Phosphorylation of LSD1 by PKCα Is Crucial for Circadian Rhythmicity and Phase Resetting

Abstract

The circadian clock is a self-sustaining oscillator that controls daily rhythms. For the proper circadian gene expression, dynamic changes in chromatin structure are important. Although chromatin modifiers have been shown to play a role in circadian gene expression, the in vivo role of circadian signal-modulated chromatin modifiers at an organism level remains to be elucidated. Here, we provide evidence that the lysine-specific demethylase 1 (LSD1) is phosphorylated by protein kinase Cα (PKCα) in a circadian manner and the phosphorylated LSD1 forms a complex with CLOCK:BMAL1 to facilitate E-box-mediated transcriptional activation. Knockin mice bearing phosphorylation-defective Lsd1(SA/SA) alleles exhibited altered circadian rhythms in locomotor behavior with attenuation of rhythmic expression of core clock genes and impaired phase resetting of circadian clock. These data demonstrate that LSD1 is a key component of the molecular circadian oscillator, which plays a pivotal role in rhythmicity and phase resetting of the circadian clock.

Sumoylation controls CLOCK-BMAL1-mediated clock resetting via CBP recruitment in nuclear transcriptional foci

“…In fact, phosphorylation in particular is regarded as the most active post-translational signal involved in eliciting circadian clock rhythmicity in response to entraining stimuli [12,30].…”

Chromatin landscape and circadian dynamics: Spatial and temporal organization of clock transcription

“…Similarly, the repressive epigenetic mark H3K27me3 is clockcontrolled at the Per1 promoter through a mechanism involving the methyltransferase EZH2 (37). Moreover, the histone demethylase JARID1a inhibits histone deacetylase 1 (HDAC1) and enhances CLOCK:BMAL1-mediated transcription (38), and so does the flavin adenine dinucleotide (FAD)-dependent demethylase LSD1 in a mechanism dependent on its circadian phosphorylation by the protein kinase PKCα (39).…”

Metabolic Signaling to Chromatin

“…Intriguingly, variable phosphorylation of LSD1 appears to control circadian gene expression by inducing direct interaction of LSD1 with the CLOCK:BMAL1 complex (see also Sec. 4.2;Nam et al 2014). Finally, the balance of methyl groups toward both histone and DNA methylation may be interdependent on reciprocal modifications, as highlighted by the requirement of LSD1 for the maintenance of global DNA methylation (Wang et al 2009).…”

“…Rather, Jarid1A is proposed to block HDAC1 to enhance CLOCK:BMAL1-mediated activation, although the precise role of HDAC1 in clock function is not fully established. A second lysine-specific demethylase, LSD1, associates with CLOCK:BMAL1 in a phosphorylation-dependent manner and participates in their recruitment (Nam et al 2014). As both Jarid1A and LSD1 target H3K4, it is still unclear whether they act on the circadian epigenome in concert or on distinct genomic subdomains or at different times of the circadian cycle.…”