PT  - JOURNAL ARTICLE
AU  - Maria Inês Alvelos
AU  - Mirko Brüggemann
AU  - FX Reymond Sutandy
AU  - Jonàs Juan-Mateu
AU  - Maikel Luis Colli
AU  - Anke Busch
AU  - Miguel Lopes
AU  - Ângela Castela
AU  - Annemieke Aartsma-Rus
AU  - Julian König
AU  - Kathi Zarnack
AU  - Décio L Eizirik
TI  - The RNA-binding profile of the splicing factor SRSF6 in immortalized human pancreatic β-cells
AID  - 10.26508/lsa.202000825
DP  - 2021 Mar 01
TA  - Life Science Alliance
PG  - e202000825
VI  - 4
IP  - 3
4099  - https://www.life-science-alliance.org/content/4/3/e202000825.short
4100  - https://www.life-science-alliance.org/content/4/3/e202000825.full
SO  - Life Sci. Alliance2021 Mar 01; 4
AB  - In pancreatic β-cells, the expression of the splicing factor SRSF6 is regulated by GLIS3, a transcription factor encoded by a diabetes susceptibility gene. SRSF6 down-regulation promotes β-cell demise through splicing dysregulation of central genes for β-cells function and survival, but how RNAs are targeted by SRSF6 remains poorly understood. Here, we define the SRSF6 binding landscape in the human pancreatic β-cell line EndoC-βH1 by integrating individual-nucleotide resolution UV cross-linking and immunoprecipitation (iCLIP) under basal conditions with RNA sequencing after SRSF6 knockdown. We detect thousands of SRSF6 bindings sites in coding sequences. Motif analyses suggest that SRSF6 specifically recognizes a purine-rich consensus motif consisting of GAA triplets and that the number of contiguous GAA triplets correlates with increasing binding site strength. The SRSF6 positioning determines the splicing fate. In line with its role in β-cell function, we identify SRSF6 binding sites on regulated exons in several diabetes susceptibility genes. In a proof-of-principle, the splicing of the susceptibility gene LMO7 is modulated by antisense oligonucleotides. Our present study unveils the splicing regulatory landscape of SRSF6 in immortalized human pancreatic β-cells.