Multiple Alternative Promoters and Alternative Splicing Enable Universal Transcription-Based Logic Computation in Mammalian Cells

Doshi, Jiten; Willis, Katie; Madurga, Angela; Stelzer, Christoph; Benenson, Yaakov

doi:10.1016/j.celrep.2020.108437

“…Moreover, our combined experimental and theoretical approach directly relates TF binding at individual enhancers with the stochastic activity of each promoter. A generalization of this approach (e.g., by including more regulatory factors) will help understand the regulatory mechanisms for cell fate decisions and enable the precise design of synthetic gene circuits 69 .…”

Section: Discussionmentioning

confidence: 99%

Differential regulation of alternative promoters emerges from unified kinetics of enhancer-promoter interaction

Wang

¹

,

Zhang

²

,

Lu

³

et al. 2022

View full text Add to dashboard Cite

Many eukaryotic genes contain alternative promoters with distinct expression patterns. How these promoters are differentially regulated remains elusive. Here, we apply single-molecule imaging to quantify the transcriptional regulation of two alternative promoters (P1 and P2) of the Bicoid (Bcd) target gene hunchback in syncytial blastoderm Drosophila embryos. Contrary to the previous notion that Bcd only activates P2, we find that Bcd activates both promoters via the same two enhancers. P1 activation is less frequent and requires binding of more Bcd molecules than P2 activation. Using a theoretical model to relate promoter activity to enhancer states, we show that the two promoters follow common transcription kinetics driven by sequential Bcd binding at the two enhancers. Bcd binding at either enhancer primarily activates P2, while P1 activation relies more on Bcd binding at both enhancers. These results provide a quantitative framework for understanding the kinetic mechanisms of complex eukaryotic gene regulation.

show abstract

“…Moreover, our combined experimental and theoretical approach directly relates TF binding at individual enhancers with the stochastic activity of each promoter. A generalization of this approach (e.g., by including more regulatory factors) will help understand complex eukaryotic gene regulation in different organisms and enable the precise design of synthetic gene circuits (Doshi et al, 2020). (D-G) Data averaged from ≥5 embryos for each nuclear cycle.…”

Section: Discussionmentioning

confidence: 99%

Differential regulation of alternative promoters emerges from unified kinetics of enhancer-promoter interaction

Wang

¹

,

Zhang

²

,

Lu

³

et al. 2021

Preprint

0

View full text Add to dashboard Cite

Many eukaryotic genes contain alternative promoters with distinct expression patterns. How these promoters are differentially regulated remains elusive. Here, we apply single-molecule imaging to quantify the transcriptional regulation of two alternative promoters (P1 and P2) of the Bicoid (Bcd) target gene hunchback in syncytial blastoderm Drosophila embryos. Contrary to the previous notion that Bcd only activates P2, we find that Bcd activates both promoters via the same two enhancers. P1 activation is less frequent and requires binding of more Bcd molecules than P2 activation. Using a theoretical model to relate promoter activity to enhancer states, we show that the two promoters follow common transcription kinetics driven by sequential Bcd binding at the two enhancers. Bcd binding at either enhancer primarily activates P2, while P1 activation relies more on Bcd binding at both enhancers. These results provide a quantitative framework for understanding the dynamics of complex eukaryotic gene regulation.

show abstract

“…Moreover, our combined experimental and theoretical approach directly relates TF binding at individual enhancers with the stochastic activity of each promoter. A generalization of this approach (e.g., by including more regulatory factors) will help understand the regulatory mechanisms for cell fate decisions and enable the precise design of synthetic gene circuits 67 .…”

Section: Discussionmentioning

confidence: 99%

Differential regulation of alternative promoters emerges from unified kinetics of enhancer-promoter interaction

Wang

¹

,

Zhang

²

,

Lu

³

et al. 2021

Preprint

0

View full text Add to dashboard Cite

Many eukaryotic genes contain alternative promoters with distinct expression patterns. How these promoters are differentially regulated remains elusive. Here, we apply single-molecule imaging to quantify the transcriptional regulation of two alternative promoters (P1 and P2) of the Bicoid (Bcd) target gene hunchback in syncytial blastoderm Drosophila embryos. Contrary to the previous notion that Bcd only activates P2, we find that Bcd activates both promoters via the same two enhancers. P1 activation is less frequent and requires binding of more Bcd molecules than P2 activation. Using a theoretical model to relate promoter activity to enhancer states, we show that the two promoters follow common transcription kinetics driven by sequential Bcd binding at the two enhancers. Bcd binding at either enhancer primarily activates P2, while P1 activation relies more on Bcd binding at both enhancers. These results provide a quantitative framework for understanding the dynamics of complex eukaryotic gene regulation.

show abstract

Multiple Alternative Promoters and Alternative Splicing Enable Universal Transcription-Based Logic Computation in Mammalian Cells

Cited by 14 publications

References 61 publications

Differential regulation of alternative promoters emerges from unified kinetics of enhancer-promoter interaction

Differential regulation of alternative promoters emerges from unified kinetics of enhancer-promoter interaction

Differential regulation of alternative promoters emerges from unified kinetics of enhancer-promoter interaction

Differential regulation of alternative promoters emerges from unified kinetics of enhancer-promoter interaction

Contact Info

Product

Resources

About