Clock-dependent chromatin topology modulates circadian transcription and behavior

Abstract

The circadian clock in animals orchestrates widespread oscillatory gene expression programs, which underlie 24-h rhythms in behavior and physiology. Several studies have shown the possible roles of transcription factors and chromatin marks in controlling cyclic gene expression. However, how daily active enhancers modulate rhythmic gene transcription in mammalian tissues is not known. Using circular chromosome conformation capture (4C) combined with sequencing (4C-seq), we discovered oscillatory promoter-enhancer interactions along the 24-h cycle in the mouse liver and kidney. Rhythms in chromatin interactions were abolished in arrhythmic knockout mice. Deleting a contacted intronic enhancer element in the () gene was sufficient to compromise the rhythmic chromatin contacts in tissues. Moreover, the deletion reduced the daily dynamics of transcriptional burst frequency and, remarkably, shortened the circadian period of locomotor activity rhythms. Our results establish oscillating and clock-controlled promoter-enhancer looping as a regulatory layer underlying circadian transcription and behavior.

Rhythmic chromatin interactions with lamin B1 reflect stochasticity in variable lamina-associated domains during the circadian cycle

“…Oscillations in chromatin conformation mediated by rhythmic chromosomal interactions contribute to the regulation of circadian gene expression (Aguilar-Arnal et al 2013;Xu et al 2016;Kim et al 2018;Mermet et al 2018;. Here, we applied MetaCycle, a tool designed to identify periodic transcript oscillations (Wu et al 2016), to identify periodic changes in genome coverage by LMNB1.…”

“…These oscillatory cistromes and chromatin modifications raise the possibility that other chromatin-linked processes also show rhythmic patterns. Indeed, periodic short-and long-range promoter-enhancer interactions regulate and connect circadian liver gene expression networks (Aguilar-Arnal et al 2013;Xu et al 2016;Kim et al 2018;Mermet et al 2018). Thus, circadian-dependent changes in chromatin topology contribute to shaping the nuclear landscape .…”

Joint reconstruction of cis-regulatory interaction networks across multiple tissues using single-cell chromatin accessibility data

“…The transcript of Gys2 is rhythmically expressed in liver during a day. In contrast, the accumulation of Gys2 mRNA is constant and low in kidney (59). We compared the Gys2 promoter related interactions in all 13 tissues and found a liver-specific contact with a region of 12kb to 21kb downstream from Gys2 TSS ( Figure 6A).…”

The importance of being rhythmic: Living in harmony with your body clocks

“…20 Posttranslational modifications, including phosphorylation, acetylation, glycosylation and sumoylation, play a critical role in regulating the kinetics of this core clock loop. 28,29 REV-ERBα may oppose these interactions between enhancers and promoters by recruitment of the NCoR-HDAC3 corepressor complex and through histone deacetylation ( Figure 1C), indicating that the rhythmic modulation of chromatin controls circadian gene transcription. 28,29 REV-ERBα may oppose these interactions between enhancers and promoters by recruitment of the NCoR-HDAC3 corepressor complex and through histone deacetylation ( Figure 1C), indicating that the rhythmic modulation of chromatin controls circadian gene transcription.…”

“…2,[21][22][23][24][25][26][27] In addition, it was recently proposed that a rhythmic modulation of chromatin state controls interactions between enhancers and promoters, and that disruption of these three-dimensional interactions affects circadian phase. 28,29 REV-ERBα may oppose these interactions between enhancers and promoters by recruitment of the NCoR-HDAC3 corepressor complex and through histone deacetylation ( Figure 1C), indicating that the rhythmic modulation of chromatin controls circadian gene transcription. 30 Noteworthy, such rhythmic enhancer-promoter interactions are tissue specific.…”