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Spatiotemporal lineage derepression by cell crowding-induced ETV4 inactivation

ABSTRACT: All extant amniotes employ a single-layered epithelium of epiblasts as a starting material for gastrulation, suggesting the necessity of the epithelial structure for three germ layer derivation. Using a human embryonic stem cell (hESC) epithelium as a model system, we found that local epithelial crowding derepresses the neuroectoderm fate by spatiotemporal inactivation of ETV4. ETV4 serves as a genetic toggle switch that links cell density to lineage fates. Mechanistically, cell crowding blocks FGF receptor endocytosis by reduced cell-extracellular matrix (ECM) interaction. Disrupted endocytosis decreases ETV4 protein stability by ERK inactivation. Mathematical modeling of epithelial crowding demonstrates that the cooperativity of integrin-ECM interaction transforms the gradient of crowdedness into bistable ETV4 transition, which ensures the switch-like function of ETV4 in lineage determination. Our results propose local cell crowding in a stem cell epithelium as a key cellular mechanism for spatiotemporal regulation of lineage fates.

ORGANISM(S): Homo sapiens

PROVIDER: GSE183702 | GEO | 2024/03/12

REPOSITORIES: GEO

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Project description:PBRM1 is the 2nd-most frequently inactivated gene in clear cell renal cell cancer (RCC) but the oncogenic mechanisms, and hence methods for correction, are unclear. PBRM1 is a subunit of the PBAF coactivator complex that transcription factors use to reposition nucleosomes (‘open chromatin’) for gene activation. We therefore looked for transcription factors that recruit endogenous PBRM1 in kidney lineage/RCC cells, as a waypoint to identifying pathways impacted by PBRM1 loss. Unbiased immunoprecipitation/mass-spectrometry analyses of the endogenous PBRM1 interactome in kidney lineage cells revealed PAX8, a master transcription factor essential for proximal tubule epithelial fates, as the major transcription factor recruiting PBRM1/PBAF. The reverse analyses of the PAX8 interactome confirmed recruitment specifically of PBRM1/PBAF, and not the functionally similar BAF coactivator complex. More conspicuous in the PAX8 hub in RCC cells, however, were several corepressors, e.g. DNMT1, which oppose coactivators to repress instead of activate genes. Accordingly, key PAX8 target genes, e.g., GATA3, LHX1, WT1, and ~1000 other downstream kidney epithelial genes, but not PAX8 or PAX2, demonstrated loss of the histone lysine 27 acetylation (H3K27ac) activation mark, increase in CpG methylation repression marks, and lower expression in RCC vs normal kidney cortex, with the greatest repression in cases with bi-allelic PBRM1 inactivation. PBRM1 re-introduction into RCC cells, or depletion of the corepressor DNMT1 using siRNA or a clinical drug decitabine, rebalanced composition and function of the PAX8 transcription factor hub to coactivators, to thereby activate terminal epithelial-fates in vitro and in vivo. In sum, PBRM1 loss in RCC cells skews coregulator composition of the PAX8 master transcription factor hub toward corepressors and repression instead of activation of the downstream terminal epithelial-program; this oncogenic action could be reversed by pharmacologic corepressor depletion/inhibition.

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Spatiotemporal lineage derepression by cell crowding-induced ETV4 inactivation

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