Open AccessCell-surface SLC nucleoside transporters and purine levels modulate BRD4-dependent chromatin states
Author(s) -
Kaichun Li,
Enrico Gottardi,
Felix Kartnig,
Sarah Grosche,
Tea Pemovska,
Johannes W. Bigenzahn,
Ulrich Goldmann,
Vitaly Sedlyarov,
Ariel Bensimon,
Sandra Schick,
Jung-Ming G. Lin,
Bettina Gürtl,
Daniela Reil,
Kristaps Klavins,
Stefan Kubicek,
Sara Sdelci,
Giulio SupertiFurga
Publication year - 2021
Publication title -
nature metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.834
H-Index - 22
ISSN - 2522-5812
DOI - 10.1038/s42255-021-00386-8
Subject(s) - chromatin , epigenetics , purine metabolism , purine , biology , histone , microbiology and biotechnology , biochemistry , nucleoside transporter , transporter , chemistry , gene , enzyme
Metabolism negotiates cell-endogenous requirements of energy, nutrients and building blocks with the immediate environment to enable various processes, including growth and differentiation. While there is an increasing number of examples of crosstalk between metabolism and chromatin, few involve uptake of exogenous metabolites. Solute carriers (SLCs) represent the largest group of transporters in the human genome and are responsible for the transport of a wide variety of substrates, including nutrients and metabolites. We aimed to investigate the possible involvement of SLC-mediated solutes uptake and cellular metabolism in regulating cellular epigenetic states. Here, we perform a CRISPR-Cas9 transporter-focused genetic screen and a metabolic compound library screen for the regulation of BRD4-dependent chromatin states in human myeloid leukaemia cells. Intersection of the two orthogonal approaches reveal that loss of transporters involved with purine transport or inhibition of de novo purine synthesis lead to dysfunction of BRD4-dependent transcriptional regulation. Through mechanistic characterization of the metabolic circuitry, we elucidate the convergence of SLC-mediated purine uptake and de novo purine synthesis on BRD4-chromatin occupancy. Moreover, adenine-related metabolite supplementation effectively restores BRD4 functionality on purine impairment. Our study highlights the specific role of purine/adenine metabolism in modulating BRD4-dependent epigenetic states.