Dual role for the methyltransferase G9a in the maintenance of β-globin gene transcription in adult erythroid cells

doi:10.1073/pnas.0906769106

Dual role for the methyltransferase G9a in the maintenance of β-globin gene transcription in adult erythroid cells

^aThe Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON Canada K1H 8L6;
^bDana-Farber Cancer Institute, Boston, MA 02115;
^cInstitute for Systems Biology, Seattle, WA 98103; and
^dDepartment of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada K1H 8L6

Edited by Mark T. Groudine, Fred Hutchinson Cancer Research Center, Seattle, WA, and approved September 4, 2009
↵¹C.-P.C. and A.M.H. contributed equally to this work. (received for review June 16, 2009)

Abstract

Using a proteomics screen, we have identified the methyltransferase G9a as an interacting partner of the hematopoietic activator NF-E2. We show that G9a is recruited to the β-globin locus in a NF-E2-dependent manner and spreads over the entire locus. While G9a is often regarded as a corepressor, knocking down this protein in differentiating adult erythroid cells leads to repression of the adult β^maj globin gene and aberrant reactivation of the embryonic β-like globin gene E^y. While in adult cells G9a maintains E^y in a repressed state via dimethylation of histone H3 at lysines 9 and 27, it activates β^maj transcription in a methyltransferase-independent manner. Interestingly, the demethylase UTX is recruited to the β^maj (but not the E^y) promoter where it antagonizes G9a-dependent H3K27 dimethylation. Collectively, these results reveal a dual role for G9a in maintaining proper expression (both repression and activation) of the β-globin genes in differentiating adult erythroid cells.

Footnotes

²To whom correspondence should be addressed. E-mail: mbrand{at}ohri.ca
Author contributions: C.-P.C., A.M.H., F.J.D., and M.B. designed research; C.-P.C., A.M.H., C.P., J.A.R., and M.B. performed research; Y.N. and F.J.D. contributed new reagents/analytic tools; C.-P.C., A.M.H., C.P.-I., J.A.R., and M.B. analyzed data; and M.B. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE15620).
This article contains supporting information online at www.pnas.org/cgi/content/full/0906769106/DCSupplemental.