BET bromodomain inhibitors regulate keratinocyte plasticity

Schutzius, Gabi; Kolter, Christian; Bergling, Sebastian; Tortelli, Federico; Fuchs, Florian; Renner, Steffen; Guagnano, Vito; Cotesta, Simona; Rueeger, Heinrich; Faller, Michael; Bouchez, Laure C.; Salathe, Adrian; Nigsch, Florian; Richards, Shola M.; Louis, Malvina; Gruber, Viktoria; Aebi, Alexandra; Turner, Jonathan; Grandjean, Frederic; Li, Jun; Dimitri, Chris; Thomas, Jason R.; Schirle, Markus; Blank, Jutta; Drueckes, Peter; Vaupel, Andrea; Tiedt, Ralph; Manley, Paul W.; Klopp, Julia; Hemmig, R.; Zink, F.; Leroy, Nelly; Carbone, Walter; Roma, Guglielmo; Keller, Caroline Gubser; Dales, Natalie A.; Beyerbach, Armin; Zimmerlin, Alfred; Bonenfant, Débora; Terranova, Rémi; Berwick, Amy; Sahambi, Sukhdeep K.; Reynolds, Aimee; Jennings, Lori L.; Ruffner, Heinz; Tarsa, Peter B.; Bouwmeester, Tewis; Driver, Vickie R.; Frederiksen, Mathias; Lohmann, Felix; Kirkland, Susan C.

doi:10.1038/s41589-020-00716-z

Cited by 13 publications

(10 citation statements)

References 59 publications

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“…BET inhibitors are a new class of small molecule drugs and additional compounds are likely to be discovered in the near future. For example, a drug screen on keratinocytes identified and optimized a new BET inhibiting compound that improved skin healing in vivo [76]. Yet, while (super) enhancers seem to be specifically sensitive to BET inhibition [76], recent work has shown that enhancer-promoter loops stay intact upon BET treatment, despite major changes at the transcriptional level [77].…”

Section: Trends In Molecular Medicinementioning

confidence: 99%

“…For example, a drug screen on keratinocytes identified and optimized a new BET inhibiting compound that improved skin healing in vivo [76]. Yet, while (super) enhancers seem to be specifically sensitive to BET inhibition [76], recent work has shown that enhancer-promoter loops stay intact upon BET treatment, despite major changes at the transcriptional level [77]. Thus, the exact role of BET proteins in transcriptional regulation is not fully understood, in part because enhancer activity upon BET inhibition is often not directly measured [63].…”

Section: Trends In Molecular Medicinementioning

confidence: 99%

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Enhancers in disease: molecular basis and emerging treatment strategies

Claringbould

Zaugg

2021

Trends in Molecular Medicine

105

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Enhancers are genomic sequences that play a key role in regulating tissue-specific gene expression levels. An increasing number of diseases are linked to impaired enhancer function through chromosomal rearrangement, genetic variation within enhancers, or epigenetic modulation. Here, we review how these enhancer disruptions have recently been implicated in congenital disorders, cancers, and common complex diseases and address the implications for diagnosis and treatment. Although further fundamental research into enhancer function, target genes, and context is required, enhancer-targeting drugs and gene editing approaches show great therapeutic promise for a range of diseases. HighlightsEnhancer disruption is increasingly implicated as a disease-driving mechanism. Chromosomal rearrangements can cause an enhancer to drive aberrant gene expression, genetic variants in enhancers can impact a transcription factor binding site, and disease-associated epigenetic changes are enriched in enhancer regions.The three big challenges in enhancer research focus on systematically identifying functional enhancers, their target genes, and the context in which they are active.Bromo-and extra-terminal (BET) inhibitors are a new class of drugs that target enhancers and inhibit gene expression. They are under investigation as treatment for cancer and other diseases.Gene editing techniques elucidate enhancer function and are being used to selectively regulate or mutate disturbed enhancers.

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Section: Trends In Molecular Medicinementioning

confidence: 99%

Section: Trends In Molecular Medicinementioning

confidence: 99%

Enhancers in disease: molecular basis and emerging treatment strategies

Claringbould

Zaugg

2021

Trends in Molecular Medicine

105

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“…These BRD4-associated super-enhancers are therapeutically relevant, as they are thought to maintain pathological gene expression in inflammatory diseases and cancer ( Delmore et al., 2011 ; Shin et al., 2019 ; Xu and Vakoc, 2014 ). Furthermore, we have shown in human keratinocytes that BETi induce exposure-dependent BRD4 chromatin occupancy profiles with some BRD4 occupancy gains, enriched at promoters, observed predominantly at low BETi concentrations ( Schutzius et al., 2021 ). Importantly, a regenerative phenotype is triggered in keratinocytes, in vitro and in vivo , exclusively by limiting BETi exposure ( Schutzius et al., 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, we have shown in human keratinocytes that BETi induce exposure-dependent BRD4 chromatin occupancy profiles with some BRD4 occupancy gains, enriched at promoters, observed predominantly at low BETi concentrations ( Schutzius et al., 2021 ). Importantly, a regenerative phenotype is triggered in keratinocytes, in vitro and in vivo , exclusively by limiting BETi exposure ( Schutzius et al., 2021 ). Likewise, JQ1-induced rescue of function in MeCP2 mutant interneurons (Rett syndrome model) was lost with a too high dosage ( Xiang et al., 2020 ) although the molecular mechanisms responsible were not identified.…”

Section: Discussionmentioning

confidence: 99%

“…To uncover mechanisms mediating resistance or sensitivity to BETi, we performed genome-wide CRISPR-Cas9 screens in HCT116 colorectal cancer cells. To reveal any concentration-dependent molecular signaling, as suggested by other studies ( Schutzius et al., 2021 ), we performed screening at two concentrations of JQ1 ( Filippakopoulos et al., 2010 ). Our screens identify genes already known to mediate BETi sensitivity alongside many others not previously described such as the Ca 2+ /Mn 2+ transporter, ATP2C1.…”

Section: Introductionmentioning

confidence: 99%

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Genome-wide CRISPR-Cas9 screens identify mechanisms of BET bromodomain inhibitor sensitivity

et al. 2021

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Summary BET bromodomain inhibitors hold promise as therapeutic agents in diverse indications, but their clinical progression has been challenging and none have received regulatory approval. Early clinical trials in cancer have shown heterogeneous clinical responses, development of resistance, and adverse events. Increased understanding of their mechanism(s) of action and identification of biomarkers are needed to identify appropriate indication(s) and achieve efficacious dosing. Using genome-wide CRISPR-Cas9 screens at different concentrations, we report molecular mechanisms defining cellular responses to BET inhibitors, some of which appear specific to a single compound concentration. We identify multiple transcriptional regulators and mTOR pathway members as key determinants of JQ1 sensitivity and two Ca 2+ /Mn 2+ transporters, ATP2C1 and TMEM165, as key determinants of JQ1 resistance. Our study reveals new molecular mediators of BET bromodomain inhibitor effects, suggests the involvement of manganese, and provides a rich resource for discovery of biomarkers and targets for combination therapies.

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