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unknown
T cell activation regulates CD6 alternative splicing by transcription dynamics and SRSF1
Authors
Alexandra Moreira
Alexandre M. Carmo
+7 more
Ana Mafalda Santos
Kamoun
Ladd
Mafalda Martins de Araújo
Rafaela Leal
Sérgio F. de Almeida
Vânia G. da Glória
Publication date
1 January 2014
Publisher
'The American Association of Immunologists'
Doi
Cite
Abstract
The T cell-surface glycoprotein CD6 is a modulator of cellular responses and has been implicated in several autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, and psoriasis. During Ag presentation, CD6 is targeted to the immunological synapse in a ligand binding-dependent manner, in which CD6 domain 3 directly contacts CD166, expressed on the APC. T cell activation results in the induction of CD6?d3, an alternatively spliced isoform that lacks the ligand-binding domain and thus no longer localizes at the immunological synapse. In this study, we investigated the molecular mechanisms regulating the expression of CD6?d3 upon human primary T cell activation. Using chromatin immunoprecipitation, we observed an increase in RNA polymerase II occupancy along the CD6 gene and augmented CD6 transcription. We showed that activation leads to transcription-related chromatin modifications, revealed by higher CD6 acetylation levels. Modulation of chromatin conformation using a histone deacetylase inhibitor that increases transcription rate causes an increase of exon 5 skipping. We further showed that the splicing factor SRSF1 binds to a regulatory element in CD6 intron 4, activating exon 5 splicing and promoting exon 5 inclusion. Concomitant with T cell activation-induced exon 5 skipping, we observed a downregulation of SRSF1. Using RNA immunoprecipitation, we showed that in activated T cells, SRSF1 recruitment to the CD6 transcript is impaired by increased chromatin acetylation levels. We propose that upon T cell activation, SRSF1 becomes limiting, and its function in CD6 exon 5 splicing is countered by an increase in CD6 transcription, dependent on chromatin acetylation. Copyright © 2014 by The American Association of Immunologists, Inc.This work was supported by the European Regional Development Fund, Programa Operacional Ciencia, Tecnologia e Inovacao 2010 (POCI and POCTI 2010), and the Fundacao para a Ciencia e Tecnologia (PTDC/SAU-GMG/116621/2010, PTDC/BEX-BCM/0468/2012, PTDC/IMI-IMU/0158/2012)
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