TOBF1 modulates mouse embryonic stem cell fate through regulating alternative splicing of pluripotency genes
Meghali Aich,
Asgar Hussain Ansari,
Li Ding,
Vytautas Iesmantavicius,
Deepanjan Paul,
Chunaram Choudhary,
Souvik Maiti,
Frank Buchholz,
Debojyoti Chakraborty
Affiliations
Meghali Aich
CSIR- Institute of Genomics and Integrative Biology, New Delhi 110025, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
Asgar Hussain Ansari
CSIR- Institute of Genomics and Integrative Biology, New Delhi 110025, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
Li Ding
Medical Systems Biology, UCC, Medical Faculty Carl Gustav Carus, TU Dresden, Fetscherstrasse 74, 01307 Dresden, Germany
Vytautas Iesmantavicius
The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
Deepanjan Paul
CSIR- Institute of Genomics and Integrative Biology, New Delhi 110025, India
Chunaram Choudhary
The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
Souvik Maiti
CSIR- Institute of Genomics and Integrative Biology, New Delhi 110025, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
Frank Buchholz
Medical Systems Biology, UCC, Medical Faculty Carl Gustav Carus, TU Dresden, Fetscherstrasse 74, 01307 Dresden, Germany
Debojyoti Chakraborty
CSIR- Institute of Genomics and Integrative Biology, New Delhi 110025, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India; Corresponding author
Summary: Embryonic stem cells (ESCs) can undergo lineage-specific differentiation, giving rise to different cell types that constitute an organism. Although roles of transcription factors and chromatin modifiers in these cells have been described, how the alternative splicing (AS) machinery regulates their expression has not been sufficiently explored. Here, we show that the long non-coding RNA (lncRNA)-associated protein TOBF1 modulates the AS of transcripts necessary for maintaining stem cell identity in mouse ESCs. Among the genes affected is serine/arginine splicing factor 1 (SRSF1), whose AS leads to global changes in splicing and expression of a large number of downstream genes involved in the maintenance of ESC pluripotency. By overlaying information derived from TOBF1 chromatin occupancy, the distribution of its pluripotency-associated OCT-SOX binding motifs, and transcripts undergoing differential expression and AS upon its knockout, we describe local nuclear territories where these distinct events converge. Collectively, these contribute to the maintenance of mouse ESC identity.
