- PROFESSOR Developmental and Regenerative Biology
Ph.D., Northwestern University
Washington University School of Medicine
For more information, please visit the Bieker Laboratory website.
Faculty Council Award for Academic Excellence
2012 Keynote Speaker
FASEB Conference on the Biology and Pathobiology of Krüppel-like Factors, Snowmass Village, CO
Tohoku Medical Society Testimonial
Tohoku University, Sendai, Japan
Weatherall Institute of Molecular Medicine, Oxford University, Oxford UK
1994 - 1999
Scholar of the Leukemia Society of America
Leopold Marcus Award for Research in Chemistry
Transcriptional regulation of red cell specific gene expression
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 Kruppel-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 ß-globin promoter over a linked fetal gamma-globin promoter led us to propose that EKLF may be an important factor for gamma- to ß-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 ß-thalassemia phenotype, and contain an altered chromatin structure at the ß-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 identify ways to alter the normal pattern of expression.
Our 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 ß-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.
For more information, please visit the Bieker Laboratory website.
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).
Bieker JJ. Krüppel-like factors: three fingers in many pies. The Journal of biological chemistry 2001 Sep; 276(37): 34355-58.
Siatecka M, Xue L, Bieker JJ. Sumoylation of EKLF promotes transcriptional repression and is involved in inhibition of megakaryopoiesis. Molecular and cellular biology 2007 Dec; 27(24): 8547-60.
Frontelo P, 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 Dec; 110(12): 3871-80.
Manwani D, Bieker JJ. The erythroblastic island. Current topics in developmental biology 2008; 82: 23-53.
Quadrini KJ, Gruzglin E, Bieker JJ. Non-random subcellular distribution of variant EKLF in erythroid cells. Experimental cell research 2008 Apr; 314(7): 1595-1604.
Lohmann F, Bieker JJ. Activation of Eklf expression during hematopoiesis by Gata2 and Smad5 prior to erythroid commitment. Development (Cambridge, England) 2008 Jun; 135(12): 2071-2082.
Sengupta T, Chen K, Milot E, Bieker JJ. Acetylation of EKLF is essential for epigenetic modification and transcriptional activation of the beta-globin locus. Molecular and cellular biology 2008 Oct; 28(20): 6160-70.
Sengupta T, Cohet N, Morlé F, Bieker JJ. Distinct modes of gene regulation by a cell-specific transcriptional activator. Proceedings of the National Academy of Sciences of the United States of America 2009 Mar; 106(11): 4213-18.
Siatecka M, Lohmann F, Bao S, Bieker JJ. EKLF directly activates the p21WAF1/CIP1 gene by proximal promoter and novel intronic regulatory regions during erythroid differentiation. Molecular and cellular biology 2010 Jun; 30(11): 2811-22.
Siatecka M, Sahr KE, Andersen SG, Mezei M, Bieker JJ, Peters LL. Severe anemia in the Nan mutant mouse caused by sequence-selective disruption of erythroid Kruppel-like factor. Proceedings of the National Academy of Sciences of the United States of America 2010 Aug; 107(34): 15151-56.
Bieker JJ. Putting a finger on the switch. Nature genetics 2010 Sep; 42(9): 733-734.
Chen J, Peterson KR, Iancu-Rubin C, Bieker JJ. Design of embedded chimeric peptide nucleic acids that efficiently enter and accurately reactivate gene expression in vivo. Proceedings of the National Academy of Sciences of the United States of America 2010 Sep; 107(39): 16846-51.
Siatecka M, Bieker JJ. The multifunctional role of EKLF/KLF1 during erythropoiesis. Blood 2011 Aug; 118(8): 2044-2054.
Yien YY, Bieker JJ. EKLF/KLF1, a tissue-restricted integrator of transcriptional control, chromatin remodeling, and lineage determination. Molecular and cellular biology 2013 Jan; 33(1): 4-13.
Xue L, Galdass M, Gnanapragasam MN, Manwani D, Bieker JJ. Extrinsic and intrinsic control by EKLF (KLF1) within a specialized erythroid niche. Development (Cambridge, England) 2014 Jun; 141(11): 2245-54.
Soni S, Pchelintsev N, Adams PD, Bieker JJ. Transcription factor EKLF (KLF1) recruitment of the histone chaperone HIRA is essential for β-globin gene expression. Proceedings of the National Academy of Sciences of the United States of America 2014 Sep; 111(37): 13337-42.
Yien YY, Gnanapragasam MN, Gupta R, Rivella S, Bieker JJ. Alternative splicing of EKLF/KLF1 in murine primary erythroid tissues. Experimental hematology 2015 Jan; 43(1): 65-70.
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