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Targeting Sufu-mediated Gli transcription alleviates ciliopathic phenotypes [kif3a_CUT&RUN]

ABSTRACT: Ciliopathies are incurable, pleiotropic diseases that result from defective cilia. Several ciliopathic phenotypes arise from improper processing and activity of Gli transcription factors yet attempts to rescue these phenotypes by overexpressing activator or repressor Gli isoforms have proven unsuccessful. Gli proteins are regulated by Sufu, and Sufu-Gli complexes accumulate in ciliopathies, fundamentally altering the normal Sufu-Gli interaction dynamics. Herein, we investigated whether targeting Sufu-Gli interactions would provide a therapeutic benefit for ciliopathies. We introduced a single copy of SufuD159R, a point mutation that disrupts Sufu-Gli binding, into a ciliopathic mouse model. This genetic modification restored Gli3 binding to DNA and the subsequent transcription of target genes, and led to a significant rescue of numerous ciliopathic phenotypes. These findings suggest that modulating Sufu-Gli interactions may serve as a promising therapeutic approach for ameliorating ciliopathic pathologies.

ORGANISM(S): Mus musculus

PROVIDER: GSE301704 | GEO | 2026/01/07

REPOSITORIES: GEO

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Targeting Sufu-mediated Gli transcription alleviates ciliopathic phenotypes [sufu_RNA-seq]

Project description:Ciliopathies are incurable, pleiotropic diseases that result from defective cilia. Several ciliopathic phenotypes arise from improper processing and activity of Gli transcription factors yet attempts to rescue these phenotypes by overexpressing activator or repressor Gli isoforms have proven unsuccessful. Gli proteins are regulated by Sufu, and Sufu-Gli complexes accumulate in ciliopathies, fundamentally altering the normal Sufu-Gli interaction dynamics. Herein, we investigated whether targeting Sufu-Gli interactions would provide a therapeutic benefit for ciliopathies. We introduced a single copy of SufuD159R, a point mutation that disrupts Sufu-Gli binding, into a ciliopathic mouse model. This genetic modification restored Gli3 binding to DNA and the subsequent transcription of target genes, and led to a significant rescue of numerous ciliopathic phenotypes. These findings suggest that modulating Sufu-Gli interactions may serve as a promising therapeutic approach for ameliorating ciliopathic pathologies.

2026-01-07 | GSE301707 | GEO

GLI transcriptional repression is inert prior to HH pathway activation

Project description:Purpose: Most Hedgehog responsive gene expression is mediated through GLI de-repression. Additionally GLI -repression is proposed to play roles in limb pre-patterning before HH pathway activation. This study evaluates if GLI repression is established prior to HH pathway activation. Methods: To determine if GLI-repression is established prior to pathway activation, we used genomic approaches to study GLI-mediated repression using the mouse developing limb as a model. We identified pre-HH (E9.25, 21-23S) and post-HH (E10.5, 32-25S) GLI3 binding regions using CUT&RUN for endogenous FLAG-tagged GLI3 proteins. Using a combination of ChIP-seq, CUT&RUN, CUT&Tag, ATAC-seq and RNA-seq, we tested whether loss of Gli3 prior to HH signaling was able to de-repress genes and enhancers, as it does after HH signaling. Results: Prior to HH signaling, GLI3 binds to poised, accessible regions with histone deacetylase (HDAC) proteins, similar to post-HH signaling. Despite GLI3 binding to most regions as it does in the post-HH limb, loss of Gli3 is unable to prematurely active target genes or enhancers. Furthermore, we find that GLI3-dependent chromatin compaction does not occur until roughly 10 hours after HH signaling would have normally been induced. Collectively, these results support that GLI repressor proteins are inert prior to HH pathway activation.

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Project description:Targeting Sufu-mediated Gli transcription alleviates ciliopathic phenotypes

| PRJNA1281601 | ENA

Project description:Targeting Sufu-mediated Gli transcription alleviates ciliopathic phenotypes

| PRJNA1283947 | ENA

Combinatorial Gli activity directs immune infiltration and tumor growth in pancreatic cancer

Project description:Proper Hedgehog (HH) signaling is essential for normal embryonic and postnatal development, while de-regulated HH signaling drives numerous pediatric and adult cancers. In pancreatic cancer, paracrine HH signaling from tumor cells to fibroblasts contributes to tumor progression. However, the role of HH signaling in pancreatic cancer remains controversial, with both tumor-promoting and tumor-restraining functions reported. Notably, the GLI family of transcription factors (GLI1, GLI2, GLI3), key downstream effectors of HH signaling, remain poorly understood in pancreatic cancer. In this study we investigated the individual and combined roles of GLI1-3 in pancreatic cancer progression. Inducible, fibroblast-specific deletion of Gli2 and Gli3 in a mouse model of pancreatic cancer progression reduces collagen deposition and decreases immunosuppressive myeloid cell infiltration. Further, Gli2 and Gli3 deletion leads to an increase in T cells during PanIN stages and an increase in NK cells in implanted tumors, which in turn suppresses tumor growth. Surprisingly, combined loss of all three Glis leads to a widespread loss of acinar cells, an increase in macrophage infiltration, and an increase in tumor growth. Together, these data indicate that a baseline level of Gli is necessary to maintain proper balance of cell types in the pancreas, and the coordinated activity of GLI1-3 directs the fibroinflammatory response in pancreatic cancer.

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CS sufu

Project description:CS sufu Raw sequence reads

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Project description:BS sufu Raw sequence reads

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