Abstract
Transcriptional regulation plays an essential role in the self-renewal and differentiation of human embryonic stem cells (hESCs). However, how external signals disrupt the self-renewal regulatory network and further drive hESC differentiation remains largely unknown. Here, we found the immune regulative protein, gamma-interferon-inducible protein 16 (IFI16) was involved in the regulation of both self-renewal and differentiation gene expression during hESC trilineage specification through interaction with p53. IFI16 expression levels were upregulated through JNK activation. IFI16 knockdown delayed the downregulation of self-renewal gene expression and suppressed the upregulation of differentiation gene expression, while IFI16 overexpression accelerated trilineage specification. Furthermore, IFI16 stabilized p53-binding in the genome through IFI16-p53 interaction and differentially regulated self-renewal and differentiation gene expression. Together, our results suggest a particular role of IFI16 in differential gene expression regulation during trilineage specification of hESCs in a manner that is dependent on the genome-wide profile of p53-binding directed by IFI16-p53 interaction.
Highlights
Human embryonic stem cells and somatic cells share almost identical DNA sequence information, human embryonic stem cells (hESCs) maintain pluripotency through selective gene expression
According to the protocol proposed by Shinya Yamanaka, somatic cells can be reprogrammed into pluripotent stem cells by ectopic expression of transcription factors such as OCT4 and SOX21, suggesting that transcriptional regulation plays a key role in the pluripotency maintenance of hESCs
1234567890():,; 2 RESULTS interferon-inducible protein 16 (IFI16) is upregulated during trilineage specification results suggest that Jun N-terminal kinases (JNKs) pathway participates in the transcriptional activation of IFI16
Summary
Human embryonic stem cells (hESCs) and somatic cells share almost identical DNA sequence information, hESCs maintain pluripotency through selective gene expression. According to the protocol proposed by Shinya Yamanaka, somatic cells can be reprogrammed into pluripotent stem cells by ectopic expression of transcription factors such as OCT4 and SOX21, suggesting that transcriptional regulation plays a key role in the pluripotency maintenance of hESCs. OCT4, SOX2, and Nanog form a core self-renewal regulatory network to maintain the pluripotent state of hESCs2,3. An observation that IFI16 upregulation induced by LIF mediating the cell cycle arrest has been demonstrated in medullary thyroid carcinoma cells[9]. Those findings above demonstrate a potential role of IFI16 in cell proliferation and nuclear protein binding. In addition to immunoregulation, whether IFI16 participates in other physiological process especially in self-renewal and differentiation of hESCs is still unknown
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