Megakaryocytes and erythroid cells are thought to derive from a common progenitor during hematopoietic differentiation. Although a number of transcriptional regulators are important for this process, they do not explain the bipotential result. We have recently shown by gain- and loss-of-function studies, expression profiling, and molecular analyses that EKLF, a transcription factor whose role in erythroid gene regulation is well established, plays an unexpected directive role in erythroid and megakaryocyte lineage decisions prior to establishment of the red cell compartment. We thus propose to extend these studies by: (1) examining the effect of EKLF gain- and loss-of-function on the bipotential lineage decisions made by the megakaryocyte-erythroid progenitor;(2) determining the mechanism by which EKLF regulates megakaryocyte gene repression, following the predictions made by a cross-antagonistic intracellular model.

Public Health Relevance

These studies are relevant to delineating the intracellular mechanisms that regulate bipotential decisions during mammalian hematopoiesis and result in commitment to specific lineages. Consequently, they are relevant to clinical studies that depend on optimal expansion of progenitors for their use in medical applications. We have novel evidence that a particular transcription factor that we identified may play a critical role in progenitor/progeny decisions during a specific stage in hematopoiesis, and would like to determine how it accomplishes this.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK077822-05
Application #
8306853
Study Section
Hematopoiesis Study Section (HP)
Program Officer
Bishop, Terry Rogers
Project Start
2008-08-15
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$348,287
Indirect Cost
$140,016
Name
Icahn School of Medicine at Mount Sinai
Department
Biology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Xue, Li; Galdass, Mariann; Gnanapragasam, Merlin Nithya et al. (2014) Extrinsic and intrinsic control by EKLF (KLF1) within a specialized erythroid niche. Development 141:2245-54
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
Siatecka, Miroslawa; Bieker, James J (2011) The multifunctional role of EKLF/KLF1 during erythropoiesis. Blood 118:2044-54
Migliaccio, Anna Rita; Bieker, James J (2011) GATA2 finds its macrophage niche. Blood 118:2647-9
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