Histone methyltransferase MLL3 contributes to genome-scale circadian transcription

Abstract

Daily cyclical expression of thousands of genes in tissues such as the liver is orchestrated by the molecular circadian clock, the disruption of which is implicated in metabolic disorders and cancer. Although we understand much about the circadian transcription factors that can switch gene expression on and off, it is still unclear how global changes in rhythmic transcription are controlled at the genomic level. Here, we demonstrate circadian modification of an activating histone mark at a significant proportion of gene loci that undergo daily transcription, implicating widespread epigenetic modification as a key node regulated by the clockwork. Furthermore, we identify the histone-remodelling enzyme mixed lineage leukemia (MLL)3 as a clock-controlled factor that is able to directly and indirectly modulate over a hundred epigenetically targeted circadian "output" genes in the liver. Importantly, catalytic inactivation of the histone methyltransferase activity of MLL3 also severely compromises the oscillation of "core" clock gene promoters, including Bmal1, mCry1, mPer2, and Rev-erbα, suggesting that rhythmic histone methylation is vital for robust transcriptional oscillator function. This highlights a pathway by which the clockwork exerts genome-wide control over transcription, which is critical for sustaining temporal programming of tissue physiology.epigenomics | systems biology T he molecular clockwork consists of well-characterized transcriptional components [including Clock, brain and muscle aryl hydrocarbon receptor nuclear translocator (ARNT)-like (Bmal) 1, Period, Cryptochrome, and nuclear receptor subfamily 1, group D, member 1/2 (Rev-erbα/β)], as well as more recently discovered posttranscriptional processes (1-4). Despite progress in understanding the make up of circadian transcriptomes and proteomes, which are thought to encompass more than 10% of known genes and proteins, the systems-level mechanisms driving their rhythmic abundance have remained unclear (5-7).Based on observations that a few specific clock-regulated genomic loci undergo changes in chromatin state over the circadian cycle (8-10), we hypothesized that this might be more generally applicable at other clock-controlled gene (CCG) loci. We investigated this by performing chromatin immunoprecipitation (ChiP) and high-throughput sequencing (ChIP-seq) on mouse liver tissue collected over the circadian cycle to delineate global changes in the epigenome over a 24-h time frame. Results and DiscussionWe focused mostly on the activation mark, H3K4me3 (histone H3 trimethylated at lysine 4) (11), which exhibited a clear circadian profile at thousands of genomic loci ( Fig. 1 A and B). This was in stark contrast to H3K9me3 (histone H3 trimethylated at lysine 9), which is associated with transcriptional inhibition (12), and unmodified histone H3, the binding of which changed only at relatively few loci (Fig. 1A). Therefore, genomic scale changes in the evolutionarily conserved activation mark H3K4me3 are regulated in a circadian manner at thousands ...

Mistimed sleep disrupts circadian regulation of the human transcriptome

“…Although the central circadian clock, as indexed by melatonin, remained largely unaffected, the temporal organization of expression of clock genes considered to be central to circadian rhythm generation was affected in the blood transcriptome, with only NR1D2 and CSNK1E remaining rhythmic when sleeping out of phase. Histone modification, and the control of transcription and translation (4)(5)(6)(7)(8)(9), is also considered central to circadian organization of the transcriptome and the time courses of transcripts associated with all of these processes were affected in this study (Fig. 3).…”

Vertebrate-like CRYPTOCHROME 2 from monarch regulates circadian transcription via independent repression of CLOCK and BMAL1 activity

“…Alternatively, given that our results were obtained in a cellular context rather than in vitro chemical shift perturbation studies (14), it is possible that additional coactivators bound to dpCLK: dpBMAL1 also compete with dpCRY2 for binding. Histonemodifying enzyme orthologs of MLL and JARID1a, which are recruited at CLOCK:BMAL1, or proteins that recruit the transcriptional machinery are all potential candidates (34)(35)(36)(37).…”

Systems Chronobiology: Global Analysis of Gene Regulation in a 24-Hour Periodic World

“…Indeed, many studies reported histone modifiers and remodelers as part of the clockwork machinery, such as the histone acetyltransferase (HAT) p300 (Etchegaray et al 2003), the histone methyltransferases MLL1 (Katada and Sassone-Corsi 2010), and MLL3 (Valekunja et al 2013). The CLOCK protein itself was reported to show HAT activity (Doi et al 2006).…”