Oct-3/4 maintains the proliferative embryonic stem cell state via specific binding to a variant octamer sequence in the regulatory region of the UTF1 locus.
The POU transcription factor Oct-3/4 has been shown to be critical for maintaining embryonic stem (ES) cell character. However, the molecular mechanisms underlying its function remain elusive. We have previously shown that among the POU transcription factor family of proteins, Oct-3/4 alone is able to bind to the regulatory region of the UTF1 gene bearing a variant octamer sequence together with Sox-2. Here, we demonstrate using Oct-3/4-Oct-6 chimeras that there is a precise correlation between the ability of proteins to form a complex on the UTF1 enhancer with Sox-2 and the ability to maintain the stem cell state in ES cells. Different chimeric proteins show differential abilities to form a Sox-2-containing complex on the UTF1 regulatory region, with a decrease in efficiency of the complex formation accompanied by a decrease in the level of UTF1 expression and the rate of cell proliferation. Overexpression of UTF1 in these slow-growing cells was able to restore their proliferation rate to wild-type levels. Moreover, UTF1 was also observed to have an effect on teratoma formation. These results suggest a molecular pathway by which Oct-3/4 induces rapid proliferation and tumorigenic properties of ES cells through activation of the UTF1 gene.
Nishimoto
Masazumi
M
Division of Developmental Biology, Research Center for Genomic Medicine, Saitama Medical School, 1397-1 Yamane, Hidaka, Saitama 350-1241, Japan.
Miyagi
Satoru
S
Yamagishi
Toshiyuki
T
Sakaguchi
Takehisa
T
Niwa
Hitoshi
H
Muramatsu
Masami
M
Okuda
Akihiko
A
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D002478:Cells, Cultured; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D024002:HMGB Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009374:Neoplasms, Experimental; D050814:Octamer Transcription Factor-3; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D055748:SOXB1 Transcription Factors; D016415:Sequence Alignment; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D013724:Teratoma / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D024002:HMGB Proteins; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C494174:Pou5f1 protein, mouse; D011993:Recombinant Fusion Proteins; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; C112198:Utf1 protein, mouse