TY - JOUR
T1 - Regulation of human and mouse telomerase genes by genomic contexts and transcription factors during embryonic stem cell differentiation
AU - Cheng, De
AU - Wang, Shuwen
AU - Jia, Wenwen
AU - Zhao, Yuanjun
AU - Zhang, Fan
AU - Kang, Jiuhong
AU - Zhu, Jiyue
N1 - Funding Information:
We would like to thank Dr. Philip Leder of Harvard Medical School for providing TC1 mouse embryonic cell line. We also thank Chloe A. Dugger for her excellent technical support. This work was supported by National Institutes of Health [R01GM071725 to J.Z., and R21OD021432 to J.Z]; and Health Sciences and Services Authority (HSSA) of Spokane County, WA, USA.
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - Differential regulation of telomerase reverse transcriptase (TERT) genes contribute to distinct aging and tumorigenic processes in humans and mice. To study TERT regulation, we generated mouse embryonic stem cell (ESC) lines containing single-copy bacterial artificial chromosome (BAC) reporters, covering hTERT and mTERT genes and their neighboring loci, via recombinase-mediated BAC targeting. ESC lines with chimeric BACs, in which two TERT promoters were swapped, were also generated. Using these chromatinized BACs, we showed that hTERT silencing during differentiation to embryoid bodies (EBs) and to fibroblast-like cells was driven by the human-specific genomic context and accompanied by increases of repressive epigenetic marks, H3K9me3 and H3K27me3, near its promoter. Conversely, the mouse genomic context did not repress TERT transcription until late during differentiation. The hTERT promoter was more active than its mouse counterpart when compared in the same genomic contexts. Mutations of E-box and E2F consensus sites at the promoter had little effect on hTERT transcription in ESCs. However, the mutant promoters were rapidly silenced upon EB differentiation, indicating that transcription factors (TFs) bound to these sites were critical in maintaining hTERT transcription during differentiation. Together, our study revealed a dynamic hTERT regulation by chromatin environment and promoter-bound TFs during ESC differentiation.
AB - Differential regulation of telomerase reverse transcriptase (TERT) genes contribute to distinct aging and tumorigenic processes in humans and mice. To study TERT regulation, we generated mouse embryonic stem cell (ESC) lines containing single-copy bacterial artificial chromosome (BAC) reporters, covering hTERT and mTERT genes and their neighboring loci, via recombinase-mediated BAC targeting. ESC lines with chimeric BACs, in which two TERT promoters were swapped, were also generated. Using these chromatinized BACs, we showed that hTERT silencing during differentiation to embryoid bodies (EBs) and to fibroblast-like cells was driven by the human-specific genomic context and accompanied by increases of repressive epigenetic marks, H3K9me3 and H3K27me3, near its promoter. Conversely, the mouse genomic context did not repress TERT transcription until late during differentiation. The hTERT promoter was more active than its mouse counterpart when compared in the same genomic contexts. Mutations of E-box and E2F consensus sites at the promoter had little effect on hTERT transcription in ESCs. However, the mutant promoters were rapidly silenced upon EB differentiation, indicating that transcription factors (TFs) bound to these sites were critical in maintaining hTERT transcription during differentiation. Together, our study revealed a dynamic hTERT regulation by chromatin environment and promoter-bound TFs during ESC differentiation.
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U2 - 10.1038/s41598-017-16764-w
DO - 10.1038/s41598-017-16764-w
M3 - Article
C2 - 29180668
AN - SCOPUS:85035332135
SN - 2045-2322
VL - 7
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 16444
ER -