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Multiscale integration of tissue and chromatin context converts cell heterogeneity into stable intestinal patterning [ChIP-Seq]

ABSTRACT: Tissue regeneration requires de novo patterning, which has been proposed to be facilitated by cellular heterogeneity. Yet, how such heterogeneities are integrated with the mechanochemical state of the tissue, and stabilized at the chromatin level into stable and spatially organised fates, remains poorly understood. Using in vivo mouse intestinal regeneration models and organoids, we identify a critical density regime which produces a permissive window of heterogeneity in the mechanosensor YAP1. We show that YAP1 heterogeneity is coupled to lineage-biased chromatin accessibility and is decoded through FOXA1, which integrates the permissive chromatin state to Delta-Notch supra-cellular feedback and lineage commitment. This circuit generates fate bistability and preserves a memory of transient YAP1 activity, maintaining spatial patterning as tissues return to homeostasis after injury. Together, our findings establish a multiscale framework in which tissue-scale mechanics tune single-cell competence and, through FOXA1-mediated bistability, convert transient heterogeneity into stable, reproducible, and self-organised tissue architecture.

ORGANISM(S): Mus musculus

PROVIDER: GSE283660 | GEO | 2026/06/30

REPOSITORIES: GEO

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Project description:Approximately 75% of breast cancers are driven by the estrogen receptor alpha (ER), and despite the advent of endocrine therapy to block ER signaling pathways, a significant portion of women develop resistance to these drugs. The pioneer factor FOXA1 has been shown to facilitate nearly all DNA-binding events of ER in response to estrogen in ER+ breast cancer (ER+BC). Notably, up-regulation of FOXA1 is a hallmark of endocrine-resistant phenotypes and has been shown to reprogram enhancer elements, leading to an altered transcriptome. However, FOXA1 is a critical pioneer factor for multiple nuclear hormone receptors aside from ER and is implicated in regulation of important factors such as HER2 and the androgen receptor (AR). With the diverse array of breast cancer molecular subtypes displaying complex interplay between ER, HER2, AR, PR, and other hormone receptors, describing the complete ensemble of FOXA1 binding partners in various contexts, such as endocrine-resistant tumors, is of increasing importance. To classify FOXA1 interactors, we generated MCF-7 cell lines stably expressing the biotin ligase miniTurbo fused to the N- or C-terminus of FOXA1. Using proximity labeling (PL) coupled with LC-MS/MS, we have comprehensively cataloged interactors of FOXA1, including expected proteins such as ER, AR, MLL3, YAP1, and GATA-3. Moreover, we have discovered 157 previously unpublished interactors of FOXA1. Importantly, poorer prognosis for relapse-free survival among ER+BC patients is associated with several of these novel interactors, including NR2C2, an orphan nuclear receptor previously shown to regulate various nuclear hormone receptor signaling but whose roles in breast cancer remain unclear. NR2C2 ChIP-seq in MCF-7 cells under control or FOXA1-depleted conditions revealed multiple NR2C2 binding mechanisms in relation to FOXA1 levels and binding, suggesting possible coordinate regulation of key loci. Integrating proteomic and genomic approaches, we have potentially highlighted new mechanisms of FOXA1 that could have future clinical impacts.

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Multiscale integration of tissue and chromatin context converts cell heterogeneity into stable intestinal patterning [ChIP-Seq]

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