Tejedor Vaquero, Juan Ramón, 1984-Papasaikas, PanagiotisValcárcel, J. (Juan)2020-11-302020-11-302015Tejedor JR, Papasaikas P, Valcárcel J. Genome-wide identification of Fas/CD95 alternative splicing regulators reveals links with iron homeostasis. Mol Cell. 2015; 57(1):23-38. DOI: 10.1016/j.molcel.2014.10.0291097-2765http://hdl.handle.net/10230/45909Alternative splicing of Fas/CD95 exon 6 generates either a membrane-bound receptor that promotes, or a soluble isoform that inhibits, apoptosis. Using an automatized genome-wide siRNA screening for alternative splicing regulators of endogenous transcripts in mammalian cells, we identified 200 genes whose knockdown modulates the ratio between Fas/CD95 isoforms. These include classical splicing regulators; core spliceosome components; and factors implicated in transcription and chromatin remodeling, RNA transport, intracellular signaling, and metabolic control. Coherent effects of genes involved in iron homeostasis and pharmacological modulation of iron levels revealed a link between intracellular iron and Fas/CD95 exon 6 inclusion. A splicing regulatory network linked iron levels with reduced activity of the Zinc-finger-containing splicing regulator SRSF7, and in vivo and in vitro assays revealed that iron inhibits SRSF7 RNA binding. Our results uncover numerous links between cellular pathways and RNA processing and a mechanism by which iron homeostasis can influence alternative splicing.application/pdfeng© Elsevier This is the published version of an article http://dx.doi.org/10.1016/j.molcel.2014.10.029 that appeared in the journal Molecular cell. It is published in an Open Archive under an Elsevier user license. Details of this licence are available here: https://www.elsevier.com/about/our-business/policies/open-access-licenses/elsevier-user-licenseinfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1016/j.molcel.2014.10.029info:eu-repo/semantics/openAccess