title: The polypyrimidine tract binding protein regulates desaturase alternative splicing and PUFA composition.
abstract: The Δ6 desaturase, encoded by FADS2, plays a crucial role in omega-3 and omega-6 fatty acid synthesis. These fatty acids are essential components of the central nervous system, and they act as precursors for eicosanoid signaling molecules and as direct modulators of gene expression. The polypyrimidine tract binding protein (PTB or hnRNP I) is a splicing factor that regulates alternative pre-mRNA splicing. Here, PTB is shown to bind an exonic splicing silencer element and repress alternative splicing of FADS2 into FADS2 AT1. PTB and FADS2AT1 were inversely correlated in neonatal baboon tissues, implicating PTB as a major regulator of tissue-specific FADS2 splicing. In HepG2 cells, PTB knockdown modulated alternative splicing of FADS2, as well as FADS3, a putative desaturase of unknown function. Omega-3 fatty acids decreased by nearly one half relative to omega-6 fatty acids in PTB knockdown cells compared with controls, with a particularly strong decrease in eicosapentaenoic acid (EPA) concentration and its ratio to arachidonic acid (ARA). This is a rare demonstration of a mechanism specifically altering the cellular omega-3 to omega-6 fatty acid ratio without any change in diet/media. These findings reveal a novel role for PTB, regulating availability of membrane components and eicosanoid precursors for cell signaling.
authors: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853.
authors: Holly T
authors: HT
authors: Reardon
authors: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853.
authors: Woo Jung
authors: WJ
authors: Park
authors: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853.
authors: Jimmy
authors: J
authors: Zhang
authors: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853.
authors: Peter
authors: P
authors: Lawrence
authors: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853.
authors: Kumar S D
authors: KSD
authors: Kothapalli
authors: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853. Electronic address: jtb4@cornell.edu.
authors: J Thomas
authors: JT
authors: Brenna
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D005091:Exons / Q000235:genetics; D044943:Fatty Acid Desaturases / Q000172:deficiency / Q000235:genetics*; D015525:Fatty Acids, Omega-3 / Q000378:metabolism*; D043371:Fatty Acids, Omega-6 / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D056945:Hep G2 Cells; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D010215:Papio; D038941:Polypyrimidine Tract-Binding Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D022821:RNA Splice Sites / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D015854:Up-Regulation
chemical_list: D015525:Fatty Acids, Omega-3; D043371:Fatty Acids, Omega-6; D034441:Heterogeneous-Nuclear Ribonucleoproteins; C450006:PTBP1 protein, human; D022821:RNA Splice Sites; D034741:RNA, Small Interfering; D038941:Polypyrimidine Tract-Binding Protein; D044943:Fatty Acid Desaturases; C533241:FADS2 protein, human; C545859:FADS3 protein, human