Dicer promotes genome stability via the bromodomain transcriptional co-activator BRD4

Gutbrod, MJ, Roche, B, Steinberg, JI, Lakhani, AA, Chang, K, Schorn, AJ, Martienssen, RA (February 2022) Dicer promotes genome stability via the bromodomain transcriptional co-activator BRD4. Nature Communications, 13 (1). p. 1001. ISSN 2041-1723

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Abstract

RNA interference is required for post-transcriptional silencing, but also has additional roles in transcriptional silencing of centromeres and genome stability. However, these roles have been controversial in mammals. Strikingly, we found that Dicer-deficient embryonic stem cells have strong proliferation and chromosome segregation defects as well as increased transcription of centromeric satellite repeats, which triggers the interferon response. We conducted a CRISPR-Cas9 genetic screen to restore viability and identified transcriptional activators, histone H3K9 methyltransferases, and chromosome segregation factors as suppressors, resembling Dicer suppressors identified in independent screens in fission yeast. The strongest suppressors were mutations in the transcriptional co-activator Brd4, which reversed the strand-specific transcription of major satellite repeats suppressing the interferon response, and in the histone acetyltransferase Elp3. We show that identical mutations in the second bromodomain of Brd4 rescue Dicer-dependent silencing and chromosome segregation defects in both mammalian cells and fission yeast. This remarkable conservation demonstrates that RNA interference has an ancient role in transcriptional silencing and in particular of satellite repeats, which is essential for cell cycle progression and proper chromosome segregation. Our results have pharmacological implications for cancer and autoimmune diseases characterized by unregulated transcription of satellite repeats.

Item Type:	Paper
Subjects:	bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > BET bromodomain coactivator protein > Brd4 Investigative techniques and equipment > CRISPR-Cas9 bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > dicer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > dicer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > genomes
CSHL Authors:	Gutbrod, Michael Roche, Benjamin Steinberg, Joshua Chang, Kenneth Schorn, Andrea Martienssen, Robert A. Lakhani, Asad Aziz
Communities:	CSHL labs > Chang lab CSHL labs > Martienssen lab CSHL labs > Schorn lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	22 February 2022
Date Deposited:	25 Feb 2022 18:50
Last Modified:	21 Mar 2022 14:19
PMCID:	PMC8863982
URI:	https://repository.cshl.edu/id/eprint/40529

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