Capicua is a fast-acting transcriptional brake

Patel, Aleena L.; Zhang, Lili; Keenan, Shannon E.; Rushlow, Christine; Fradin, Cécile; Shvartsman, Stanislav Y.

doi:10.1016/j.cub.2021.05.061

Cited by 10 publications

(12 citation statements)

References 52 publications

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“…A strength of the optogenetic approach is that stimuli can be varied over time, either by switching between light and dark conditions or by varying the developmental time at which the stimulus is applied. Importantly, such dynamic experiments are possible because transcriptional repression by Capicua (Cic) is restored within minutes of turning off an optogenetic input to the ERK pathway (Patel et al 2021).…”

Section: Resultsmentioning

confidence: 99%

“…It is primarily controlled by just a single input: activation of the Torso receptor tyrosine kinase at the embryo’s poles which produces a gradient of active, doubly-phosphorylated ERK (dpERK), known as the terminal pattern (Casanova and Struhl 1989; Lu et al 1993; Sprenger and Nüsslein-Volhard 1992). ERK then inactivates the transcriptional repressor Capicua (Cic), leading to the expression of two essential transcription factors, tailless ( tll ) and huckebein ( hkb ) ( Figure 1A ) (Coppey et al 2008; Jiménez et al 2000; Strecker et al 1986; Weigel et al 1990; Pignoni et al 1990; Bronner and Jackle 1991; Keenan et al 2020; Patel et al 2021). Tll is sensitive even to low doses of ERK and thus is expressed broadly, whereas hkb requires a high dose and thus is expressed at only the most posterior positions (Greenwood and Struhl 1997; Ghiglione et al 1999).…”

Section: Introductionmentioning

confidence: 99%

“…Optogenetics has proven to be a powerful approach to interrogate developmental circuits; the precision of light patterning enables the experimentalist to systematically vary the spatial and temporal parameters of an input while monitoring outputs ranging from gene expression to morphogenesis (McFann et al 2021; Singh et al 2022; Huang et al 2017; Guglielmi et al 2015). In particular, measuring responses after acute changes in stimulus can provide information about the timescale with which signals are transmitted through a developmental gene network (Singh et al 2022; Patel et al 2021; Keenan et al 2020). We find that low- and high-amplitude optogenetic ERK stimuli are dynamically interpreted to generate either transient or sustained byn transcription.…”

Section: Introductionmentioning

confidence: 99%

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Dynamics of an incoherent feedforward loop drive ERK-dependent pattern formation in the earlyDrosophilaembryo

Oatman

McFann

et al. 2023

Preprint

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Positional information in developing tissues often takes the form of stripes of gene expression that mark the boundaries of a particular cell type or morphogenetic process. How stripes form is still in many cases poorly understood. Here we use optogenetics and live-cell biosensors to investigate one such pattern: the posterior stripe ofbrachyenteron (byn)expression in the earlyDrosophilaembryo. Thisbynstripe depends on interpretation of an upstream signal — a gradient of ERK kinase activity — and the expression of two target genestailless (tll)andhuckebein (hkb)that exert antagonistic control overbyn. We find that high or low doses of ERK signaling produce either transient or sustainedbynexpression, respectively. These ERK stimuli also regulatetllandhkbexpression with distinct dynamics:tlltranscription is rapidly induced under both low and high stimuli, whereashkbtranscription converts graded ERK inputs into an output switch with a variable time delay. Antagonistic regulatory paths acting on different timescales are hallmarks of an incoherent feedforward loop architecture, which is sufficient to explain transient or sustainedbyndynamics and adds temporal complexity to the steady-state model ofbynstripe formation. We further show that an all-or-none stimulus can be blurred through intracellular diffusion to non-locally produce a stripe ofbyngene expression. Overall, our study provides a blueprint for using optogenetic inputs to dissect developmental signal interpretation in space and time.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dynamics of an incoherent feedforward loop drive ERK-dependent pattern formation in the earlyDrosophilaembryo

Oatman

McFann

et al. 2023

Preprint

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“…In the case of Bcd, there is experimental evidence that cooperativity is involved in binding to DNA target sites (7,19), and it might in part explain the steepness of the hb transcriptional response (20)(21)(22)(23). Cooperative binding is also thought to be implicated in Cic repression (14). It is unclear, however, how search for target gene and cooperativity play out at the molecular level and affect transcription.…”

Section: Introductionmentioning

confidence: 99%

“…Gene expression in response to Bcd nuclear import is established in only a couple of minutes (11, 12). Cic gene repression triggered by optogenetic methods is complete within the same time frame (13, 14). This points to a very efficient search mechanism to locate target genes.…”

Section: Introductionmentioning

confidence: 99%

Both the transcriptional activator, Bcd, and transcriptional repressor, Cic, form small mobile oligomeric clusters in early fly embryo nuclei

Zhang,

Hodgins,

Sakib

et al. 2024

Preprint

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Transcription factors play an essential role in pattern formation during early embryo development, generating a strikingly fast and precise transcriptional response that results in sharp gene expression boundaries. To characterize the steps leading up to transcription, we performed a side-by-side comparison of the nuclear dynamics of two morphogens, a transcriptional activator, Bicoid (Bcd), and a transcriptional repressor, Capicua (Cic), both involved in body patterning along the anterior-posterior axis of the early Drosophila embryo. We used a combination of fluorescence recovery after photobleaching, fluorescence correlation spectroscopy, and single particle tracking to access a wide range of dynamical timescales. Despite their opposite effects on gene transcription, we find that Bcd and Cic have very similar nuclear dynamics, characterized by the co-existence of a freely diffusing monomer population with a number of oligomeric clusters, which range from low stoichiometry and high mobility clusters to larger, DNA-bound hubs. Our observations are consistent with the inclusion of both Bcd and Cic into transcriptional hubs or condensates, while putting constraints on the mechanism by which these form. These results fit in with the recent proposal that many transcription factors might share a common search strategy for target genes regulatory regions that makes use of their large unstructured regions, and may eventually help explain how the transcriptional response they elicit can be at the same time so fast and so precise.

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Using FCS to accurately measure protein concentration in the presence of noise and photobleaching

Zhang

Perez-Romero

Dostatni

et al. 2021

Biophysical Journal

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Capicua is a fast-acting transcriptional brake

Cited by 10 publications

References 52 publications

Dynamics of an incoherent feedforward loop drive ERK-dependent pattern formation in the earlyDrosophilaembryo

Dynamics of an incoherent feedforward loop drive ERK-dependent pattern formation in the earlyDrosophilaembryo

Both the transcriptional activator, Bcd, and transcriptional repressor, Cic, form small mobile oligomeric clusters in early fly embryo nuclei

Using FCS to accurately measure protein concentration in the presence of noise and photobleaching

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