The Catalytic and Non-catalytic Functions of the Brahma Chromatin-Remodeling Protein Collaborate to Fine-Tune Circadian Transcription in Drosophila

Autor: Joanna C. Chiu, Anna J. Lei, Isaac Edery, Rosanna S. Kwok, Ying H. Li
Přispěvatelé: Emery, Patrick
Jazyk: angličtina
Rok vydání: 2015
Předmět:
Zdroj: PLoS Genetics, Vol 11, Iss 7, p e1005307 (2015)
PLoS Genetics
PLoS genetics, vol 11, iss 7
ISSN: 1553-7404
1553-7390
Popis: Daily rhythms in gene expression play a critical role in the progression of circadian clocks, and are under regulation by transcription factor binding, histone modifications, RNA polymerase II (RNAPII) recruitment and elongation, and post-transcriptional mechanisms. Although previous studies have shown that clock-controlled genes exhibit rhythmic chromatin modifications, less is known about the functions performed by chromatin remodelers in animal clockwork. Here we have identified the Brahma (Brm) complex as a regulator of the Drosophila clock. In Drosophila, CLOCK (CLK) is the master transcriptional activator driving cyclical gene expression by participating in an auto-inhibitory feedback loop that involves stimulating the expression of the main negative regulators, period (per) and timeless (tim). BRM functions catalytically to increase nucleosome density at the promoters of per and tim, creating an overall restrictive chromatin landscape to limit transcriptional output during the active phase of cycling gene expression. In addition, the non-catalytic function of BRM regulates the level and binding of CLK to target promoters and maintains transient RNAPII stalling at the per promoter, likely by recruiting repressive and pausing factors. By disentangling its catalytic versus non-catalytic functions at the promoters of CLK target genes, we uncovered a multi-leveled mechanism in which BRM fine-tunes circadian transcription.
Author Summary The circadian clock is an endogenous timing system that enables organisms to anticipate daily changes in their external environment and temporally coordinate key biological functions that are important to their survival. Central to Drosophila clockwork is a key transcription factor CLOCK (CLK). CLK activates expression of target genes only during specific parts of the day, thereby orchestrating rhythmic expression of hundreds of clock-controlled genes, which consequently manifest into daily rhythms in physiology and behavior. In this study, we demonstrated that the Brahma (Brm) chromatin-remodeling protein interacts with CLK and fine-tune the levels of CLK-dependent transcription to maintain the robustness of the circadian clock. Specifically, we uncovered two distinct but collaborative functions of Brm. Brm possesses a non-catalytic function that negatively regulates the binding of CLK to target genes and limits transcriptional output, likely by recruiting repressive protein complexes. Catalytically, Brm functions by condensing the chromatin at CLK target genes, specifically when transcription is active. This serves to precisely control the level of repressive factors likely recruited by Brm as well as other transcriptional regulators. By disentangling these two roles of Brm, our study uncovered a multi-layered mechanism in which a chromatin remodeler regulates the circadian clock.
Databáze: OpenAIRE
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