Alternative splicing links histone modifications to stem cell fate decision.

Abstract:

BACKGROUND:Understanding the embryonic stem cell (ESC) fate decision between self-renewal and proper differentiation is important for developmental biology and regenerative medicine. Attention has focused on mechanisms involving histone modifications, alternative pre-messenger RNA splicing, and cell-cycle progression. However, their intricate interrelations and joint contributions to ESC fate decision remain unclear. RESULTS:We analyze the transcriptomes and epigenomes of human ESC and five types of differentiated cells. We identify thousands of alternatively spliced exons and reveal their development and lineage-dependent characterizations. Several histone modifications show dynamic changes in alternatively spliced exons and three are strongly associated with 52.8% of alternative splicing events upon hESC differentiation. The histone modification-associated alternatively spliced genes predominantly function in G2/M phases and ATM/ATR-mediated DNA damage response pathway for cell differentiation, whereas other alternatively spliced genes are enriched in the G1 phase and pathways for self-renewal. These results imply a potential epigenetic mechanism by which some histone modifications contribute to ESC fate decision through the regulation of alternative splicing in specific pathways and cell-cycle genes. Supported by experimental validations and extended datasets from Roadmap/ENCODE projects, we exemplify this mechanism by a cell-cycle-related transcription factor, PBX1, which regulates the pluripotency regulatory network by binding to NANOG. We suggest that the isoform switch from PBX1a to PBX1b links H3K36me3 to hESC fate determination through the PSIP1/SRSF1 adaptor, which results in the exon skipping of PBX1. CONCLUSION:We reveal the mechanism by which alternative splicing links histone modifications to stem cell fate decision.

journal_name

Genome Biol

journal_title

Genome biology

authors

Xu Y,Zhao W,Olson SD,Prabhakara KS,Zhou X

doi

10.1186/s13059-018-1512-3

subject

Has Abstract

pub_date

2018-09-14 00:00:00

pages

133

issue

1

eissn

1474-7596

issn

1474-760X

pii

10.1186/s13059-018-1512-3

journal_volume

19

pub_type

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