Sequence context and partner availability specify divergent cell fates from a single transcription factor

Farooq, H.; Joves, K.; Petenkaya, A.; Solomon, I.; Leung, E. H. W.; Zhang, S.; Menhart, M.; Farhat, A.; Du, L.; Hay, N.; Pinho, S.; Chronis, C.

doi:10.64898/2026.11.09.758913

bioRxiv · 10.64898/2026.11.09.758913

Sequence context and partner availability specify divergent cell fates from a single transcription factor

Farooq, H.·Joves, K.·Petenkaya, A.·Solomon, I.·Leung, E. H. W.·Zhang, S.·Menhart, M.·Farhat, A.·Du, L.·Hay, N.·Pinho, S.·Chronis, C.

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Abstract

Transcription factors drive the gene regulatory networks that control developmental transitions, yet which of their many targets a cell uses remains unresolved. Expressing Cebp, Cebp{beta} or Cebp{delta} identically, alone or with Oct4, Sox2, Klf4 and cMyc, gave four outcomes: adipocyte from fibroblasts and neural stem cells, trophectoderm from embryonic stem cells, and myeloid from B cells. Raising Cebp levels changed how many sites it reached, not which sequence it read: clustered motifs maintained somatic enhancers, while spillover onto low-copy sites created de novo enhancers carrying composites of Cebp and cell-type-restricted partners. In fibroblasts, Cebp also redistributed Oct4, Sox2 and Klf4 from early targets, blocking iPSC formation. Supplying the predicted partners rewrote the output: Spi1 redirected Cebp into parallel adipogenic and myeloid programs, via a transient PpargCD45 state using separate enhancers for each; TFAP2C abolished adipogenic conversion. Motif density and partner composites therefore assemble a factor's instructive output in the receiving cell.

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Farooq, H., Joves, K., Petenkaya, A., Solomon, I., Leung, E. H. W., Zhang, S., Menhart, M., Farhat, A., Du, L., Hay, N., Pinho, S., Chronis, C.. 2026-11-11. Sequence context and partner availability specify divergent cell fates from a single transcription factor. https://doi.org/10.64898/2026.11.09.758913

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