Early mammalian erythropoiesis requires the Dot1L methyltransferase.
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.
Feng
Yi
Y
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.
Yang
Yanping
Y
Ortega
Manoela M
MM
Copeland
Jessica N
JN
Zhang
Mingcai
M
Jacob
Jennifer B
JB
Fields
Timothy A
TA
Vivian
Jay L
JL
Fields
Patrick E
PE
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
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
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