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Conformational changes in the negative arm of the circadian clock correlate with dynamic interactomes involved in post-transcriptional regulation.

ABSTRACT: Biology is tuned to the Earth's diurnal cycle by the circadian clock, a transcriptional/translational negative feedback loop that regulates physiology via transcriptional activation and other post-transcriptional mechanisms. We hypothesize that circadian post-transcriptional regulation might stem from conformational shifts in the intrinsically disordered proteins that comprise the negative arm of the feedback loop to coordinate variation in negative-arm-centered macromolecular complexes. This work demonstrates temporal conformational fluidity in the negative arm that correlates with 24-h variation in physiologically diverse macromolecular complex components in eukaryotic clock proteins. Short linear motifs on the negative-arm proteins that correspond with the interactors localized to disordered regions and known temporal phosphorylation sites suggesting changes in these macromolecular complexes could be due to conformational changes imparted by the temporal phospho-state. Interactors that oscillate in the macromolecular complexes over circadian time correlate with post-transcriptionally regulated proteins, highlighting how time-of-day variation in the negative-arm protein complexes may tune cellular physiology.

SUBMITTER: Pelham JF

PROVIDER: S-EPMC10562519 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Conformational changes in the negative arm of the circadian clock correlate with dynamic interactomes involved in post-transcriptional regulation.

Pelham Jacqueline F JF Mosier Alexander E AE Altshuler Samuel C SC Rhodes Morgan L ML Kirchhoff Christopher L CL Fall William B WB Mann Catherine C Baik Lisa S LS Chiu Joanna C JC Hurley Jennifer M JM

Cell reports 20230410 4

Biology is tuned to the Earth's diurnal cycle by the circadian clock, a transcriptional/translational negative feedback loop that regulates physiology via transcriptional activation and other post-transcriptional mechanisms. We hypothesize that circadian post-transcriptional regulation might stem from conformational shifts in the intrinsically disordered proteins that comprise the negative arm of the feedback loop to coordinate variation in negative-arm-centered macromolecular complexes. This wo ...[more]

PMID: 37043358

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Project description:Post-translational modifications (PTMs) on histones have been found to play diverse functions in regulating chromatin events and gene expression. The operation of circadian clocks heavily relies on finely tuned and timely expression of the proteins comprising core oscillators. However, most studies of PTMs' effects on circadian clocks have been conducted using static systems in which circadian clocks are rendered arrhythmic due to the essential role of PTMs on gene expression. In the Neurospora circadian system, the White Collar Complex (WCC), a heterodimeric transcription factor formed from White Collar-1 (WC-1) and White Collar-2 (WC-2), serves the function of the BMAL1/CLOCK heterodimer in mammals, driving expression of circadian negative arm component(s), a principal one in Neurospora encoded by the gene frequency (frq). FRQ interacts with FRH (FRQ-interacting helicase) and CK-1 forming a stable complex that represses its own expression by inhibiting WCC. In this study, a genetic screen identified a gene, designated as eaf-8, that encodes a novel conserved subunit of the NuA4 histone acetylation complex. Loss of eaf-8 reduces H4 acetylation and RNA polymerase (Pol) II occupancy at frq and other known circadian genes, and leads to a long circadian period, delayed phase, and defective overt circadian output at some temperatures. In addition to strongly associating with the NuA4 histone acetyltransferase complex, EAF-8 is also found complexed with the transcription elongation regulator BYE-1. Expression of eaf-8, bye-1, histone hH2Az, and several NuA4 subunits is controlled by the circadian clock, indicating that the molecular clock both regulates the basic chromatin status and is regulated by changes in chromatin. Taken together, our data identify a new type of the NuA4 complex including EAF-8 and BYE-1 which, along with conventional NuA4 subunits, is required for timely and dynamic frq expression and thereby a normal and persistent circadian rhythm.

Dataset Information

Conformational changes in the negative arm of the circadian clock correlate with dynamic interactomes involved in post-transcriptional regulation.

Publications

Conformational changes in the negative arm of the circadian clock correlate with dynamic interactomes involved in post-transcriptional regulation.

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