Definition of germ layer cell lineage alternative splicing programs reveals a critical role for Quaking in specifying cardiac cell fate.
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
20 05 2022
20 05 2022
Historique:
accepted:
25
04
2022
revised:
14
04
2022
received:
17
02
2022
pubmed:
12
5
2022
medline:
25
5
2022
entrez:
11
5
2022
Statut:
ppublish
Résumé
Alternative splicing is critical for development; however, its role in the specification of the three embryonic germ layers is poorly understood. By performing RNA-Seq on human embryonic stem cells (hESCs) and derived definitive endoderm, cardiac mesoderm, and ectoderm cell lineages, we detect distinct alternative splicing programs associated with each lineage. The most prominent splicing program differences are observed between definitive endoderm and cardiac mesoderm. Integrative multi-omics analyses link each program with lineage-enriched RNA binding protein regulators, and further suggest a widespread role for Quaking (QKI) in the specification of cardiac mesoderm. Remarkably, knockout of QKI disrupts the cardiac mesoderm-associated alternative splicing program and formation of myocytes. These changes arise in part through reduced expression of BIN1 splice variants linked to cardiac development. Mechanistically, we find that QKI represses inclusion of exon 7 in BIN1 pre-mRNA via an exonic ACUAA motif, and this is concomitant with intron removal and cleavage from chromatin. Collectively, our results uncover alternative splicing programs associated with the three germ lineages and demonstrate an important role for QKI in the formation of cardiac mesoderm.
Identifiants
pubmed: 35544276
pii: 6584437
doi: 10.1093/nar/gkac327
pmc: PMC9122611
doi:
Substances chimiques
QKI protein, human
0
RNA-Binding Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
5313-5334Subventions
Organisme : NIAID NIH HHS
ID : U01 AI130830
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR073228
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS099068
Pays : United States
Organisme : NHGRI NIH HHS
ID : R01 HG010730
Pays : United States
Organisme : NCATS NIH HHS
ID : KL2 TR001441
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM055479
Pays : United States
Organisme : NIAID NIH HHS
ID : P01 AI150585
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA204806
Pays : United States
Informations de copyright
© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.
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