Maternal pluripotency factors prime the zygotic genome to respond to intercellular signals

Author's response

George Gentsch and Jim Smith shared

Does the degradation of maternal pioneer factors provide a time-critical window of a poised chromatin landscape that can competently respond to signaling cues?

Cells continue to respond to the same signals beyond the maternal influence. However, early signal-dependent cell trajectories of the three germ layers very much depend on maternal pioneer factors. Later, zygotically expressed pioneer factors further specify cell fate decisions to generate the many derivatives of the germ layers.

 

Here you focused here on the role of Sox3/PouV, but noted a correlation of other maternal factors with the binding sites of genes activated during ZGA. Do you think that there is a master upstream pioneer factor during ZGA that acts to recruit the other factors and increase chromatin accessibility or this is a synchronised team effort?

Based on our results in Xenopus, this is an orchestrated effort of several maternal transcription factor families and they initiate the accessibility of specific DNA regulatory sequences by recognizing canonical DNA recognition motifs in nucleosomes. It appears that the chromatin accessibility and thus the operation of an early cell fate-specific gene regulatory network is frequently encoded by the SOX/POU motifs in enhancers.

 

Do you have an insight into whether Sox3 and PouV physically interact during Xenopus ZGA, does one recruit the other or do they both bind to the same sites but independently?

First, Sox3 and Pou5f3 are detected in the same nuclei of the early embryo. Second, they share a synergistic relationship in regulating ZGA. Third, their canonical binding sites are often detected as pairs suggesting heterodimerization between Sox3 and Pou5f3. Although we do not provide direct evidence of dimerization previous EMSA experiments have shown that Sox2 and Pou5f1 (Oct4) can simultaneously occupy the SOX/POU motif.

 

Does PouV/Sox directly recruit signaling effectors or indirectly through chromatin remodeling and creating favorable binding environment in their vicinity?

We do not know the answer to this question, which is the subject of current research. Based on our working model, direct interaction between Pou5f3 or Sox3 and signal mediators may not be required. However, it seems that signal mediators have poor pioneering activity and thus rely on the precedent opening of compacted chromatin by other DNA sequence-specific factors.

 

When thinking about introducing pioneer factors into somatic cells to increase reprogramming efficiency, could the opportunistic binding of pioneer factors (e.g. Sox3) to other factors present in somatic cells (e.g. MyoD) interrupt the efficiency of pioneer factors to drive chromatin remodelling? Might some cell types be more amenable to this approach than others depending on the proteins present?

Opportunistic (non-specific to DNA sequence) binding of pioneer factors seems to have minor effects on transcription. However, potent transcription factors like MyoD do interfere with any other (non-muscle) reprogramming attempts. Thus, MyoD requires silencing to induce SoxB1/Pou5F-dependent pluripotency. Some combinations of counteracting pioneer factors are normally transiently detected in cells of multi-lineage priming, i.e. cells giving rise to opposite cell fates.