Programmable human histone phosphorylation and gene activation using a CRISPR/Cas9-based chromatin kinase

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dc.citation.articleNumber896en_US
dc.citation.journalTitleNature Communicationsen_US
dc.citation.volumeNumber12en_US
dc.contributor.authorLi, Jingen_US
dc.contributor.authorMahata, Barunen_US
dc.contributor.authorEscobar, Marioen_US
dc.contributor.authorGoell, Jacoben_US
dc.contributor.authorWang, Kaiyuanen_US
dc.contributor.authorKhemka, Pranaven_US
dc.contributor.authorHilton, Isaac B.en_US
dc.date.accessioned2021-03-09T15:44:38Zen_US
dc.date.available2021-03-09T15:44:38Zen_US
dc.date.issued2021en_US
dc.description.abstractHistone phosphorylation is a ubiquitous post-translational modification that allows eukaryotic cells to rapidly respond to environmental stimuli. Despite correlative evidence linking histone phosphorylation to changes in gene expression, establishing the causal role of this key epigenomic modification at diverse loci within native chromatin has been hampered by a lack of technologies enabling robust, locus-specific deposition of endogenous histone phosphorylation. To address this technological gap, here we build a programmable chromatin kinase, called dCas9-dMSK1, by directly fusing nuclease-null CRISPR/Cas9 to a hyperactive, truncated variant of the human MSK1 histone kinase. Targeting dCas9-dMSK1 to human promoters results in increased target histone phosphorylation and gene activation and demonstrates that hyperphosphorylation of histone H3 serine 28 (H3S28ph) in particular plays a causal role in the transactivation of human promoters. In addition, we uncover mediators of resistance to the BRAF V600E inhibitor PLX-4720 in human melanoma cells using genome-scale screening with dCas9-dMSK1. Collectively, our findings enable a facile way to reshape human chromatin using CRISPR/Cas9-based epigenome editing and further define the causal link between histone phosphorylation and human gene activation.en_US
dc.description.sponsorshipFondren Library Open Access Author Funden_US
dc.identifier.citationLi, Jing, Mahata, Barun, Escobar, Mario, et al.. "Programmable human histone phosphorylation and gene activation using a CRISPR/Cas9-based chromatin kinase." <i>Nature Communications,</i> 12, (2021) Springer Nature: https://doi.org/10.1038/s41467-021-21188-2.en_US
dc.identifier.digitals41467-021-21188-2en_US
dc.identifier.doihttps://doi.org/10.1038/s41467-021-21188-2en_US
dc.identifier.urihttps://hdl.handle.net/1911/110163en_US
dc.language.isoengen_US
dc.publisherSpringer Natureen_US
dc.rightsThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.en_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.titleProgrammable human histone phosphorylation and gene activation using a CRISPR/Cas9-based chromatin kinaseen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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