Opposing roles of polycomb repressive complexes in hematopoietic stem and progenitor cells.
Polycomb group (PcG) proteins are transcriptional repressors with a central role in the establishment and maintenance of gene expression patterns during development. We have investigated the role of polycomb repressive complexes (PRCs) in hematopoietic stem cells (HSCs) and progenitor populations. We show that mice with loss of function mutations in PRC2 components display enhanced HSC/progenitor population activity, whereas mutations that disrupt PRC1 or pleiohomeotic repressive complex are associated with HSC/progenitor cell defects. Because the hierarchical model of PRC action would predict synergistic effects of PRC1 and PRC2 mutation, these opposing effects suggest this model does not hold true in HSC/progenitor cells. To investigate the molecular targets of each complex in HSC/progenitor cells, we measured genome-wide expression changes associated with PRC deficiency, and identified transcriptional networks that are differentially regulated by PRC1 and PRC2. These studies provide new insights into the mechanistic interplay between distinct PRCs and have important implications for approaching PcG proteins as therapeutic targets.
Majewski
Ian J
IJ
Molecular Medicine Division.
Ritchie
Matthew E
ME
Phipson
Belinda
B
Corbin
Jason
J
Pakusch
Miha
M
Ebert
Anja
A
Busslinger
Meinrad
M
Koseki
Haruhiko
H
Hu
Yifang
Y
Smyth
Gordon K
GK
Alexander
Warren S
WS
Hilton
Douglas J
DJ
Blewitt
Marnie E
ME
D000818:Animals; D016026:Bone Marrow Transplantation; D000071221:Enhancer of Zeste Homolog 2 Protein; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes; D009154:Mutation; D010641:Phenotype; D063151:Polycomb Repressive Complex 2; D063146:Polycomb-Group Proteins; D034622:RNA Interference; D011828:Radiation Chimera; D012097:Repressor Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D014158:Transcription, Genetic; D050986:YY1 Transcription Factor / Q000502:physiology
C107275:Eed protein, mouse; D046912:Multiprotein Complexes; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins; C485818:Sfmbt1 protein, mouse; C494163:Suz12 protein, mouse; D050986:YY1 Transcription Factor; C494699:Yy1 protein, mouse; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2