Pairing of segmentation clock genes drives robust pattern formation

Zinani, Oriana Q. H.; Keseroğlu, Kemal; Ay, Ahmet; Özbudak, Ertuğrul M.

doi:10.1038/s41586-020-03055-0

Cited by 35 publications

(70 citation statements)

References 35 publications

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“…Zinani et al . [47] found that in the unpaired embryos, transcriptional coordination between genes is lost and proper somite segmentation is disrupted (fig. 6b).…”

Section: Resultsmentioning

confidence: 99%

“…We find that DNA supercoiling acts as a mechanism for coordinating expression between divergently expressed genes in the segmentation network. Supercoiling-dependent feedback supports tight regulation of these proximal clock genes, providing a molecular mechanism for the precise coordination of gene expression observed during somite formation [47]. Thus, supercoiling-mediated feedback represents a novel, testable regulatory mechanism that can both explain native behaviors and guide synthetic designs.…”

Section: Introductionmentioning

confidence: 99%

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Supercoiling-mediated feedback rapidly couples and tunes transcription

Johnstone¹,

Galloway²

2022

Preprint

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Transcription induces a wave of DNA supercoiling, altering the binding affinity of RNA polymerases and reshaping the biochemical landscape of gene regulation. As supercoiling rapidly diffuses, transcription dynamically reshapes the regulation of proximal genes, forming a complex feedback loop. The resulting intergene coupling may provide a mechanism to control transcriptional variance in engineered gene networks and explain the behavior of co-localized native circuits. However, a theoretical framework is needed for integrating both biophysical and biochemical transcriptional regulation to investigate the role of supercoiling-mediated feedback within multi-gene systems. Here, we model transcriptional regulation under the influence of supercoiling-mediated polymerase dynamics, allowing us to identify patterns of expression that result from physical intergene coupling and explore integration of this biophysical model with a set of canonical biochemical gene regulatory systems. We find that gene syntax--the relative ordering and orientation of genes--defines the expression profiles, variance, burst dynamics, and intergene correlation of two-gene systems. By applying our model to both a synthetic toggle switch and the endogenous zebrafish segmentation network, we find that supercoiling can enhance or weaken conventional biochemical regulatory strategies such as mRNA- and protein-mediated feedback loops. Together, our results suggest that supercoiling couples behavior between neighboring genes, representing a novel regulatory mechanism. Integrating biophysical regulation into the analysis and design of gene regulation provides a framework for enhanced understanding of native networks and engineering of synthetic gene circuits.

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“…Zinani et al . [47] found that in the unpaired embryos, transcriptional coordination between genes is lost and proper somite segmentation is disrupted (fig. 6b).…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Supercoiling-mediated feedback rapidly couples and tunes transcription

Johnstone¹,

Galloway²

2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Hes6 is highly expressed in the nervous system and promotes neural differentiation ( 23 ). On the other hand, since Hes7 exhibits the essential characteristics of a segmentation clock ( 24 ) and neighboring genes can influence the expressions with each other during somitogenesis in zebrafish ( 25 ), we focused on the effect of the regulation mechanism of the circadian clock on segmentation clock oscillation. Therefore, we investigated the effect of the CLOCK/BMAL1-mediated activation of Per1 transcription on the segmentation clock oscillation in iPSM, an in vitro recapitulating model of a segmentation clock, using ESCs carrying the Hes7 -promoter–driven luciferase reporter ( pHes7-luc ) ( 26 ) ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Circadian key component CLOCK/BMAL1 interferes with segmentation clock in mouse embryonic organoids

Umemura

Koike

Tsuchiya

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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In mammals, circadian clocks are strictly suppressed during early embryonic stages, as well as in pluripotent stem cells, by the lack of CLOCK/BMAL1-mediated circadian feedback loops. During ontogenesis, the innate circadian clocks emerge gradually at a late developmental stage, and with these, the circadian temporal order is invested in each cell level throughout a body. Meanwhile, in the early developmental stage, a segmented body plan is essential for an intact developmental process, and somitogenesis is controlled by another cell-autonomous oscillator, the segmentation clock, in the posterior presomitic mesoderm (PSM). In the present study, focusing upon the interaction between circadian key components and the segmentation clock, we investigated the effect of the CLOCK/BMAL1 on the segmentation clock Hes7 oscillation, revealing that the expression of functional CLOCK/BMAL1 severely interferes with the ultradian rhythm of segmentation clock in induced PSM and gastruloids. RNA sequencing analysis implied that the premature expression of CLOCK/BMAL1 affects the Hes7 transcription and its regulatory pathways. These results suggest that the suppression of CLOCK/BMAL1-mediated transcriptional regulation during the somitogenesis may be inevitable for intact mammalian development.

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“…1A). Since Hes7 exhibits the essential characteristics of a segmentation clock (23) and neighboring genes can influence the expressions with each other during somitogenesis in zebrafish (24), we focused on the effect of the regulation mechanism of the circadian clock on segmentation clock oscillation. Therefore, we investigated the effect of the CLOCK/BMAL1-mediated activation of Per1 transcription on the segmentation clock oscillation in induced presomitic mesoderm (iPSM), an in vitro recapitulating model of a segmentation clock, using ESCs carrying the Hes7-promoter-driven luciferase reporter (pHes7-luc) (25) (Fig.…”

Section: A Circadian Clock Gene Per1 and A Segmentation Clock Gene Hes7 Are Adjacent Genes In The Mammalian Genomementioning

confidence: 99%

Circadian key component CLOCK/BMAL1 interferes with segmentation clock in mouse embryonic organoids

Umemura

Koike

Tsuchiya

et al. 2020

Preprint

View full text Add to dashboard Cite

In the mammalian developmental process, the segmentation clock and circadian clock appear sequentially in the embryo. However, there is no clear information about the biological significance of the mutual exclusiveness of these rhythms. Here we show that excess of the circadian components CLOCK/BMAL1 in mouse embryonic organoids, induced presomitic mesoderm and gastruloids, disrupts the Hes7 ultradian rhythm and somitogenesis. RNA sequencing analysis showed that CLOCK/BMAL1 activates the signaling pathways regulating Hes7. After establishment of the circadian clock, the expression of endogenous Hes7 and another segmentation clock gene, Lfng, tended to fluctuate with a circadian period, implying that the circadian clock potentially interferes with the segmentation clock. These results suggest that strict timing regulation of the emergence of circadian clock oscillation is essential for mammalian development.

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Pairing of segmentation clock genes drives robust pattern formation

Cited by 35 publications

References 35 publications

Supercoiling-mediated feedback rapidly couples and tunes transcription

Supercoiling-mediated feedback rapidly couples and tunes transcription

Circadian key component CLOCK/BMAL1 interferes with segmentation clock in mouse embryonic organoids

Circadian key component CLOCK/BMAL1 interferes with segmentation clock in mouse embryonic organoids

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