Pioneer factors in development and cancer

Abstract

Transcription factors (TFs) are essential mediators of epigenetic regulation and modifiers of penetrance. Studies from the past decades have revealed a sub-class of TF that is capable of remodeling closed chromatin states through targeting nucleosomal motifs. This pioneer factor (PF) class of chromatin remodeler is ATP independent in its roles in epigenetic initiation, with nucleosome-motif recognition and association with repressive chromatin regions. Increasing evidence suggests that the fundamental properties of PFs can be coopted in human cancers. We explore the role of PFs in the larger context of tissue-specific epigenetic regulation. Moreover, we highlight an emerging class of chimeric PF derived from translocation partners in human disease and PFs associated with rare tumors. In the age of site-directed genome editing and targeted protein degradation, increasing our understanding of PFs will provide access to next-generation therapy for human disease driven from altered transcriptional circuitry.

Keywords: Cancer systems biology; Epigenetics; Molecular biology; Systems biology.

Graphical abstract

Figure 1

Pioneer function and epigenetic state changes Evidence suggests that pioneer function is an early step in the establishment of an epigenetic state, with nucleosomal-motif recognition and binding in repressive chromatin regions. For distinct classes of pioneer factors, the recruitment of epigenetic machinery for chromatin activation might have distinct mechanisms.

Figure 2

Integration of the site exposure model with pioneer function at nucleosomal motifs (A) Conceptual model for the kinetics of pioneer factors, which can associate with nucleosomes in wrapped or unwrapped states. (B) Fitting our derived equation for fractional motif occupancy (Equation 3) with kinetic rate constants from Zaret and Poirier for pioneer factors and transcription factors in the context of fractional occupancy of TF-motif pairs.

Figure 3

Pioneer factors exhibit lineage-restricted expression and vulnerabilities (A and B) Data analysis from the GTEx Consortium for expression levels of key pioneer factors in various tissues, with a focus on OCT4, SOX2, ASCL1, MYOD, PAX3, PAX7, FOXA1, FOXO1, FOXD3, FOXA2, GATA3, PU.1, CEBPα, β and (B) Examples of pioneer factors whose activity drives human cancers, with data analyses from DepMap, with a focus on SOX2, ASCL1, MYOD, PAX3, PAX7, FOXA1, FOXO1, PU.1, and CEBPα.