Integrating cell-state and enhancer constraints discriminates models of PU.1 regulation during hematopoietic differentiation
- 1Rice University
Abstract
Distinct PU.1 levels are associated with progenitor, B-cell, and macrophage states during hematopoietic differentiation. A previous dynamical-systems model attributed these levels to multistability generated by PU.1 autoregulation coupled to feedback between PU.1 abundance and cell-cycle progression, but its predictions were not quantitatively evaluated against the motivating measurements. Here, we test this mechanism using reported measurements of PU.1 abundance, its synthesis rate, and cell-cycle duration, and develop progressively more mechanistic alternatives. The original growth-feedback model neither represents the two reported progenitor groups nor reproduces the nonmonotonic relationship between PU.1 abundance and cell-cycle length. Even with experimentally measured cell-type-specific growth rates, PU.1 autoregulation alone does not reproduce the observed PU.1 abundance and synthesis rates across cell states. Reproducing the cell-state measurements requires an additional cell-state-dependent input to PU.1 production. Guided by enhancer regulation, we model positive feedback between PU.1 and C/EBP and constrain it with reporter measurements, but this architecture cannot jointly reproduce the reporter and cell-state datasets. Adding RUNX1 permits data-consistent stable states when high effective cooperativity in PU.1-dependent C/EBP activation is allowed. Thus, combined dynamical and cis-regulatory constraints support additional regulation of PU.1 production beyond autoregulation, cell-type-specific dilution, and C/EBP feedback. The RUNX1-extended architecture provides one biologically grounded realization and generates experimentally testable hypotheses for differentiation networks.
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BibTeX
@misc{igoshin2026integrating,
title = {{Integrating cell-state and enhancer constraints discriminates models of PU.1 regulation during hematopoietic differentiation}},
author = {O. A. Igoshin and Y. Zhang},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.01.756127},
url = {https://www.biorxiv.org/content/10.64898/2026.10.01.756127v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Integrating cell-state and enhancer constraints discriminates models of PU.1 regulation during hematopoietic differentiation
AU - O. A. Igoshin
AU - Y. Zhang
PY - 2026
DA - 2026/10/01
PB - bioRxiv
DO - 10.64898/2026.10.01.756127
UR - https://www.biorxiv.org/content/10.64898/2026.10.01.756127v1
AB - Distinct PU.1 levels are associated with progenitor, B-cell, and macrophage states during hematopoietic differentiation. A previous dynamical-systems model attributed these levels to multistability generated by PU.1 autoregulation coupled to feedback between PU.1 abundance and cell-cycle progression, but its predictions were not quantitatively evaluated against the motivating measurements. Here, we test this mechanism using reported measurements of PU.1 abundance, its synthesis rate, and cell-cycle duration, and develop progressively more mechanistic alternatives. The original growth-feedback model neither represents the two reported progenitor groups nor reproduces the nonmonotonic relationship between PU.1 abundance and cell-cycle length. Even with experimentally measured cell-type-specific growth rates, PU.1 autoregulation alone does not reproduce the observed PU.1 abundance and synthesis rates across cell states. Reproducing the cell-state measurements requires an additional cell-state-dependent input to PU.1 production. Guided by enhancer regulation, we model positive feedback between PU.1 and C/EBP and constrain it with reporter measurements, but this architecture cannot jointly reproduce the reporter and cell-state datasets. Adding RUNX1 permits data-consistent stable states when high effective cooperativity in PU.1-dependent C/EBP activation is allowed. Thus, combined dynamical and cis-regulatory constraints support additional regulation of PU.1 production beyond autoregulation, cell-type-specific dilution, and C/EBP feedback. The RUNX1-extended architecture provides one biologically grounded realization and generates experimentally testable hypotheses for differentiation networks.
ER -