Bromodomain factor 5 is an essential regulator of transcription in Leishmania

Nathaniel G. Jones (), Vincent Geoghegan, Gareth Moore, Juliana B. T. Carnielli, Katherine Newling, Félix Calderón, Raquel Gabarró, Julio Martín, Rab K. Prinjha, Inmaculada Rioja, Anthony J. Wilkinson and Jeremy C. Mottram
Additional contact information
Nathaniel G. Jones: University of York
Vincent Geoghegan: University of York
Gareth Moore: University of York
Juliana B. T. Carnielli: University of York
Katherine Newling: University of York
Félix Calderón: GSK Global Health, Tres Cantos
Raquel Gabarró: GSK Global Health, Tres Cantos
Julio Martín: GSK Global Health, Tres Cantos
Rab K. Prinjha: R&D GSK
Inmaculada Rioja: R&D GSK
Anthony J. Wilkinson: University of York
Jeremy C. Mottram: University of York

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31742-1

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