title: Histone methyltransferase Setd8 represses Gata2 expression and regulates erythroid maturation.
abstract: Setd8 is the sole histone methyltransferase in mammals capable of monomethylating histone H4 lysine 20 (H4K20me1). Setd8 is expressed at significantly higher levels in erythroid cells than any other cell or tissue type, suggesting that Setd8 has an erythroid-cell-specific function. To test this hypothesis, stable Setd8 knockdown was established in extensively self-renewing erythroblasts (ESREs), a well-characterized, nontransformed model of erythroid maturation. Knockdown of Setd8 resulted in impaired erythroid maturation characterized by a delay in hemoglobin accumulation, larger mean cell area, persistent ckit expression, incomplete nuclear condensation, and lower rates of enucleation. Setd8 knockdown did not alter ESRE proliferation or viability or result in accumulation of DNA damage. Global gene expression analyses following Setd8 knockdown demonstrated that in erythroid cells, Setd8 functions primarily as a repressor. Most notably, Gata2 expression was significantly higher in knockdown cells than in control cells and Gata2 knockdown rescued some of the maturation impairments associated with Setd8 disruption. Setd8 occupies critical regulatory elements in the Gata2 locus, and knockdown of Setd8 resulted in loss of H4K20me1 and gain of H4 acetylation at the Gata2 1S promoter. These results suggest that Setd8 is an important regulator of erythroid maturation that works in part through repression of Gata2 expression.
authors.affiliation: University of Rochester Medical Center, Department of Pediatrics, Center for Pediatric Biomedical Research, Rochester, New York, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Malik
authors.affiliation: University of Rochester Medical Center, Department of Pediatrics, Center for Pediatric Biomedical Research, Rochester, New York, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Getman
authors.affiliation: University of Rochester Medical Center, Department of Pediatrics, Center for Pediatric Biomedical Research, Rochester, New York, USA Laurie_Steiner@urmc.rochester.edu.
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Steiner
mesh_terms: D000107:Acetylation; D000818:Animals; D002478:Cells, Cultured; D004900:Erythroblasts / Q000166:cytology / Q000378:metabolism; D041905:Erythroid Cells / Q000166:cytology* / Q000378:metabolism; D004920:Erythropoiesis; D050989:GATA2 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D050989:GATA2 Transcription Factor; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones; D034741:RNA, Small Interfering; C529566:KMT5a protein, mouse
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