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Bromodomain factor 5 is an essential regulator of transcription in Leishmania

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Publication details

JournalNature Communications
DateAccepted/In press - 30 Jun 2022
DatePublished (current) - 13 Jul 2022
Issue number1
Volume13
Number of pages18
Original languageEnglish

Abstract

Leishmania are unicellular parasites that cause human and animal diseases. Like other kinetoplastids, they possess large transcriptional start regions (TSRs) which are defined by histone variants and histone lysine acetylation. Cellular interpretation of these chromatin marks is not well understood. Eight bromodomain factors, the reader modules for acetyl-lysine, are found across Leishmania genomes. Using L. mexicana, Cas9-driven gene deletions indicate that BDF1–5 are essential for promastigotes. Dimerisable, split Cre recombinase (DiCre)-inducible gene deletion of BDF5 show it is essential for both promastigotes and murine infection. ChIP-seq identifies BDF5 as enriched at TSRs. XL-BioID proximity proteomics shows the BDF5 landscape is enriched for BDFs, HAT2, proteins involved in transcriptional activity, and RNA processing; revealing a Conserved Regulators of Kinetoplastid Transcription (CRKT) Complex. Inducible deletion of BDF5 causes global reduction in RNA polymerase II transcription. Our results indicate the requirement of Leishmania to interpret histone acetylation marks through the bromodomain-enriched CRKT complex for normal gene expression and cellular viability.

Bibliographical note

Funding Information:
This work was supported by funding from GSK through the Pipeline Futures Group and a Fellowship from a Research Council United Kingdom Grand Challenges Research Funder under grant agreement ‘A Global Network for Neglected Tropical Diseases’ grant number MR/P027989/1. to Nathaniel Jones. This work was part-funded by the Wellcome Trust [ref: 204829] through the Centre for Future Health (CFH) at the University of York. Elmarie Myburgh, University of York, assisted with lymph-node dissection and parasite burden assays. We thank our colleagues in The Bioscience Technology Facility of the University of York, who provided expertise and technical support that assisted this work, and Robert Kirkpatrick (former GSK employee) for his critical input to develop the collaboration between University of York and GSK.

Funding Information:
This work was supported by funding from GSK through the Pipeline Futures Group and a Fellowship from a Research Council United Kingdom Grand Challenges Research Funder under grant agreement ‘A Global Network for Neglected Tropical Diseases’ grant number MR/P027989/1. to Nathaniel Jones. This work was part-funded by the Wellcome Trust [ref: 204829] through the Centre for Future Health (CFH) at the University of York. Elmarie Myburgh, University of York, assisted with lymph-node dissection and parasite burden assays. We thank our colleagues in The Bioscience Technology Facility of the University of York, who provided expertise and technical support that assisted this work, and Robert Kirkpatrick (former GSK employee) for his critical input to develop the collaboration between University of York and GSK.

Publisher Copyright:
© 2022, The Author(s).

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