LSD1-mediated epigenetic modification is required for TAL1 function and hematopoiesis

doi:10.1073/pnas.0900437106

LSD1-mediated epigenetic modification is required for TAL1 function and hematopoiesis

Departments of ^aBiochemistry and Molecular Biology and
^dAnatomy and Cell Biology,
^fGenetics Institute, and
^eShands Cancer Center, University of Florida College of Medicine, Gainesville, FL 32610;
^bCollege of Life Science, Jilin University, Changchun 130023, China; and
^cMolecular Medicine Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892

Edited by Gary Felsenfeld, National Institutes of Health, Bethesda, MD, and approved April 30, 2009 (received for review January 14, 2009)

Abstract

TAL1 is a critical transcription factor required for hematopoiesis. However, perturbation of its activity often leads to T cell leukemia. Whether and how its transcriptional activities are regulated during hematopoiesis remains to be addressed. Here, we show that TAL1 is associated with histone demethylase complexes containing lysine-specific demethylase 1 (LSD1), RE1 silencing transcription factor corepressor (CoREST), histone deacetylase 1 (HDAC1), and histone deacetylase 2 in erythroleukemia and T cell leukemia cells. The enzymatic domain of LSD1 plays an important role in repressing the TAL1-directed transcription of GAL4 reporter linked to a thymidine kniase minimal promoter. Furthermore, we demonstrate that the TAL1-associated LSD1, HDAC1, and their enzymatic activities are coordinately down-regulated during the early phases of erythroid differentiation. Consistent with the rapid changes of TAL1–corepressor complex during differentiation, TAL1 recruits LSD1 to the silenced p4.2 promoter in undifferentiated, but not in differentiated, murine erythroleukemia (MEL) cells. Finally, shRNA-mediated knockdown of LSD1 in MEL cells resulted in derepression of the TAL1 target gene accompanied by increasing dimeH3K4 at the promoter region. Thus, our data revealed that histone lysine demethylase LSD1 may negatively regulate TAL1-mediated transcription and suggest that the dynamic regulation of TAL1-associated LSD1/HDAC1 complex may determine the onset of erythroid differentiation programs.

Footnotes

¹To whom correspondence should be addressed. E-mail: sumingh{at}ufl.edu
Author contributions: Y.Q. and S.H. designed research; X.H., X.L., and K.V. performed research; C.N. contributed new reagents/analytic tools; X.H., X.L., X.F., Y.Q., and S.H. analyzed data; and S.H. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0900437106/DCSupplemental.