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Uhrf1 loss alters Ctcf-mediated topological organization during early mouse embryogenesis

ABSTRACT: UHRF1 is a chromatin-binding protein essential for maintaining DNA methylation and histone modification states, yet its integrated role in vivo remains incompletely understood. To define its function, we generated conditional Uhrf1 knockout embryonic stem cells (ESCs) and embryos. Uhrf1⁻/⁻ ESCs exhibited near-complete loss of 5mC and 5hmC but maintained pluripotency, whereas Uhrf1-null embryos developed normally until E8.5 and then failed to further develop by E9.5, phenocopying Dnmt1 loss. Single-cell multi-omic (ME-seq) profiling of E8.5 embryos revealed impaired lineage stabilization, widespread hypomethylation, and disrupted chromatin architecture. Uhrf1 loss predicted altered CTCF occupancy, accompanied with disorganized enhancer-promoter interactions, and defective Bmp signaling, particularly within neural crest populations. These findings identify Uhrf1 as a central regulator tightly coupling DNA methylation maintenance to 3D genome organization during gastrulation to direct early lineage specification, positioning Uhrf1 as a pivotal mediator of epigenetic information transfer during early embryogenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE308175 | GEO | 2026/03/15

REPOSITORIES: GEO

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Project description:Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma characterized by early metastasis, immune evasion, and limited therapeutic progress. While its genomic landscape is well defined, the epigenetic programs sustaining its lineage fidelity, metastatic potential, and immune evasion remain incompletely understood. We used inducible CRISPR-Cas9 knockout models, transcriptomic and epigenetic profiling, immune-competent allografts, and genetically engineered mouse models (GEMMs) to investigate the role of the chromatin regulator UHRF1 in SCLC progression. We identify the chromatin remodeler UHRF1 as a subtype-independent oncogenic driver in SCLC, with high expression correlating with poor survival. UHRF1 loss impaired proliferation, invasion, and metastasis across ASCL1-, NEUROD1-, and POU2F3-driven subtypes. Mechanistically, UHRF1 maintained neuroendocrine lineage identity and suppressed immune gene expression via DNA methylation and interaction with PRC2. UHRF1-deficient tumors displayed increased infiltration of CD8⁺ T cells, monocytes, neutrophils, and dendritic cells, along with a higher CD8⁺/Treg ratio. Secretome profiling revealed upregulation of chemokines, linking UHRF1 loss to active recruitment of immune effector cells. In parallel, UHRF1 regulated the pro-metastatic sialyltransferase ST6GALNAC5 via the transcription factor GATA2. UHRF1 loss downregulated GATA2 and ST6GALNAC5, impairing tumor dissemination. Lastly, UHRF1 depletion increased expression of cancer/testis antigens such as MAGE-A4, without altering DLL3 levels, suggesting compatibility with both antigen-specific and DLL3-targeted immunotherapies. In conclusion, UHRF1 is a master regulator of tumor progression in SCLC, promoting lineage stability, immune evasion, and metastatic spread. Its inhibition reprograms tumors toward an inflamed, less metastatic, and more immunogenic state. These findings establish UHRF1 as a compelling therapeutic target for overcoming the epigenetic and immune resistance barriers in small cell lung cancer.

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Uhrf1 loss alters Ctcf-mediated topological organization during early mouse embryogenesis

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