Temporal resolution of gene derepression and proteome changes upon PROTAC-mediated degra-dation of BCL11A protein in erythroid cells
- Mehta, S.
- Buyanbat, A.
- Kai, Y.
- Karayel, O.
- Goldman, S.
- Seruggia, D.
- Zhang, K.
- Fujiwara, Y.
- Donovan, K.
- Zhu, Q.
- Yang, H.
- Nabet, B.
- Gray, N.
- Mann, M.
- Fischer, E.
- Adelman, K.
- Orkin, S.
DOIAbstract
Reactivation of fetal hemoglobin expression by the downregulation of BCL11A is a promising treatment for b-hemoglobinopathies. A detailed understanding of BCL11A-mediated repression of g-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 h. Robus...
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