Direct lineage reprogramming via pioneer factors; a detour through developmental gene regulatory networks

Abstract

Although many approaches have been employed to generate defined fate in vitro, the resultant cells often appear developmentally immature or incompletely specified, limiting their utility. Growing evidence suggests that current methods of direct lineage conversion may rely on the transition through a developmental intermediate. Here, I hypothesize that complete conversion between cell fates is more probable and feasible via reversion to a developmentally immature state. I posit that this is due to the role of pioneer transcription factors in engaging silent, unmarked chromatin and activating hierarchical gene regulatory networks responsible for embryonic patterning. Understanding these developmental contexts will be essential for the precise engineering of cell identity.

FoxA expression pattern in two polychaete species, Alitta virens and Platynereis dumerilii: Examination of the conserved key regulator of the gut development from cleavage through larval life, postlarval growth, and regeneration

“…Forkhead proteins, in particular FoxA group, are called pioneer factors. Binding to inactive chromatin and changing its structure, these proteins make chromatin accessible for many other transcription factors (Carlsson and Malhapuu, ; Morris, ). The ability to convert chromatin to the active state makes Forkhead proteins instrumental in regulating transcription and epigenetic modifications.…”

Developmental chromatin restriction of pro-growth gene networks acts as an epigenetic barrier to axon regeneration in cortical neurons

“…However, it is notable that in the absence of any other transcription factors, pioneer TF binding alone is insufficient to induce changes in gene expression; conversely other TFs are unable to engage silent chromatin without the assistance of pioneers (Morris, 2016;Guo and Morris, 2017). Therefore, efficient cellular reprogramming requires an optimal combination of both pioneer factors and cell-specific TFs, which act co-operatively to initiate transcriptional activation at specific genomic loci.…”

Programming and reprogramming the brain: a meeting of minds in neural fate

“…This Meeting Review summarises the new and exciting findings that were presented at the meeting, ranging from how neuronal diversity is programmed in vivo -either during development or in the natural transdifferentiation of cells into neurons -to the forced reprogramming of various cell types in vitro and in vivo. These two sides of the neuronal coin encircle the central question of how similar or different the developmental and reprogramming programs actually are (for discussion of this, see Masserdotti et al, 2016;Morris, 2016). Although there is still some way to go in unravelling the relationship between these processes, it was clear from this meeting that they are sufficiently similar to each benefit immensely from the findings of the other.…”