A functional role for the histone demethylase UTX in normal and malignant hematopoietic cells.
Ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX), an H3K27Me2/3 demethylase, has been implicated in development, self-renewal, and differentiation of various organs and embryonic stem cells through chromatin modifications and transcriptional regulation of important developmentally related genes, such as Hox genes. However, the function of UTX in hematopoiesis is not well understood. To study the role of UTX in the mammalian hematopoietic system, we used lentiviral short hairpin RNA constructs to knockdown UTX in the murine hematopoietic progenitor cell line EML, in primary murine bone marrow cells and in leukemic cell lines. We report that Utx is highly expressed in the hematopoietic compartment and that it plays an important role in cell proliferation and homeostasis of hematopoietic cells in vitro. Knockdown of UTX in EML and primary murine bone marrow cells impairs their colony-forming ability. Moreover, knockdown of UTX affects expression of key genes that regulate hematopoietic differentiation such as Mll1, Runx1, and Scl in primary murine bone marrow cells. And we further demonstrate that UTX directly associates with the promoters of the Mll1, Runx1, and Scl genes and modulate their transcription by controlling H3K27me3 marks on respective promoter regions. In addition, UTX depletion severely impaired proliferation of several human leukemia cell lines. Together, these data demonstrate a functional role for UTX in normal and malignant hematopoiesis.
Division of Hematology, Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02215, USA. Jianing_liu@hms.harvard.edu
Jianing
J
Liu
Thomas
T
Mercher
Claudia
C
Scholl
Kristina
K
Brumme
D Gary
DG
Gilliland
Nan
N
Zhu
D000818:Animals; D001854:Bone Marrow Cells / Q000201:enzymology*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D019337:Hematologic Neoplasms / Q000201:enzymology* / Q000473:pathology; D006410:Hematopoiesis; D056466:Histone Demethylases / Q000235:genetics / Q000502:physiology*; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D014158:Transcription, Genetic
D009687:Nuclear Proteins; D056466:Histone Demethylases; C523998:KDM6A protein, human