Genome-wide identification of Fas/CD95 alternative splicing regulators reveals links with iron homeostasis

Tejedor Vaquero, Juan Ramón, 1984-; Papasaikas, Panagiotis; Valcárcel, J. (Juan)

doi:http://dx.doi.org/10.1016/j.molcel.2014.10.029

Genome-wide identification of Fas/CD95 alternative splicing regulators reveals links with iron homeostasis

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Tejedor 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.2014.10.029

Abstract

Alternative 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.