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MBC in Press, published online ahead of print August 1, 2007
Mol. Biol. Cell 10.1091/mbc.E07-03-0245

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Submitted on March 16, 2007
Revised on July 9, 2007
Accepted on July 20, 2007

Aberrant Chromatin Remodeling by Retinoic Acid Receptor {alpha} Fusion Proteins Assessed at the Single-Cell Level

Jihui Qiu,* Ying Huang,{dagger} Guoqiang Chen,{dagger} Zhu Chen,{dagger} David J. Tweardy,*{ddagger} and Shuo Dong*{dagger}

*Department of Medicine, Section of Infectious Disease, and {ddagger}Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030; {dagger}Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China

Monitoring Editor: Wendy Bickmore

Acute promyelocytic leukemia (APL) is characterized by specific chromosomal translocations, which generate fusion proteins such as PML-RAR{alpha} and PLZF-RAR{alpha} (X-RAR{alpha}). In this study, we have applied lac operator array systems to study the effects of X-RAR{alpha} versus wild-type RAR{alpha} on large-scale chromatin structure. The targeting of these enhanced cyan fluorescent protein (CFP)-lac repressor tagged RAR{alpha}-containing proteins to the gene-amplification chromosomal region by lac operator repeats led to local chromatin condensation, recruitment of nuclear receptor corepressor and histone deacetylase complex. The addition of retinoic acid (RA) induced large-scale chromatin decondensation in cells expressing RAR{alpha}, however, cells expressing X-RAR{alpha}, especially PML-RAR{alpha}, demonstrated insensitive response to this effect of ATRA. While, we did not reveal differences in RA-dependent colocalization of either SMRT or SRC-1 with RAR{alpha} versus X-RAR{alpha}, the hormone-independent association between SRC-1 and X-RAR{alpha} on the array has been identified. Rather, compared with cells expressing RAR{alpha}, fluorescence recovery after photobleaching (FRAP) of live transfected cells, demonstrated decreased mobility of SRC-1 on the X-RAR{alpha}-bound chromatin. Thus, the impaired ability of APL fusion proteins to activate gene transcription in response to ATRA corresponds to their reduced ability to remodel chromatin, which may link to their ability to impair the mobility of key nuclear receptor coregulators. Keywords: acute promyelocytic leukemia (APL); retinoic acid receptor {alpha} (RAR{alpha}); X-RAR{alpha}; chromatin remodeling

Address correspondence to: David J. Tweardy (dtweardy{at}bcm.tmc.edu) or Shuo Dong (sdong{at}bcm.tmc.edu)






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