Cell-restricted transcriptional modulators play critical roles in the process of selective gene regulation during hematopoiesis. We have been investigating the molecular and biological function of Erythroid Kr?ppel-like Factor (EKLF;KLF1). EKLF is a cell-restricted transcription factor that is essential for the erythroid program. Analysis of EKLF target gene regulation has revealed distinct transactivation mechanisms, and its protein interaction partners suggest additional unexplored roles in transcript control. The experiments of Aim 1 are directed at exploring the parameters of EKLF interactions with proteins and promoter DNA essential for these regulatory steps that lead to successful transcription. Analysis of EKLF's role in establishing an open chromatin structure, coupled with its interaction with histone H3 and the selective increase of H3.3 at the ?-globin promoter, suggest these observations are linked. As a result, the experiments of Aim 2 will address EKLF's role in coordinating histone H3.3 incorporation into chromatin. Analysis of the anemia in the heterozygous Nan mutant mouse has exposed an unexplained mechanism of gene-selective EKLF activation that leads to unique protein deficiency. The experiments of Aim 3 are designed to illuminate the molecular mechanism of the genetic distortion that results from the presence of Nan-EKLF in the erythroid cell. These studies will be aided by the use of in vivo assays, EKLF rescue systems, and primary or minimally manipulated cells. Elucidating EKLF's role in regulatory phenomena will continue to illuminate novel aspects of erythroid biology and the essential mechanisms by which a cell-restricted transcription factor can exert varied yet highly controlled influences on genetic expression and epigenetics.

Public Health Relevance

This proposal focuses on a continuing investigation of EKLF structure/function and how its protein-protein and protein-DNA interactions facilitate its ability o coordinate erythroid cell-specific control of chromatin modulation and gene transcription.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1-VH-D (02))
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Bishop, Terry Rogers
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Icahn School of Medicine at Mount Sinai
Schools of Medicine
New York
United States
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Soni, Shefali; Pchelintsev, Nikolay; Adams, Peter D et al. (2014) Transcription factor EKLF (KLF1) recruitment of the histone chaperone HIRA is essential for ?-globin gene expression. Proc Natl Acad Sci U S A 111:13337-42
Varricchio, Lilian; Dell'Aversana, Carmela; Nebbioso, Angela et al. (2014) Identification of NuRSERY, a new functional HDAC complex composed by HDAC5, GATA1, EKLF and pERK present in human erythroid cells. Int J Biochem Cell Biol 50:112-22
Yien, Yvette Y; Bieker, James J (2013) EKLF/KLF1, a tissue-restricted integrator of transcriptional control, chromatin remodeling, and lineage determination. Mol Cell Biol 33:4-13
Yien, Yvette Y; Bieker, James J (2012) Functional interactions between erythroid Kr├╝ppel-like factor (EKLF/KLF1) and protein phosphatase PPM1B/PP2C?. J Biol Chem 287:15193-204
Mas, Caroline; Lussier-Price, Mathieu; Soni, Shefali et al. (2011) Structural and functional characterization of an atypical activation domain in erythroid Kruppel-like factor (EKLF). Proc Natl Acad Sci U S A 108:10484-9
Migliaccio, Anna Rita; Bieker, James J (2011) GATA2 finds its macrophage niche. Blood 118:2647-9
Siatecka, Miroslawa; Bieker, James J (2011) The multifunctional role of EKLF/KLF1 during erythropoiesis. Blood 118:2044-54
Siatecka, Miroslawa; Sahr, Kenneth E; Andersen, Sabra G et al. (2010) Severe anemia in the Nan mutant mouse caused by sequence-selective disruption of erythroid Kruppel-like factor. Proc Natl Acad Sci U S A 107:15151-6
Siatecka, Miroslawa; Lohmann, Felix; Bao, Sujin et al. (2010) EKLF directly activates the p21WAF1/CIP1 gene by proximal promoter and novel intronic regulatory regions during erythroid differentiation. Mol Cell Biol 30:2811-22
Perrine, Susan P; Mankidy, Rishikesh; Boosalis, Michael S et al. (2009) Erythroid Kruppel-like factor (EKLF) is recruited to the gamma-globin gene promoter as a co-activator and is required for gamma-globin gene induction by short-chain fatty acid derivatives. Eur J Haematol 82:466-76

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