Sickle cell disease is a globin disorder that causes anemia, pain episodes, and a litany of complications that lead to increased morbidity and mortality and affects approximately 100,000 people in the United States and many more world-wide, and the current treatments are not viable options for many patients. Manipulating the globin switching process is known to ameliorate the symptoms of sickle cell anemia and thalassemia, and identifying novel regulators of globin switching has the potential to help many of these patients. To identify additional critical regulatory pathways in this process, I screened over 3000 chemical compounds for induction of adult globin in zebrafish embryos. Two of the top hits were T3 and T4, thyroid hormone receptor ligands. Antisense morpholinos against THRB blocked the T3/T4 induction of adult globin in zebrafish embryos. To assess the occupancy of the THR signaling complexes, Chip-Seq analysis of THRB, RXR, and NCOA1 was performed in K562 cells, a human erythroid cell line. THRB, RXR, and NCOA1 significantly bound to the enhancers of the ?- and ?-globin loci, indicating that THR signaling directly regulates globin expression. Adult zebrafish blood treated ex vivo with a THR antagonist was found to induce fetal (and embryonic) globins and knocking-down THRB with shRNA in erythroid cells derived from human CD34+ HSCs induced fetal globin. Given this convergence on the thyroid signaling pathway, I hypothesize that thyroid hormone receptor regulates globin switching by binding to globin regulatory elements and modulating the activity of specific enhancers.

Public Health Relevance

Sickle cell disease is a blood disorder that causes anemia, pain episodes, and a litany of complications that lead to increased morbidity and mortality and affects approximately 100,000 people in the United States and many more world-wide. Manipulating the globin switching process is known to ameliorate the symptoms of sickle cell disease, and I have identified a novel regulatory pathway, thyroid hormone signaling, involved in this process. I plan to identify how the thyroid hormone signaling affects globin switching, and I will test putative small molecules that may help many of these patients.

Agency
National Institute of Health (NIH)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32HL123251-01
Application #
8717344
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Werner, Ellen
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115