Mass Spectrometry Laboratory, Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK.
Joanna F
JF
McGouran
Department of Cardiovascular Medicine and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
Shoumo
S
Bhattacharya
TDI Mass Spectrometry Laboratory, Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK.
Benedikt M
BM
Kessler
Developmental Epigenetics, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK neil.brockdorff@bioch.ox.ac.uk sarah.cooper@bioch.ox.ac.uk.
Neil
N
Brockdorff
Developmental Epigenetics, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK neil.brockdorff@bioch.ox.ac.uk sarah.cooper@bioch.ox.ac.uk.
Sarah
0000-0001-9659-578X
S
Cooper
D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D005260:Female; D006657:Histones / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism*; D040901:Proteomics / Q000379:methods*; D012097:Repressor Proteins
C541953:Aebp2 protein, mouse; D004268:DNA-Binding Proteins; D006657:Histones; D009687:Nuclear Proteins; D012097:Repressor Proteins; D063151:Polycomb Repressive Complex 2
AEBP2; Chromatin; Mouse; PRC2; Polycomb; Trithorax