Gender	Male
E-mail	james.bieker@mssm.edu
Education and Training	Ph.D., Northwestern University
	Postdoctoral Training, Rockefeller University
	Postdoctoral Training, Washington University School of Medicine
Awards	1998 - 2003 NIH Comprehensive Sickle Cell Center
	1994 - 1999 Scholar of the Leukemia Society of America
	1974 Leopold Marcus Award for Research in Chemistry

Other Webpage: http://www.drbsinai.org/pc/bieker.html

Education and Training	Ph.D., Northwestern University
	Postdoctoral Training, Rockefeller University
	Postdoctoral Training, Washington University School of Medicine

Research

Specific Clinical/Research Interest:
Transcriptional regulation of red cell specific gene expression
Current Students: PhD: Joy Chen, Yvette Yien
Postdoctoral Fellows: Mirka Siatecka, Chunhong Gong, Shefali Soni, Gerson Rothschild
Research Personnel: Technical: Li Xue
Summary of Research Studies:
The molecular events that confer the ability to express lineage-specific genes upon an initially uncommitted, pluripotent hematopoietic stem cell remain a major question in cell differentiation. Use of an immortalized erythroid cell line as a means to isolate genes that may be important for erythroid function allowed us to identify a novel, erythroid-specific gene, which was named EKLF (erythroid Krppel-like factor). EKLF binds to and activates transcription from the CACCC element, one of a trio of localized promoter and enhancer DNA binding sites known to be crucial for transcription of globin and other erythroid cell-specific genes. Biological analyses reveal that murine EKLF is expressed in primitive erythroid cells by embryonic day 7.5, and in definitive erythroid cells within the hepatic primordia by embryonic day 9.5. However, its ability to preferentially activate an adult B-globin promoter over a linked fetal gamma-globin promoter led us to propose that EKLF may be an important factor for gamma- to B-globin gene switching. This was verified by studies showing that EKLF is absolutely required for normal red cell development, since its genetic disruption leads to death by embryonic day 14-16 (precisely the time of the switch in mice) due to a deficiency of mature, definitive red cells. EKLF-deficient mice exhibit drastically low-globin expression at the transcriptional level,! i.e., a severe B-thalassemia phenotype, and contain an altered chromatin structure at the B-globin locus. These molecular and biological studies have established that EKLF is an essential component required for globin switching and completion of the definitive erythroid program. Disorders of hemoglobin expression can lead to a variety of hemoglobinopathies, including sickle cell anemia and -thalassemia (Cooley's anemia). As a result, our examination of EKLF's mechanism of action has illuminated how it regulates the globin locus, and has provided us with a way to reconstruct EKLF so that it can potentially rectify one type of hemoglobin disorder.  Our discovery of EKLF has stimulated other investigators to search for analogous genes that can work in a similar fashion to regulate unique targets in other tissues.  EKLF is now the founding member (KLF1) of a family of seventeen proteins, some of which have been directly implicated in suppression of a specific subset of cancers.  We are vigorously continuing its study using a number of approaches, including biochemical and structure/function analyses of the EKLF protein, identification of its protein partners, and monitoring how EKLF expression itself is so precisely regulated during development. In addition, differentiating embryonic stem cells in culture are being used as one powerful approach to address these issues in diverse ways: to identify extracellular molecules and illuminate the intracellular pathway they use to play a directive role in erythroid gene expression; to functionally test the cis-acting sequences that control one of these downstream targets, EKLF; to establish gain-of-function studies that address lineage determination mechanisms during developing and differentiation; and to gain further insight into globin switching mechanisms and ide ntify ways to alter the normal pattern of expression. Our most recent studies show that EKLF becomes acetylated by virtue of its association with a subset of coactivators, leading to enhanced interaction with chromatin remodelers that leads to activated transcription. Surprisingly, EKLF can also associate with corepressors and decrease transcription at selected promoters, suggesting other activities beyond activation of the adult B-globin gene.  Finally, the BMP4/Smad pathway plays a critical role in transcriptional activation of EKLF in the erythroid cell, likely via a relatively small promoter region proximal to its initiation site.

Lohmann F, Bieker JJ. Activation of Eklf expression during hematopoiesis by Gata2 and Smad5 prior to erythroid commitment [highlighted as an In this Issue preview]. Development 2008; 135: 2071-2082.

Quadrini KJ, Gruzglin E, Bieker JJ. Non-random subcellular distribution of variant EKLF in erythroid cells. Experimental Cell Research 2008; 314: 1595-1604.

Manwani D, Bieker JJ. The Erythroblastic Island. Current Topics in Developmental Biology 2008; 82: 23-53.

Frontelo* MP, Manwani* D, Galdass M, Karsunky H, Lohmann F, Gallagher PG, Bieker JJ. Novel role for EKLF in megakaryocyte lineage commitment [*co-first authors] [highlighted as an Inside Blood preview]. Blood 2007; 110: 3871-3880.

Siatecka M, Xue L, Bieker JJ. Sumoylation of EKLF Promotes Transcriptional Repression and Is Involved in Inhibition of Megakaryopoiesis. Molecular and Cellular Biology 2007; 27: 8547-8560.

Manwani D, Galdass M, Bieker JJ. Altered Regulation of beta-like Globin Genes by a Redesigned Erythroid Transcription Factor. Experimental Hematology 2007; 35: 39-47.

Im H, Grass JA, Johnson KD, Kim S, Boyer ME, Imbalzano AN, Bieker JJ, Bresnick EH. Chromatin Domain Activation Via GATA-1 Utilization of a Small Subset of Dispersed GATA Motifs Within a Broad Chromosomal Region. Proc. Natl. Acad. Sci. 2005; 102: 17065-17070.

Chen X, Bieker JJ. Stage-specific Repression by the EKLF Transcriptional Activator. Molecular and Cellular Biology 2004; 24: 10416-10424.

Bieker JJ. Kruppel-like Factors: Three Fingers in Many Pies. J. Biol. Chem 2001; 276: 34355-34358.

Bieker JJ. EKLF and the development of the erythroid lineage. In: Ravid K, Licht J, editors. Transcription Factors: Normal and Malignant Development of Blood Cells (2000).