Recruitment of CTCF to the SIRT1 promoter after Oxidative Stress mediates Cardioprotective Transcription

Wagner, T.; Priyanka, P.; Micheletti, R.; Friedman, M. J.; Nair, S. J.; Gamliel, A.; Taylor, H.; Song, X.; Cho, M.; Oh, S.; Li, W.; Han, J.; Ohgi, K. A.; Abrass, M.; D'Antonio-Chronowska, A.; D'Antonio, M.; Hazuda, H.; Duggirala, R.; Blangero, J.; Ding, S.; Guzmann, C.; Frazer, K.; Aggarwal, A. K.; Zemljic-Harpf, A. E.; Rosenfeld, M. G.; Suh, Y.

doi:10.1101/2024.05.17.594600

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bioRxiv · 10.1101/2024.05.17.594600

Recruitment of CTCF to the SIRT1 promoter after Oxidative Stress mediates Cardioprotective Transcription

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Abstract

Because most DNA-binding transcription factors (dbTFs), including the architectural regulator CTCF, bind RNA and exhibit di-/multimerization, a central conundrum is whether these distinct properties are regulated post-transcriptionally to modulate transcriptional programs. Here, investigating stress-dependent activation of SIRT1, encoding an evolutionarily-conserved protein deacetylase, we show that induced phosphorylation of CTCF acts as a rheostat to permit CTCF occupancy of low-affinity promoter DNA sites to precisely the levels necessary. This CTCF recruitment to the SIRT1 promoter is eliciting a cardioprotective cardiomyocyte transcriptional activation program and provides resilience against the stress of the beating heart in vivo. Mice harboring a mutation in the conserved low-affinity CTCF promoter binding site exhibit an altered, cardiomyocyte-specific transcriptional program and a systolic heart failure phenotype. This transcriptional role for CTCF reveals that a covalent dbTF modification regulating signal-dependent transcription serves as a previously unsuspected component of the oxidative stress response.

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Wagner, T., Priyanka, P., Micheletti, R., Friedman, M. J., Nair, S. J., Gamliel, A., Taylor, H., Song, X., Cho, M., Oh, S., Li, W., Han, J., Ohgi, K. A., Abrass, M., D'Antonio-Chronowska, A., D'Antonio, M., Hazuda, H., Duggirala, R., Blangero, J., Ding, S., Guzmann, C., Frazer, K., Aggarwal, A. K., Zemljic-Harpf, A. E., Rosenfeld, M. G., Suh, Y.. 2024-05-19. Recruitment of CTCF to the SIRT1 promoter after Oxidative Stress mediates Cardioprotective Transcription. https://doi.org/10.1101/2024.05.17.594600

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