Pioneer factors in development and cancer

Abstract

Summary 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.

Probing cell identity hierarchies by fate titration and collision during direct reprogramming

“…Strikingly, we found that the mesodermal factor MyoD1 was most potent in imposing its fate and repressing the original mesodermal fibroblast identity. This might seem surprising since not only MyoD1 but also Ascl1, FoxA2, Sox2, and Oct4 have been attributed pioneer factor activity and are all considered key drivers of their respective reprogramming paradigms (Iwafuchi‐Doi & Zaret, 2014 ; Zaret & Mango, 2016 ; Zaret, 2020 ; Sunkel & Stanton, 2021 ). Indeed, Ascl1 and MyoD1 are, on their own, sufficient to reprogram MEFs into induced neurons and muscles, respectively (Davis et al , 1987 ; Chanda et al , 2014 ).…”

The 3D chromatin landscape of rhabdomyosarcoma

“…CC-BY-NC-ND 4.0 International license perpetuity. It is made available under a preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in The copyright holder for this this version posted December 5, 2022. ; https://doi.org/10.1101/2022.12.05.519166 doi: bioRxiv preprint structural domains (40,41). These data suggest that the master regulatory factors PAX3-FOXO1 and MYOD have distinct chromatin structural roles in RMS, as opposed to overlapping functions.…”

“…Chromatin samples were immunoprecipitated overnight at 4 C with antibodies targeting MYOD (CST cat#13812S), H3K27ac (Active Motif, cat#39133). DNA purifications were performed with modified ChIP protocol described previously 40 . For sample normalization 2 million C2C12 cells of were added to 6 million RMS cells before sonication.…”

Androgen Receptor-Mediated Transcription in Prostate Cancer

“…PFs engage with nucleosomes [ 33 ] that are dynamically transitioning between fully wrapped and transient exposure states [ 34 , 35 ]. The window of exposure is sufficient to allow binding of PFs as well as other TFs [ 36 ]. PFs typically bind to poised/active enhancers containing histone marks such as histone 3 lysine 4 mono/di-methylation (H3K4me1/me2) [ 37 , 38 ] and histone 3 lysine 9/27 acetylation (H3K9/27ac) [ 39 , 40 ].…”

“…This is strongly influenced by AR itself, as those sites that are unaffected following FOXA1 knockdown generally have higher AR occupancy [ 54 ]. GATA2 (GATA-binding factor 2) is another well-characterized PF that increases accessibility at ARBS [ 36 , 55 ]. Although GATA2 chromatin accessibility induction is less effective than FOXA1 [ 52 ], GATA proteins facilitate binding of AR and estrogen receptor (ER) in prostate [ 56 ] and breast cancer [ 57 ], respectively.…”