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Molecular and Cellular Biology, October 2009, p. 5399-5412, Vol. 29, No. 20
0270-7306/09/$08.00+0     doi:10.1128/MCB.00777-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Chromatin Architecture and Transcription Factor Binding Regulate Expression of Erythrocyte Membrane Protein Genes{triangledown} ,{dagger}

Laurie A. Steiner,1 Yelena Maksimova,1 Vincent Schulz,1 Clara Wong,1 Debasish Raha,2 Milind C. Mahajan,3 Sherman M. Weissman,3 and Patrick G. Gallagher1*

Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut 06520-8021,1 Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut 06520-8103,2 Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06520-80053

Received 15 June 2009/ Returned for modification 27 July 2009/ Accepted 9 August 2009

Erythrocyte membrane protein genes serve as excellent models of complex gene locus structure and function, but their study has been complicated by both their large size and their complexity. To begin to understand the intricate interplay of transcription, dynamic chromatin architecture, transcription factor binding, and genomic organization in regulation of erythrocyte membrane protein genes, we performed chromatin immunoprecipitation (ChIP) coupled with microarray analysis and ChIP coupled with massively parallel DNA sequencing in both erythroid and nonerythroid cells. Unexpectedly, most regions of GATA-1 and NF-E2 binding were remote from gene promoters and transcriptional start sites, located primarily in introns. Cooccupancy with FOG-1, SCL, and MTA-2 was found at all regions of GATA-1 binding, with cooccupancy of SCL and MTA-2 also found at regions of NF-E2 binding. Cooccupancy of GATA-1 and NF-E2 was found frequently. A common signature of histone H3 trimethylation at lysine 4, GATA-1, NF-E2, FOG-1, SCL, and MTA-2 binding and consensus GATA-1-E-box binding motifs located 34 to 90 bp away from NF-E2 binding motifs was found frequently in erythroid cell-expressed genes. These results provide insights into our understanding of membrane protein gene regulation in erythropoiesis and the regulation of complex genetic loci in erythroid and nonerythroid cells and identify numerous candidate regions for mutations associated with membrane-linked hemolytic anemia.

* Corresponding author. Mailing address: Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, P.O. Box 208064, New Haven, CT 06520-8064. Phone: (203) 688-2896. Fax: (203) 785-6974. E-mail: patrick.gallagher{at}yale.edu

{triangledown} Published ahead of print on 17 August 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, October 2009, p. 5399-5412, Vol. 29, No. 20
0270-7306/09/$08.00+0     doi:10.1128/MCB.00777-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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