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Blood, 1 March 2006, Vol. 107, No. 5, pp. 2138-2145.
Prepublished online as a Blood First Edition Paper on November 1, 2005; DOI 10.1182/blood-2005-06-2497.
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Submitted June 23, 2005
Accepted October 17, 2005
Repression of human  -globin gene expression by a short isoform of the NF-E4 protein is associated with loss of NF-E2 and RNA polymerase II recruitment to the promoter
Quan Zhao, Wen-lai Zhou, Gerhard Rank, Rosemary Sutton, Xi Wang, Helen Cumming, Loretta Cerruti, John M Cunningham, and Stephen M Jane*
Rotary Bone Marrow Research Laboratories, Royal Melbourne Hospital Research Foundation, Parkville, VIC, Australia; The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences,Nanjing University, Nanjing, China
Rotary Bone Marrow Research Laboratories, Royal Melbourne Hospital Research Foundation, Parkville, VIC, Australia
Division of Experimental Hematology, St Jude Children's Research Hospital, Memphis, TN, USA
* Corresponding author; email: jane{at}wehi.edu.au.
Binding of the stage selector protein (SSP) to the stage selector element (SSE) in the human  -globin promoter contributes to the preferential expression of the -gene in fetal erythroid cells. The SSP contains the transcription factor CP2 and an erythroid-specific partner, NF-E4. The NF-E4 gene encodes a 22 kD polypeptide employing a non-AUG initiation codon. Anti-sera specific to NF-E4 detects this species and an additional 14 kD protein, which initiates from an internal methionine. Enforced expression of p14 NF-E4 in the K562 fetal/erythroid cell line, and in primary erythroid cord blood progenitors results in repression of -gene expression. Biochemical studies reveal that p14 NF-E4 interacts with CP2, resulting in diminished association of CP2 with the SSE in chromatin immunoprecipitation assays. p45 NF-E2 recruitment to the -promoter is also lost, resulting in a reduction in RNA polymerase II and TBP binding, and a fall in promoter transcriptional activity. This effect is specific, as enforced expression of a mutant form of p14 NF-E4, which fails to interact with CP2, also fails to repress -gene expression in K562 cells. These findings provide one potential mechanism that could contribute to the autonomous silencing of the human -genes in adult erythroid cells.
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