Temporal resolution of gene derepression and proteome changes upon PROTAC-mediated degradation of BCL11A protein in erythroid cells

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Temporal resolution of gene derepression and proteome changes upon PROTAC-mediated degradation of BCL11A protein in erythroid cells. / Mehta, Stuti; Buyanbat, Altantsetseg; Kai, Yan; Karayel, Ozge; Goldman, Seth Raphael; Seruggia, Davide; Zhang, Kevin; Fujiwara, Yuko; Donovan, Katherine A; Zhu, Qian; Yang, Huan; Nabet, Behnam; Gray, Nathanael S; Mann, Matthias; Fischer, Eric S; Adelman, Karen; Orkin, Stuart H.

In: Cell Chemical Biology, Vol. 29, No. 8, 18.08.2022, p. 1273-1287.e8.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Mehta, S, Buyanbat, A, Kai, Y, Karayel, O, Goldman, SR, Seruggia, D, Zhang, K, Fujiwara, Y, Donovan, KA, Zhu, Q, Yang, H, Nabet, B, Gray, NS, Mann, M, Fischer, ES, Adelman, K & Orkin, SH 2022, 'Temporal resolution of gene derepression and proteome changes upon PROTAC-mediated degradation of BCL11A protein in erythroid cells', Cell Chemical Biology, vol. 29, no. 8, pp. 1273-1287.e8. https://doi.org/10.1016/j.chembiol.2022.06.007

APA

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

Vancouver

Mehta S, Buyanbat A, Kai Y, Karayel O, Goldman SR, Seruggia D et al. Temporal resolution of gene derepression and proteome changes upon PROTAC-mediated degradation of BCL11A protein in erythroid cells. Cell Chemical Biology. 2022 Aug 18;29(8):1273-1287.e8. https://doi.org/10.1016/j.chembiol.2022.06.007

Author

Mehta, Stuti ; Buyanbat, Altantsetseg ; Kai, Yan ; Karayel, Ozge ; Goldman, Seth Raphael ; Seruggia, Davide ; Zhang, Kevin ; Fujiwara, Yuko ; Donovan, Katherine A ; Zhu, Qian ; Yang, Huan ; Nabet, Behnam ; Gray, Nathanael S ; Mann, Matthias ; Fischer, Eric S ; Adelman, Karen ; Orkin, Stuart H. / Temporal resolution of gene derepression and proteome changes upon PROTAC-mediated degradation of BCL11A protein in erythroid cells. In: Cell Chemical Biology. 2022 ; Vol. 29, No. 8. pp. 1273-1287.e8.

Bibtex

@article{4d0319cd6a404e7694d2acc21f5393f7,
title = "Temporal resolution of gene derepression and proteome changes upon PROTAC-mediated degradation of BCL11A protein in erythroid cells",
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 h. Robust HBG1/2 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.",
keywords = "Carrier Proteins/metabolism, Chromatin/genetics, Erythroid Cells/metabolism, Intercellular Signaling Peptides and Proteins, Nuclear Proteins/metabolism, Proteome/metabolism, Repressor Proteins/genetics, Transcription Factors/metabolism",
author = "Stuti Mehta and Altantsetseg Buyanbat and Yan Kai and Ozge Karayel and Goldman, {Seth Raphael} and Davide Seruggia and Kevin Zhang and Yuko Fujiwara and Donovan, {Katherine A} and Qian Zhu and Huan Yang and Behnam Nabet and Gray, {Nathanael S} and Matthias Mann and Fischer, {Eric S} and Karen Adelman and Orkin, {Stuart H}",
note = "Copyright {\textcopyright} 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.",
year = "2022",
month = aug,
day = "18",
doi = "10.1016/j.chembiol.2022.06.007",
language = "English",
volume = "29",
pages = "1273--1287.e8",
journal = "Chemistry and Biology",
issn = "2451-9448",
publisher = "Elsevier",
number = "8",

}

RIS

TY - JOUR

T1 - Temporal resolution of gene derepression and proteome changes upon PROTAC-mediated degradation of BCL11A protein in erythroid cells

AU - Mehta, Stuti

AU - Buyanbat, Altantsetseg

AU - Kai, Yan

AU - Karayel, Ozge

AU - Goldman, Seth Raphael

AU - Seruggia, Davide

AU - Zhang, Kevin

AU - Fujiwara, Yuko

AU - Donovan, Katherine A

AU - Zhu, Qian

AU - Yang, Huan

AU - Nabet, Behnam

AU - Gray, Nathanael S

AU - Mann, Matthias

AU - Fischer, Eric S

AU - Adelman, Karen

AU - Orkin, Stuart H

N1 - Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.

PY - 2022/8/18

Y1 - 2022/8/18

N2 - 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 h. Robust HBG1/2 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.

AB - 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 h. Robust HBG1/2 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.

KW - Carrier Proteins/metabolism

KW - Chromatin/genetics

KW - Erythroid Cells/metabolism

KW - Intercellular Signaling Peptides and Proteins

KW - Nuclear Proteins/metabolism

KW - Proteome/metabolism

KW - Repressor Proteins/genetics

KW - Transcription Factors/metabolism

U2 - 10.1016/j.chembiol.2022.06.007

DO - 10.1016/j.chembiol.2022.06.007

M3 - Journal article

C2 - 35839780

VL - 29

SP - 1273-1287.e8

JO - Chemistry and Biology

JF - Chemistry and Biology

SN - 2451-9448

IS - 8

ER -

ID: 321783064