oa Unraveling molecular switches determining cell fate

The Yamanaka factors (Oct4, sox2, Klf4, cMyc) used to produce induced pluripotent stem cells (iPSC) have become a staple of stem cell biology and ChIP-seq studies have led to an understanding of the genomic landscape of how these as well as other recently discovered factors transduce their effects to form iPSC. A conundrum that previously existed was that the Sox family has high homology and yet various members drive completely different cell fates. My lab in collaboration with Larry Stanton's lab at the Genome Institute of Singapore unraveled part of the mystery by identifying and validating a single residue within the hmg domain of the Sox family responsible for a specific interaction with Oct4 (pou5F1 domain) which then decides specific cell fates. In addition a novel genomic motif was discovered which has a single base difference between the Oct4 and Sox binding sites. Using this knowledge we were able to transform the function of pluripotent Sox2 into an endodermal TF and endodermal Sox17 into a pluripotent TF. In fact the mutated Sox17 TF was even more efficient in forming iPSC (compared to Sox2) which was not expected. Recently we investigated the C-terminal activation domains of these Sox family members and discovered that they play a major role in the level of activation of iPSC. Conversion of Sox17 into a Pluripotency Reprogramming Factor by re-engineering its Association with Oct4 on DNA. Ralf Jauch, Irene Aksoy, Andrew Paul Hutchins, Calista Keow Leng Ng, Xian Feng Tian, Jiaxuan Chen, Paaventhan Palasingam, Paul Robson, Lawrence W. Stanton and Prasanna R Kolatkar. Stem Cells. 2011. Jun;29(6):940-51. Oct4 switches partnering from Sox2 to Sox17 to reinterpret the enhancer code and specify endoderm. Aksoy I, Jauch R, Chen J, Dyla M, Divakar U, Bogu GK, Teo R, Leng Ng CK, Herath W, Lili S, Hutchins AP, Robson P, Kolatkar PR, Stanton LW. EMBO J. 2013. 32(7): 938-53. Sox transcription factors require selective interactions with Oct4 and specific transactivation functions to mediate reprogramming. Aksoy, I., Jauch, R., Eras, V., Bin, A.C-W., Chen, J., Divakar, U., Ng, C. K-L., Kolatkar, P.R., Stanton, L.W. Stem Cells. 2013.