The Histone Methyltransferase Gene Absent, Small, or Homeotic Discs-1 Like Is Required for Normal Hox Gene Expression and Fertility in Mice.
Chromatin remodeling influences gene expression in developing and adult organisms. Active and repressive marks of histone methylation dictate the embryonic expression boundaries of developmentally regulated genes, including the Hox gene cluster. Drosophila ash1 (absent, small or homeotic discs 1) gene encodes a histone methyltransferase essential for regulation of Hox gene expression that interacts genetically with other members of the trithorax group (TrxG). While mammalian members of the mixed lineage leukemia (Mll) family of TrxG genes have roles in regulation of Hox gene expression, little is known about the expression and function of the mammalian ortholog of the Drosophila ash1 gene, Ash1-like (Ash1l). Here we report the expression of mouse Ash1l gene in specific structures within various organs and provide evidence that reduced Ash1l expression has tissue-specific effects on mammalian development and adult homeostasis. Mutants exhibit partially penetrant postnatal lethality and failure to thrive. Surviving mutants have growth insufficiency, skeletal transformations, and infertility associated with developmental defects in both male and female reproductive organs. Specifically, expression of Hoxa11 and Hoxd10 are altered in the epididymis of Ash1l mutant males and Hoxa10 is reduced in the uterus of Ash1l mutant females. In summary, we show that the histone methyltransferase Ash1l is important for the development and function of several tissues and for proper expression of homeotic genes in mammals.
Department of Human Genetics, University of Michigan, Ann Arbor, Michigan.
Michelle L
ML
Brinkmeier
Graduate Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan.
Krista A
KA
Geister
Graduate Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan.
Morgan
M
Jones
Department of Human Genetics, University of Michigan, Ann Arbor, Michigan.
Meriam
M
Waqas
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan Life Sciences Institute, University of Michigan, Ann Arbor, Michigan.
Ivan
I
Maillard
Department of Human Genetics, University of Michigan, Ann Arbor, Michigan Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan scamper@umich.edu.
Sally A
SA
Camper
D000483:Alleles; D000818:Animals; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D004822:Epididymis / Q000002:abnormalities* / Q000378:metabolism; D005260:Female; D005298:Fertility; D005801:Genes, Homeobox; D011495:Histone-Lysine N-Methyltransferase; D018398:Homeodomain Proteins / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics; D014599:Uterus / Q000002:abnormalities*
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D014157:Transcription Factors; C490911:ASH1L protein, human; D011495:Histone-Lysine N-Methyltransferase
Hoxa11; Hoxd10; abdominal fat; axial skeleton; epigenetic; infertility; reproduction