Abstract
Rhythmic activation and repression of the frequency (frq) gene are essential for normal function of the Neurospora circadian clock. WHITE COLLAR (WC) complex, the positive element of the Neurospora circadian system, is responsible for stimulation of frq transcription. We report that a C2H2 finger domain-containing protein IEC-1 and its associated chromatin remodeling complex INO80 play important roles in normal Neurospora circadian clock function. In iec-1KO strains, circadian rhythms are abolished, and the frq transcript levels are increased compared to that of the wild-type strain. Similar results are observed in mutant strains of the INO80 subunits. Furthermore, ChIP data show that recruitment of the INO80 complex to the frq promoter is IEC-1-dependent. WC-mediated transcription of frq contributes to the rhythmic binding of the INO80 complex at the frq promoter. As demonstrated by ChIP analysis, the INO80 complex is required for the re-establishment of the dense chromatin environment at the frq promoter. In addition, WC-independent frq transcription is present in ino80 mutants. Altogether, our data indicate that the INO80 complex suppresses frq transcription by re-assembling the suppressive mechanisms at the frq promoter after transcription of frq.
Highlights
From the filamentous fungus Neurospora crassa to animals, circadian oscillation is a conserved mechanism based on an auto-regulatory feedback loop composed of negative and positive elements [1,2,3,4,5,6]
We showed that a C2H2 finger domain-containing protein IEC-1 and its associated chromatin remodeling complex INO80 are required for transcriptional repression of the core clock gene frq in the Neurospora circadian system
While casein kinases regulate the stability of FRQ, the casein kinases are countered by multiple protein phosphatases, including PP1, PP2A and PP4 [22,23], The PP1 dephosphorylates and stabilizes FRQ protein while PP2a and PP4 activities influence frq transcription by dephosphorylating WHITE COLLAR (WC)-2
Summary
From the filamentous fungus Neurospora crassa to animals, circadian oscillation is a conserved mechanism based on an auto-regulatory feedback loop composed of negative and positive elements [1,2,3,4,5,6]. In Neurospora, the heterodimeric WHITE COLLAR (WC) complex, consisting of WC-1 and WC-2, acts as the positive element that binds to the frq promoter and activates frq transcription [7,8,9,10,11,12,13]. The negative elements FRQ and FRQ-interacting RNA helicase (FRH) form the FRQ/FRH complex and mediate the phosphorylation of WCs, which inhibits their WC complex activity and promotes the cytoplasmic localization of the WC complex [12,14,15,16]. Similar to CKI, many of the sites on FRQ protein can be phosphorylated by CKII, which promotes its degradation [12,21]. Epigenetic modifications were reported to regulate frq transcription in Neurospora. Antisense transcription was shown to inhibit sense expression by mediating chromatin modifications and premature termination of transcription in the frq locus [28]
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