In adult erythroid cells, the LCR normally loops to the active adult β-globin gene, while the fetal γ-globin genes are epigenetically silenced and excluded from looping. Experiments showed that re-targeting the LCR to the γ-globin genes by using an LDB1-based artificial protein or inhibiting the H3K9 methyltransferase G9a led to relief of γ-globin silencing, redistribution of LCR looping, and increased γ-globin expression to potentially therapeutic levels for β-hemoglobinopathies. These experiments suggest that modulating chromosome looping may be a therapeutic target for gene activation in diseases like sickle cell anemia and β-thalas
23. Summary
In adult erythroid cells, the LCR loops to the active adult -globin
gene and the fetal -globin genes are epigenetically silenced and
excluded from looping.
• Re-targeting the LCR to the β-globin genes in adult
cells by using an LDB1-based artificial protein
• Relief of γ-globin silencing and re-distribution of
LDB1 and LCR looping by inhibiting the G9a
Increase γ-globin expression to levels potentially therapeutic in
β-thalassemia and sickle cell disease cab be achieved by:
These experiments suggest that chromosome looping can be
considered a therapeutic target for gene activation in
β-hemoglobinopathies.
24. Acknowledgements
LCDB, NIDDK
• Ann Dean
• Jennifer Plank
• Soledad Ivaldi
• Jun Zhang
• Francine Katz
• Matthew Miller
Molecular Medicine Branch, NIDDK
• Jeffery Miller
• Colleen Byrnes
• Jaira F. de Vasconcellos
• Y. Terry Lee
• Megha Kaushal
Perelman School of Medicine, UPEN
• Gerd Blobel
• Wulan Deng
• Jeremy Rupon
Perelman School of Medicine, UPEN
• Stefano Rivella
• Laura Breda
• Irene Motta