Cell fate control by pioneer transcription factors

Abstract

Distinct combinations of transcription factors are necessary to elicit cell fate changes in embryonic development. Yet within each group of fate-changing transcription factors, a subset called 'pioneer factors' are dominant in their ability to engage silent, unmarked chromatin and initiate the recruitment of other factors, thereby imparting new function to regulatory DNA sequences. Recent studies have shown that pioneer factors are also crucial for cellular reprogramming and that they are implicated in the marked changes in gene regulatory networks that occur in various cancers. Here, we provide an overview of the contexts in which pioneer factors function, how they can target silent genes, and their limitations at regions of heterochromatin. Understanding how pioneer factors regulate gene expression greatly enhances our understanding of how specific developmental lineages are established as well as how cell fates can be manipulated.

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

“…Thus, not surprisingly, the most potent transcription factors endowed with reprogramming activity are pioneer factors. Pioneer factors are transcription factors that initiate transcriptional programs leading to cell fate change via their engagement with silent, unmarked chromatin (Iwafuchi-Doi and Zaret, 2014Zaret, , 2016Zaret and Carroll, 2011). These low-signal chromatin regions are characterized by their relative lack of histone modifications (Ho et al, 2014;Kharchenko et al, 2011), where transcription is instead likely to be repressed by the presence of linker histones (Iwafuchi-Doi and Zaret, 2016).…”

“…Pioneer factors are transcription factors that initiate transcriptional programs leading to cell fate change via their engagement with silent, unmarked chromatin (Iwafuchi-Doi and Zaret, 2014Zaret, , 2016Zaret and Carroll, 2011). These low-signal chromatin regions are characterized by their relative lack of histone modifications (Ho et al, 2014;Kharchenko et al, 2011), where transcription is instead likely to be repressed by the presence of linker histones (Iwafuchi-Doi and Zaret, 2016). Pioneer factor binding results in the local opening of this silent chromatin (Soufi et al, 2012;van Oevelen et al, 2015), although in the absence of any other transcription factors this is insufficient to induce changes in gene expression.…”

Direct neuronal reprogramming: learning from and for development

“…Removing trimethylation of histone 3 lysine 9 via the expression of JmJD2d (Kdm4d) resulted in impaired efficiency of neuronal conversion. The ability of Ascl1 to act as a pioneer transcription factor (Iwafuchi-Doi and Zaret, 2016;Zaret and Mango, 2016) seems to be associated with this epigenetic signature, because in cells with low levels of these marks, such as human keratinocytes and osteoblasts, Ascl1 occupies almost completely different, offtarget sites lacking the E-box motif. These cells, as well as adult human pericytes and human liver cells, can be poorly, if at all, reprogrammed by Ascl1 alone (Karow et al, 2012;Marro et al, 2011;Wapinski et al, 2013).…”

“…Pioneer factor. A transcription factor that is capable of engaging silent, unmarked chromatin and initiating the recruitment of other factors to activate genes specific to a new fate (Iwafuchi-Doi and Zaret, 2016). Proneural factor.…”

A small-molecule screen reveals that HSP90β promotes the conversion of induced pluripotent stem cell-derived endoderm to a hepatic fate and regulates HNF4A turnover

“…Success in identifying proteins that control hepatic specification and hepatocyte differentiation has facilitated the generation of protocols that can be used to produce hepatocyte-like cells from human pluripotent stem cells (Cai et al, 2007;Hay et al, 2008;Basma et al, 2009;Si-Tayeb et al, 2010b;Sullivan et al, 2010;Touboul et al, 2010). Several reviews have discussed the molecular basis of liver development in depth (Lemaigre, 2009;Si-Tayeb et al, 2010a;Iwafuchi-Doi and Zaret, 2016). Briefly, the parenchymal cells of the liver originate from the ventral foregut endoderm.…”