Transcription factor activity rhythms and tissue-specific chromatin interactions explain circadian gene expression across organs

Yeung, Jake; J, Mermet; Jouffe, Céline; Marquis, Julien; Charpagne, Aline; Gachon, Frédéric; Naef, Félix

doi:10.1101/207787

Cited by 8 publications

(10 citation statements)

References 70 publications

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“…30 Noteworthy, such rhythmic enhancer-promoter interactions are tissue specific. 31,32 The resulting core clock autoregulatory feedback loop lasts about 24 hours, and its molecular composition is identical for central and peripheral oscillators ( Figure 1C). In fact, circadian oscillators function in a cell-autonomous and self-sustained manner in nearly all cells of the body, thereby establishing a complex network that is regulated at the cellular, organ and organismal levels.…”

Section: Of 14 |mentioning

confidence: 99%

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

Dibner

2019

Acta Physiologica

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OSCILLATORSThe time-keeping system, dubbed "circadian" from Latin circa diem (about a day), allows light-sensitive beings, including humans, to coordinate their physiology and behaviour to the daily changes in geophysical time (Figure 1). The mammalian network of body clocks is organized in a strictly hierarchical manner. A master oscillator, residing in the paired suprachiasmatic nuclei (SCN) of the hypothalamus ( Figure 1A), synchronizes a myriad of peripheral oscillators situated in each organ ( Figure 1B) on a daily basis. In turn, rhythmicity in the SCN is entrained by external timecues or Zeitgebers (German term for time givers). Daily changes in light intensity, detected by classical photoreceptors and intrinsically light-sensitive retinal ganglion cells expressing AbstractCircadian rhythms have developed in all light-sensitive organisms, including humans, as a fundamental anticipatory mechanism that enables proactive adaptation to environmental changes. The circadian system is organized in a highly hierarchical manner, with clocks operative in most cells of the body ensuring the temporal coordination of physiological processes. Circadian misalignment, stemming from modern life style, draws increasing attention due to its tight association with the development of metabolic, cardiovascular, inflammatory and mental diseases as well as cancer.This review highlights recent findings emphasizing the role of the circadian system in the temporal orchestration of physiology, with a particular focus on implications of circadian misalignment in human pathologies. K E Y W O R D Scircadian clock, circadian misalignment, continuous recording of circadian bioluminescence, human physiology How to cite this article: Dibner C. The importance of being rhythmic: Living in harmony with your body clocks. Acta Physiol. 2020;228:e13281. https ://doi.

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Section: Of 14 |mentioning

confidence: 99%

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

Dibner

2019

Acta Physiologica

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“…The widespread lack of correspondence between promoter and transcription dynamics hint at a model where transcription happens from an accessible promoter under the regulation of a distal element mediated by transcription factors (TF). A TF motif activity analysis (40,41) taking advantage of our paired RNA-seq and ATACseq data predicted the SRF (serum response factor) motif to be by far the most statistically significant candidate in the entire temporal gene expression dataset (i.e.…”

Section: Gene Expression Correlates With Chromatin Accessibility At Dmentioning

confidence: 99%

“…binding site predictions and the temporal mRNA abundance, using a penalized regression model (MARA) as previously described (40,41) and using an L 2 norm penalty for regularization (ridge regression). Prior to the regression, we meancentered the input matrix of temporal mRNA abundances, standardized the columns of the site count matrix (each motif across genes), and excluded genes that were assigned to the flat model (F).…”

Section: Prediction Of Transcription Factor (Tf) Binding Site (Tfbs) mentioning

confidence: 99%

Simple and complex interactions between sleep-wake driven and circadian processes shape daily genome regulatory dynamics in the mouse

Yeung

et al. 2019

Preprint

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The timing and duration of sleep results from the interaction between a sleepwake driven, or homeostatic, process (S) and a circadian process (C), and involves changes in gene expression and genomic regulation. Unraveling the respective contributions of S and C, and their interaction, to transcriptional and epigenomic regulatory dynamics requires sampling over time under unperturbed conditions and conditions of perturbed sleep. Here, we profiled mRNA expression and chromatin accessibility in the cerebral cortex of mice over a three-day period, including a 6-hour sleep deprivation (SD) on day two. Mathematical modeling established that a large proportion of rhythmic genes are actually governed by Process S with varying degrees of interaction with Process C, sometimes working in opposition. Remarkably, SD causes long-term effects on gene expression dynamics, outlasting phenotypic recovery, most strikingly illustrated by a dampening of the oscillation of most core clock genes, including Bmal1, suggesting that enforced wakefulness directly impacts the molecular clock machinery. Chromatin accessibility proved highly plastic and dynamically affected by SD. Distal regions, rather than promoters, display dynamics corresponding to gene transcription, implying that changes in mRNA expression result from constantly accessible promoters under the influence of distal enhancers or repressors. Srf was predicted as a transcriptional regulator driving immediate response, suggesting that Srf activity mirrors the build-up and release of sleep pressure. Our results demonstrate that a single, short SD has long-term aftereffects at the genomic regulatory level. Such effects might accumulate with repeated sleep restrictions, thereby contributing to their adverse health effects. Significance statementWhen and how long we sleep is determined by the time-of-day and how long we have been awake, which are tracked molecularly by a circadian and a sleep-wake driven process, respectively. We measured the long-term consequences of a short-term sleep deprivation (SD) on gene expression and regulation in the mouse brain, and used mathematical models to determine the relative contributions of the circadian and sleep-wake driven processes. We find that many genes, including most of the genes that constitute the molecular circadian clock, are perturbed by SD long after the mice ceased showing behavioral signs of sleep loss. Our results have implications for human health, given the high prevalence of insufficient and poor quality sleep in our contemporary society. 4

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“…During macrophage differentiation, extensive changes are observed to gene expression, the enhancer landscape, and chromatin interactions linking them [73]; however IMR90 cells show extensive changes in enhancer activity and gene expression in response to TNFa treatment yet virtually no differences in DNA looping are observed [74]. Studies on circadian effects in mouse liver have shown selective interactions between circadian oscillating genes and oscillating enhancers, but did not directly show a related rhythmicity of 3D interactions (either no observed differences [75], or the comparison was not made [76]). Based on the sensitivity of distally-regulated genes to cohesin depletion, we predict that looping from distal sex-biased enhancers would be more responsive to alterations of the plasma growth hormone pattern.…”

Section: Matthews and Waxman -Pagementioning

confidence: 99%

Impact of 3-dimensional genome organization, guided by cohesin and CTCF looping, on sex-biased chromatin interactions and gene expression in mouse liver

Matthews

Waxman

2019

Preprint

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More than 1,000 genes are differentially expressed between male and female mouse liver. However, ~90% of 4,000 sex-differential open chromatin regions harboring regulatory elements implicated in liver sex bias are distal enhancers. To elucidate the role of 3D nuclear organization and address the challenge of linking distal regulatory regions to sex-biased gene targets, we performed ChIP-seq for CTCF and cohesin, known mediators of 3D nuclear organization, and identified ~1,000 binding sites showing significant differential occupancy by these factors in male and female mouse liver. Distal genomic regions showing sex-differential CTCF and/or cohesin binding were evaluated as potential factors in sex-dependent looping controlling sex-biased proximal effects on gene expression. Results were integrated with a study of cohesin depletion in mouse liver to evaluate the impact of cohesin loss on the expression of putative gene targets. Further, circularized chromosome conformation capture with sequencing (4C-seq) was used to discover striking sex-differences in 3D looping, linking distal sex-biased enhancers to proximal sex-biased gene expression for both male-biased (C9, Nudt7, Nox4) and female-biased genes (A1bg, Sult3a2). Our findings also illustrate the importance of a nested intra-TAD loop for insulation of sex-specific enhancer-promoter contacts for Nox4. These studies reveal how chromatin interactions and 3-dimensional genome organization guided both directly and indirectly by CTCF and cohesin looping contribute to liver sex bias. Matthews and Waxman -page 2Here we took a multi-pronged approach to characterize the role of architectural proteins and 3D genome organization in the maintenance of mouse liver sex differences. First, we performed ChIP-seq for CTCF and cohesin using chromatin from male and female mouse livers and show that the majority of sex-biased binding of these factors occurs at distal intergenic sites. Only a minority of these binding sites are cis to sex-biased genes, which may cis-proximal (within 20 kb) or more cis-distal (> 20 kb, but within the same TAD) to a sex biased gene. Specific examples of cis proximal and distal CTCF/cohesin binding are shown for male-biased genes (proximal: Cml5, Nat8; distal, C8a, C8b) and female-biased genes (proximal: Fam84b; distal: Slc22a29). Using a publicly available cohesin depletion dataset for male liver [21], we find that distally-regulated malebiased genes are considerably more sensitive to cohesin loss than those with proximal sex bias. To directly measure differences in chromatin interactions, we use 4C-seq for six viewpoints at or nearby five genes showing liver sex bias in expression, ranging from 2-fold to 700-fold (female-biased: A1bg and Sult3a1; malebiased: C9, Nudt7, and Nox4). Finally, we show the importance of a nested intra-TAD loop for insulation of enhancer-promoter contacts for Nox4. Overall, we describe how 3-dimensional genome organization contributes to liver sex bias in both direct and indirect ways. RESULTS Global differences in CTCF/Coh...

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Transcription factor activity rhythms and tissue-specific chromatin interactions explain circadian gene expression across organs

Cited by 8 publications

References 70 publications

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

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

Simple and complex interactions between sleep-wake driven and circadian processes shape daily genome regulatory dynamics in the mouse

Impact of 3-dimensional genome organization, guided by cohesin and CTCF looping, on sex-biased chromatin interactions and gene expression in mouse liver

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