title: Early mammalian erythropoiesis requires the Dot1L methyltransferase.
abstract: Histone methylation is an important regulator of gene expression; its coordinated activity is critical in complex developmental processes such as hematopoiesis. Disruptor of telomere silencing 1-like (DOT1L) is a unique histone methyltransferase that specifically methylates histone H3 at lysine 79. We analyzed Dot1L-mutant mice to determine influence of this enzyme on embryonic hematopoiesis. Mutant mice developed more slowly than wild-type embryos and died between embryonic days 10.5 and 13.5, displaying a striking anemia, especially apparent in small vessels of the yolk sac. Further, a severe, selective defect in erythroid, but not myeloid, differentiation was observed. Erythroid progenitors failed to develop normally, showing retarded progression through the cell cycle, accumulation during G₀/G₁ stage, and marked increase in apoptosis in response to erythroid growth factors. GATA2, a factor essential for early erythropoiesis, was significantly reduced in Dot1L-deficient cells, whereas expression of PU.1, a transcription factor that inhibits erythropoiesis and promotes myelopoiesis, was increased. These data suggest a model whereby DOT1L-dependent lysine 79 of histone H3 methylation serves as a critical regulator of a differentiation switch during early hematopoiesis, regulating steady-state levels of GATA2 and PU.1 transcription, thus controlling numbers of circulating erythroid and myeloid cells.
authors.affiliation: Department of Pathology and Laboratory Medicine, Division of Cancer and Developmental Biology, Institute for Reproductive Health and Regenerative Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Feng
authors.forename: Yanping
authors.initials: Y
authors.lastname: Yang
authors.forename: Manoela M
authors.initials: MM
authors.lastname: Ortega
authors.forename: Jessica N
authors.initials: JN
authors.lastname: Copeland
authors.forename: Mingcai
authors.initials: M
authors.lastname: Zhang
authors.forename: Jennifer B
authors.initials: JB
authors.lastname: Jacob
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Fields
authors.forename: Jay L
authors.initials: JL
authors.lastname: Vivian
authors.forename: Patrick E
authors.initials: PE
authors.lastname: Fields
mesh_terms: D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology / Q000196:embryology / Q000473:pathology*; D004920:Erythropoiesis; D005260:Female; D050989:GATA2 Transcription Factor / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000378:metabolism; D008745:Methylation; D008780:Methyltransferases / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics; D014158:Transcription, Genetic; D015017:Yolk Sac / Q000166:cytology / Q000378:metabolism; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D050989:GATA2 Transcription Factor; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones; D008780:Methyltransferases; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C494712:Gata2 protein, mouse; C481527:Dot1l protein, mouse
references.citation: Mol Cell Biol. 2006 Oct;26(19):7056-67
references.pmid: 16980610
references.citation: J Cell Physiol. 1988 Oct;137(1):65-74
references.pmid: 2459142
references.citation: Development. 2007 Sep;134(18):3317-26
references.pmid: 17720695
references.citation: Blood. 2003 Mar 1;101(5):1669-76
references.pmid: 12406884
references.citation: Blood. 1979 Sep;54(3):673-83
references.pmid: 465735
references.citation: Mol Cell Biol. 2008 Apr;28(8):2825-39
references.pmid: 18285465
references.citation: Biochem J. 2004 Feb 1;377(Pt 3):641-51
references.pmid: 14572310
references.citation: Blood. 2006 Mar 1;107(5):1857-63
references.pmid: 16254139
references.citation: Circ Res. 2003 Feb 7;92(2):133-5
references.pmid: 12574139
references.citation: Genetics. 1998 Oct;150(2):613-32
references.pmid: 9755194
references.citation: Curr Top Dev Biol. 2008;82:85-116
references.pmid: 18282518
references.citation: Oncogene. 2007 Oct 15;26(47):6697-714
references.pmid: 17934479
references.citation: J Cell Sci. 2004 May 15;117(Pt 12):2491-501
references.pmid: 15128874
references.citation: Blood. 2009 Jul 30;114(5):983-94
references.pmid: 19491391
references.citation: Mol Cell Biol. 2005 Oct;25(19):8430-43
references.pmid: 16166626
references.citation: Blood. 1993 Jan 15;81(2):373-84
references.pmid: 7678514
references.citation: Curr Top Dev Biol. 2008;82:55-83
references.pmid: 18282517
references.citation: J Biol Chem. 2007 May 11;282(19):14665-74
references.pmid: 17347142
references.citation: Mol Cell Biol. 1997 Mar;17(3):1642-51
references.pmid: 9032291
references.citation: Oncogene. 2007 Oct 15;26(47):6777-94
references.pmid: 17934485
references.citation: Curr Opin Hematol. 2005 May;12(3):217-21
references.pmid: 15867578
references.citation: Development. 2007 May;134(9):1703-12
references.pmid: 17395646
references.citation: Genetics. 2009 Jun;182(2):437-46
references.pmid: 19332880
references.citation: Dev Cell. 2005 Jan;8(1):109-16
references.pmid: 15621534
references.citation: Cell. 2002 Jun 14;109(6):745-56
references.pmid: 12086673
references.citation: Curr Biol. 2002 Jun 25;12(12):1052-8
references.pmid: 12123582
references.citation: Blood. 2008 Apr 1;111(7):3435-8
references.pmid: 17932251
references.citation: Proc Natl Acad Sci U S A. 1999 Jul 20;96(15):8705-10
references.pmid: 10411939
references.citation: J Exp Med. 2004 Oct 4;200(7):871-82
references.pmid: 15466621
references.citation: Development. 1999 Nov;126(22):5073-84
references.pmid: 10529424
references.citation: PLoS Genet. 2008 Sep 12;4(9):e1000190
references.pmid: 18787701
references.citation: Blood. 2005 Jul 15;106(2):477-84
references.pmid: 15811962
references.citation: Blood. 2000 Oct 15;96(8):2641-8
references.pmid: 11023493
references.citation: Blood. 2008 Jul 15;112(2):406-14
references.pmid: 18441235
references.citation: IUBMB Life. 2009 Aug;61(8):800-30
references.pmid: 19621348
references.citation: Science. 1990 Apr 20;248(4953):378-81
references.pmid: 2326648
references.citation: Mol Cell Biol. 2007 Nov;27(21):7425-38
references.pmid: 17785440
references.citation: Genes Dev. 2002 Jun 15;16(12):1518-27
references.pmid: 12080090
references.citation: J Biol Chem. 2003 May 16;278(20):18346-52
references.pmid: 12604594
references.citation: Curr Top Dev Biol. 2008;82:1-22
references.pmid: 18282515
references.citation: Nature. 1994 Sep 15;371(6494):221-6
references.pmid: 8078582
references.citation: Genes Dev. 1999 Jan 1;13(1):112-24
references.pmid: 9887104
references.citation: Methods. 2001 Dec;25(4):402-8
references.pmid: 11846609
references.citation: Epigenetics. 2009 Aug 16;4(6):357-61
references.pmid: 19736520
references.citation: Blood. 2004 Jul 1;104(1):19-25
references.pmid: 15031208
references.citation: Blood. 2003 Jan 15;101(2):508-16
references.pmid: 12393529