Temporal resolution of gene derepression and proteome changes upon PROTAC-mediated degradation of BCL11A protein in erythroid cells.
Publication/Presentation Date
8-18-2022
Abstract
Reactivation of fetal hemoglobin expression by the downregulation of BCL11A is a promising treatment for β-hemoglobinopathies. A detailed understanding of BCL11A-mediated repression of γ-globin gene (HBG1/2) transcription is lacking, as studies to date used perturbations by shRNA or CRISPR-Cas9 gene editing. We leveraged the dTAG PROTAC degradation platform to acutely deplete BCL11A protein in erythroid cells and examined consequences by nascent transcriptomics, proteomics, chromatin accessibility, and histone profiling. Among 31 genes repressed by BCL11A, HBG1/2 and HBZ show the most abundant and progressive changes in transcription and chromatin accessibility upon BCL11A loss. Transcriptional changes at HBG1/2 were detected in/2 reactivation upon acute BCL11A depletion occurred without the loss of promoter 5-methylcytosine (5mC). Using targeted protein degradation, we establish a hierarchy of gene reactivation at BCL11A targets, in which nascent transcription is followed by increased chromatin accessibility, and both are uncoupled from promoter DNA methylation at the HBG1/2 loci.
Volume
29
Issue
8
First Page
1273
Last Page
1287
ISSN
2451-9448
Published In/Presented At
Mehta, S., Buyanbat, A., Kai, Y., Karayel, O., Goldman, S. R., Seruggia, D., Zhang, K., Fujiwara, Y., Donovan, K. A., Zhu, Q., Yang, H., Nabet, B., Gray, N. S., Mann, M., Fischer, E. S., Adelman, K., & Orkin, S. H. (2022). Temporal resolution of gene derepression and proteome changes upon PROTAC-mediated degradation of BCL11A protein in erythroid cells. Cell chemical biology, 29(8), 1273–1287.e8. https://doi.org/10.1016/j.chembiol.2022.06.007
Disciplines
Medicine and Health Sciences
PubMedID
35839780
Department(s)
Fellows and Residents
Document Type
Article