Sox transcription factors require selective interactions with oct4 and specific transactivation functions to mediate reprogramming

Irene Aksoy, Ralf Jauch, Volker Eras, Wen Bin Alfred Chng, Jiaxuan Chen, Ushashree Divakar, Calista Keow Leng Ng, Prasanna Kolatkar, Lawrence W. Stanton

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

The unique ability of Sox2 to cooperate with Oct4 at selective binding sites in the genome is critical for reprogramming somatic cells into induced pluripotent stem cells (iPSCs). We have recently demonstrated that Sox17 can be converted into a reprogramming factor by alteration of a single amino acid (Sox17EK) within its DNA binding HMG domain. Here we expanded this study by introducing analogous mutations to 10 other Sox proteins and interrogated the role of N-and C-termini on the reprogramming efficiency. We found that point-mutated Sox7 and Sox17 can convert human and mouse fibroblasts into iPSCs, but Sox4, Sox5, Sox6, Sox8, Sox9, Sox11, Sox12, Sox13, and Sox18 cannot. Next we studied regions outside the HMG domain and found that the C-terminal transactivation domain of Sox17 and Sox7 enhances the potency of Sox2 in iPSC assays and confers weak reprogramming potential to the otherwise inactive Sox4EK and Sox18EK proteins. These results suggest that the glutamate (E) to lysine (K) mutation in the HMG domain is necessary but insufficient to swap the function of Sox factors. Moreover, the HMG domain alone fused to the VP16 transactivation domain is able to induce reprogramming, albeit at low efficiency. By molecular dissection of the C-terminus of Sox17, we found that the b-catenin interaction region contributes to the enhanced reprogramming efficiency of Sox17EK. To mechanistically understand the enhanced reprogramming potential of Sox17EK, we analyzed ChIPsequencing and expression data and identified a subset of candidate genes specifically regulated by Sox17EK and not by Sox2.

Original languageEnglish
Pages (from-to)2632-2646
Number of pages15
JournalStem Cells
Volume31
Issue number12
DOIs
Publication statusPublished - 1 Dec 2013

Fingerprint

Induced Pluripotent Stem Cells
Transcriptional Activation
Transcription Factors
Colony-Forming Units Assay
Catenins
Mutation
Lysine
Dissection
Glutamic Acid
Proteins
Fibroblasts
Binding Sites
Genome
Amino Acids
DNA
Genes

Keywords

  • C-terminal transactivation domain
  • High-mobility group domain
  • Induced pluripotent stem cells
  • LIF/STAT3 pathway
  • Reprogramming
  • Sox transcription factors
  • Wnt/b-catenin pathway

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Molecular Medicine

Cite this

Aksoy, I., Jauch, R., Eras, V., Chng, W. B. A., Chen, J., Divakar, U., ... Stanton, L. W. (2013). Sox transcription factors require selective interactions with oct4 and specific transactivation functions to mediate reprogramming. Stem Cells, 31(12), 2632-2646. https://doi.org/10.1002/stem.1522

Sox transcription factors require selective interactions with oct4 and specific transactivation functions to mediate reprogramming. / Aksoy, Irene; Jauch, Ralf; Eras, Volker; Chng, Wen Bin Alfred; Chen, Jiaxuan; Divakar, Ushashree; Ng, Calista Keow Leng; Kolatkar, Prasanna; Stanton, Lawrence W.

In: Stem Cells, Vol. 31, No. 12, 01.12.2013, p. 2632-2646.

Research output: Contribution to journalArticle

Aksoy, I, Jauch, R, Eras, V, Chng, WBA, Chen, J, Divakar, U, Ng, CKL, Kolatkar, P & Stanton, LW 2013, 'Sox transcription factors require selective interactions with oct4 and specific transactivation functions to mediate reprogramming', Stem Cells, vol. 31, no. 12, pp. 2632-2646. https://doi.org/10.1002/stem.1522
Aksoy, Irene ; Jauch, Ralf ; Eras, Volker ; Chng, Wen Bin Alfred ; Chen, Jiaxuan ; Divakar, Ushashree ; Ng, Calista Keow Leng ; Kolatkar, Prasanna ; Stanton, Lawrence W. / Sox transcription factors require selective interactions with oct4 and specific transactivation functions to mediate reprogramming. In: Stem Cells. 2013 ; Vol. 31, No. 12. pp. 2632-2646.
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