The switch from fetal to adult hemoglobin in humans is regulated by transcription factors that enhance or inhibit interactions of the gamma- or beta-globin gene with the powerful Locus Control Region. We recently demonstrated that knockdowns of KLF1 in human and mouse adult erythroid progenitors reduce BCL11A levels and increase human gamma- to beta-globin gene expression ratios. These results suggest that KLF1 controls globin gene switching by directly activating beta-globin and indirectly repressing gamma-globin gene expression. In addition, we have recently isolated a protein (FOKLF1;Friend of KLF1) that complexes with KLF1 and activates beta-globin gene expression. Interestingly, knockdowns of FOKLF1 dramatically increase human gamma- to beta-globin gene ratios. These results suggest that controlled knockdown or pharmacological inhibition of FOKLF1 in adult erythroid progenitors may provide a method for activating fetal hemoglobin in patients with beta-thalassemia and sickle cell disease.
The Specific Aims of our proposal are as follows: (1) To define FOKLF1 domains essential for gamma- to beta-globin genes witching (2) To define FOKLF1 and KLF1 gene regulatory elements responsible for the up-regulation of these genes during development. (3) To identify HPFH (Hereditary Persistence of Fetal Hemoglobin) individuals who have mutations/variations in the FOKLF1 gene.

Public Health Relevance

We have recently isolated a protein (FOKLF1;Friend of KLF1) that interacts with KLF1 in adult definitive progenitors and activates beta-globin gene expression. Interestingly, knockdowns of FOKLF1 dramatically increase human gamma- to beta-globin gene ratios. These results suggest that controlled knockdown or pharmacological inhibition of FOKLF1 in adult erythroid progenitors may provide a method for activating fetal hemoglobin in individuals with beta-thalassemia and sickle cell disease.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01DK073391-07
Application #
8699756
Study Section
Molecular and Cellular Hematology (MCH)
Program Officer
Bishop, Terry Rogers
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Zhang, Zhuo; Jones, Amanda; Sun, Chiao-Wang et al. (2011) PRC2 complexes with JARID2, MTF2, and esPRC2p48 in ES cells to modulate ES cell pluripotency and somatic cell reprogramming. Stem Cells 29:229-40
Zhou, Dewang; Liu, Kaimao; Sun, Chiao-Wang et al. (2010) KLF1 regulates BCL11A expression and gamma- to beta-globin gene switching. Nat Genet 42:742-4