TY - JOUR
T1 - A functional role for the histone demethylase UTX in normal and malignant hematopoietic cells
AU - Liu, Jianing
AU - Mercher, Thomas
AU - Scholl, Claudia
AU - Brumme, Kristina
AU - Gilliland, D. Gary
AU - Zhu, Nan
N1 - Funding Information:
We are very grateful to Dr. Kai Ge (National Institutes of Health, Bethesda, MD, USA) and Dr. Fei Lan (Constellation Pharmaceuticals, Cambridge, MA, USA) for kindly providing the UTX antibody, to Dr. Jian Chen from Dr. Nancy Berliner’s laboratory for EML and BHK/MKL cell lines. This work was supported in part by the Howard Hughes Medical Institute, Chevy Chase , MD, USA (D.G.G.).
PY - 2012/1/1
Y1 - 2012/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84862777232&partnerID=8YFLogxK
U2 - 10.1016/j.exphem.2012.01.017
DO - 10.1016/j.exphem.2012.01.017
M3 - Article
AN - SCOPUS:84862777232
SN - 0301-472X
VL - 40
SP - 487-498.e3
JO - Experimental Hematology
JF - Experimental Hematology
IS - 6
ER -