Collaborative binding by diverse pioneer transcription factors amplifies Polycomb repression to preserve lineage fidelity
- 1Cincinnati Children's Hospital Medical Center, University of Cincinnati
Abstract
Cooperative and collaborative modes of transcription factor (TF) binding are central to eukaryotic gene activation, providing regulatory specificity and robustness in cell fate control. However, gene activation is only half the story of transcriptional regulation, and cells also require mechanisms to repress inappropriate gene programs. It remains largely unknown how broadly expressed repressive TFs and epigenetic regulators achieve context-specific repression required for proper cell differentiation. Here, we show that the repressive TF PRDM1 cooperates with lineage- and stage-specific pioneer TFs during human endoderm differentiation. Notably, the number of diverse pioneer TFs bound at enhancers determines the strength of PRDM1-mediated enhancer repression. Mechanistically, collaborative binding by multiple pioneer TFs synergistically promotes local nucleosome remodeling and stabilizes PRDM1 occupancy, culminating in the formation of hyper-bivalent enhancers that are characterized by strongly elevated levels of H3K4me1 and Polycomb-associated modifications. These enhancers reinforce the repression of alternative-lineage, and past and future developmental programs. Together, our findings redefine the roles of TF cooperation and chromatin accessibility beyond the prevailing activation-centric view. We propose a collaborative repression model in which diverse pioneer TFs establish focal chromatin accessibility that reinforces the context-specific assembly of repressive regulators, thereby safeguarding lineage and developmental fidelity.
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BibTeX
@misc{mirizio2026collaborative,
title = {{Collaborative binding by diverse pioneer transcription factors amplifies Polycomb repression to preserve lineage fidelity}},
author = {G. Mirizio and M. Buckley and K. Ludwig and S. Matsui and S. Sampson and H.-W. Lim and M. Iwafuchi},
howpublished = {bioRxiv},
year = {2026},
month = may,
doi = {10.64898/2026.05.19.726322},
url = {https://www.biorxiv.org/content/10.64898/2026.05.19.726322v2},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Collaborative binding by diverse pioneer transcription factors amplifies Polycomb repression to preserve lineage fidelity
AU - G. Mirizio
AU - M. Buckley
AU - K. Ludwig
AU - S. Matsui
AU - S. Sampson
AU - H.-W. Lim
AU - M. Iwafuchi
PY - 2026
DA - 2026/05/19
PB - bioRxiv
DO - 10.64898/2026.05.19.726322
UR - https://www.biorxiv.org/content/10.64898/2026.05.19.726322v2
AB - Cooperative and collaborative modes of transcription factor (TF) binding are central to eukaryotic gene activation, providing regulatory specificity and robustness in cell fate control. However, gene activation is only half the story of transcriptional regulation, and cells also require mechanisms to repress inappropriate gene programs. It remains largely unknown how broadly expressed repressive TFs and epigenetic regulators achieve context-specific repression required for proper cell differentiation. Here, we show that the repressive TF PRDM1 cooperates with lineage- and stage-specific pioneer TFs during human endoderm differentiation. Notably, the number of diverse pioneer TFs bound at enhancers determines the strength of PRDM1-mediated enhancer repression. Mechanistically, collaborative binding by multiple pioneer TFs synergistically promotes local nucleosome remodeling and stabilizes PRDM1 occupancy, culminating in the formation of hyper-bivalent enhancers that are characterized by strongly elevated levels of H3K4me1 and Polycomb-associated modifications. These enhancers reinforce the repression of alternative-lineage, and past and future developmental programs. Together, our findings redefine the roles of TF cooperation and chromatin accessibility beyond the prevailing activation-centric view. We propose a collaborative repression model in which diverse pioneer TFs establish focal chromatin accessibility that reinforces the context-specific assembly of repressive regulators, thereby safeguarding lineage and developmental fidelity.
ER -