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 invivo 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 Lsd1SA/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.
| Original language | English |
|---|---|
| Pages (from-to) | 791-805 |
| Number of pages | 15 |
| Journal | Molecular Cell |
| Volume | 53 |
| Issue number | 5 |
| DOIs | |
| State | Published - 6 Mar 2014 |
Bibliographical note
Funding Information:We thank Geoff Rosenfeld for providing Lsd1-knockout MEFs, and Choogon Lee and Eun Young Kim for critical reading of our manuscript. This work was supported by Creative Research Initiatives Program (Research Center for Chromatin Dynamics, 2009-0081563) to S.H.B., Korea Research Foundation (KRF) grant (2009-0088886) to S.C. and G.H.S., ICT and Future Planning Program (2012049932) to W.S., DFG Grants Schu688/9-1,10-2,11-2,12-1 and ERC-2012-AdGrant 322844-LSD1 to R.S., and SNU fellowship and brain Korea 21 to H.J.N. from the National Research Foundation (NRF) grant funded by the Korea government (MSIP).