Abstract
The actions of transcription factors, chromatin modifiers and noncoding RNAs are crucial for the programming of cell states. Although the importance of various epigenetic machineries for controlling pluripotency of embryonic stem (ES) cells has been previously studied, how chromatin modifiers cooperate with specific transcription factors still remains largely elusive. Here, we find that Pontin chromatin remodelling factor plays an essential role as a coactivator for Oct4 for maintenance of pluripotency in mouse ES cells. Genome-wide analyses reveal that Pontin and Oct4 share a substantial set of target genes involved in ES cell maintenance. Intriguingly, we find that the Oct4-dependent coactivator function of Pontin extends to the transcription of large intergenic noncoding RNAs (lincRNAs) and in particular linc1253, a lineage programme repressing lincRNA, is a Pontin-dependent Oct4 target lincRNA. Together, our findings demonstrate that the Oct4-Pontin module plays critical roles in the regulation of genes involved in ES cell fate determination.
Highlights
The actions of transcription factors, chromatin modifiers and noncoding RNAs are crucial for the programming of cell states
Pontin heterozygous (Pontin þ / À ) mice were fertile and showed no detectable developmental abnormalities over 1.5-year-observation period, none of the Pontin-deficient homozygous (Pontin À / À ) animals were obtained from 168 offsprings (Supplementary Fig. 1d), indicating that lack of Pontin resulted in embryonic lethality
On the basis of the 30 rapid amplification of cDNA ends (RACE) experiment followed by cDNA cloning, we found that linc1253 is an B1,500-nucleotide transcript comprising three exons at the locus of chr10: 94,906,836–94,923,359 (Fig. 6c), which is consistent with our mRNA-sequencing data in embryonic stem (ES) cells (Fig. 6d)
Summary
The actions of transcription factors, chromatin modifiers and noncoding RNAs are crucial for the programming of cell states. Recent studies have highlighted that non-coding RNAs are important for both the maintenance of pluripotency and repression of differentiation programme in ES cells, along with key transcription factors and chromatin modifiers[11,12,13]. There are over 200 lincRNAs identified in ES cells, and some of them including linc1368, linc1577 and linc1634 function to maintain the pluripotent state through regulation of Oct[4] or Nanog expression[18]. A subset of Oct4-dependent lincRNAs is regulated by Oct4Pontin module, and these Oct4/Pontin-dependent lincRNAs are mainly involved in the repression of differentiation programme in ES cells Together, these findings demonstrate a functional link between lincRNAs and chromatin modifiers, which is mediated by Oct[4] to orchestrate the programming of cell states in ES cells
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