Abstract
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.
Highlights
Circadian clocks are endogenous timekeeping mechanisms that drive rhythms in physiology and behavior with an approximately 24-hour period, allowing organisms from all kingdoms of life to anticipate and operate through predictable daily environmental changes
We focused on the interaction between BRM and CLK, rather than BRM and CYC, as CLK has been shown to be the limiting factor in CLK-CYC dependent transcriptional activation [42] and ectopic clocks can be generated by misexpressing CLK alone, indicating its central role in circadian gene activation [43]
Prior work has shown that exogenous expression of CLK in Schneider 2 (S2) cells can interact with endogenous CYC to activate circadian promoters and is responsive to the inhibitory effects of PER-TIM, indicating that the core CLK-dependent transcriptional machinery can operate in S2 cells [44]
Summary
Circadian clocks are endogenous timekeeping mechanisms that drive rhythms in physiology and behavior with an approximately 24-hour period, allowing organisms from all kingdoms of life to anticipate and operate through predictable daily environmental changes. Much progress has been made in understanding the architecture of the molecular oscillators regulating these cell-autonomous clocks in different organisms, and the mechanisms in which the core oscillators communicate temporal information via circadian transcription that drives many overt physiological rhythms [1,2,3]. CLK and CYC form heterodimers and bind to E-box regulatory elements on genes encoding the main negative factors PERIOD (PER) and TIMELESS (TIM) that inhibit the transcriptional activity of CLK-CYC, and their own transcription, closing off one autoregulatory feedback circuit. VRILLE (VRI), a basic leucine zipper (bZIP) transcription factor, binds to D-box ( called V/P box) elements on the Clk promoter to repress Clk activation by PAR Domain Protein 1ε (PDP1ε)
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