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Disrupting Pitx1 regulatory topology results in overtly normal limb development

Richard Sarro, Deena Emera, Severin Uebbing, Emily V. Dutrow, Scott D. Weatherbee, Timothy Nottoli, James P. Noonan
doi: https://doi.org/10.1101/138644
Richard Sarro
1Department of Genetics, Yale School of Medicine, New Haven, CT 06520
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Deena Emera
1Department of Genetics, Yale School of Medicine, New Haven, CT 06520
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Severin Uebbing
1Department of Genetics, Yale School of Medicine, New Haven, CT 06520
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Emily V. Dutrow
1Department of Genetics, Yale School of Medicine, New Haven, CT 06520
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Scott D. Weatherbee
1Department of Genetics, Yale School of Medicine, New Haven, CT 06520
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Timothy Nottoli
2Department of Comparative Medicine, Yale School of Medicine, New Haven, CT 06520
3Yale Genome Editing Center, Yale School of Medicine, New Haven, CT 06520
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James P. Noonan
1Department of Genetics, Yale School of Medicine, New Haven, CT 06520
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  • For correspondence: james.noonan@yale.edu.
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Abstract

Gene expression patterns during development are orchestrated in part by thousands of distant-acting transcriptional enhancers. However, identifying enhancers that are essential for expression of their target genes has proven challenging. Genetic perturbation of individual enhancers in some cases results in profound molecular and developmental phenotypes, but in mild or no phenotypes in others. Topological maps of long-range regulatory interactions may provide the means to identify enhancers critical for developmental gene expression. Here, we leveraged chromatin topology to characterize and disrupt the major promoter-enhancer interaction for Pitx1, which is essential for hindlimb development. We found that Pitx1 primarily interacts with a single distal enhancer in the hindlimb. Using genome editing, we deleted this enhancer in the mouse. Although loss of the enhancer completely disrupts the predominant topological interaction in the Pitx1 locus, Pitx1 expression in the hindlimb is only reduced by ~14%, with no apparent changes in spatial distribution or evidence of regulatory compensation. Pitx1 enhancer null mice did not exhibit any of the characteristic morphological defects of the Pitx1−/− mutant. Our results indicate that Pitx1 expression is robust to the loss of its primary enhancer interaction, suggesting disruptions of regulatory topology at essential developmental genes may have mild phenotypic effects.

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Posted May 26, 2017.
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Disrupting Pitx1 regulatory topology results in overtly normal limb development
Richard Sarro, Deena Emera, Severin Uebbing, Emily V. Dutrow, Scott D. Weatherbee, Timothy Nottoli, James P. Noonan
bioRxiv 138644; doi: https://doi.org/10.1101/138644
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Disrupting Pitx1 regulatory topology results in overtly normal limb development
Richard Sarro, Deena Emera, Severin Uebbing, Emily V. Dutrow, Scott D. Weatherbee, Timothy Nottoli, James P. Noonan
bioRxiv 138644; doi: https://doi.org/10.1101/138644

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