Harnessing endogenous transcription factors directly by small molecules for chemically induced pluripotency inception

Chemistry-alone approach has recently been applied for incepting pluripotency in somatic cells, representing a breakthrough in biology. However, chemical reprogramming is hampered by low efficiency, and the underlying molecular mechanisms remain unclear. Particularly, chemical compounds do not have specific DNA-recognition domains or transcription regulatory domains, and then how do small molecules work as a driving force for reinstating pluripotency in somatic cells? Furthermore, how to efficiently clear materials and structures of an old cell to prepare the rebuilding of a new one? Here, we show that small molecule CD3254 activates endogenous existing transcription factor RXRa to significantly promote mouse chemical reprogramming. Mechanistically, CD3254-RXRa axis can directly activate all the 11 RNA exosome component genes (Exosc1-10 and Dis3) at transcriptional level. Unexpectedly, rather than degrading mRNAs as its substrates, RNA exosome mainly modulates the degradation of transposable element (TE)-associated RNAs, particularly MMVL30, which is identified as a new barrier for cell-fate determination. In turn, MMVL30-mediated inflammation (IFN-? and TNF-a pathways) is reduced, contributing to the promotion of successful reprogramming. Collectively, our study provides conceptual advances for translating environmental cues into pluripotency inception, particularly, identifies that CD3254-RXRa-RNA exosome axis can promote chemical reprogramming, and suggests modulation of TE-mediated inflammation via CD3254-inducible RNA exosome as important opportunities for controlling cell fates and regenerative medicine.

Automated summary

Chemistry-alone approach has been used to initiate pluripotency in somatic cells, but it has low efficiency and lacks understanding of the underlying mechanisms. This study reveals that the small molecule CD3254 activates the transcription factor RXRa and promotes chemical reprogramming in mice. The CD3254-RXRa-RNA exosome axis directly activates RNA exosome component genes, leading to the degradation of transposable element-associated RNAs and reduction of TE-mediated inflammation, ultimately promoting successful reprogramming.