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Analysis of AP-1 regulation on Smad3 genome-wide DNA binding sites in resistant basal cell carcinoma

ABSTRACT: Tumor heterogeneity and lack of knowledge about resistant cell states remain a significant barrier to effective targeted cancer therapies. Basal cell carcinomas (BCCs) uniformly depend on Hedgehog (Hh)/Gli signaling for cell growth. We previously identified a nuclear myocardin-related transcription factor (nMRTF) resistance pathway that amplifies Gli1 activity, but nMRTF cell state and key factors driving its accumulation remain unknown. Epigenetic analysis of isolated nMRTF human tumor subpopulations demonstrates that cooperative AP-1 and TGFß signaling drive nMRTF activation. In this study, we find that AP-1 signaling drives changes in chromatin accessibility leading to differential Smad3 DNA binding and a transcriptional program of upstream activators of Rho, including RhoGEFs, that facilitate nMRTF activity.

ORGANISM(S): Mus musculus

PROVIDER: GSE142469 | GEO | 2020/08/25

REPOSITORIES: GEO

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AP-1 dependent changes in chromatin accessibility in resistant basal cell carcinoma cell line

Project description:Tumor heterogeneity and lack of knowledge about resistant cell states remain a significant barrier to effective targeted cancer therapies. Basal cell carcinomas (BCCs) uniformly depend on Hedgehog (Hh)/Gli signaling for cell growth. We previously identified a nuclear myocardin-related transcription factor (nMRTF) resistance pathway that amplifies Gli1 activity, but nMRTF cell state and key factors driving its accumulation remain unknown. We have determined that AP-1 transcription factor activity is essential to maintain MRTF activation. Here, we treat a murine BCC cell line with small molecule AP-1 inhibitor and analyze chromatin accessibility profiles.

2020-08-25 | GSE156764 | GEO

AP-1 and TGFb-dependent transcriptomic changes in resistant basal cell carcinoma cell line

Project description:Tumor heterogeneity and lack of knowledge about resistant cell states remain a significant barrier to effective targeted cancer therapies. Basal cell carcinomas (BCCs) uniformly depend on Hedgehog (Hh)/Gli signaling for cell growth. We previously identified a nuclear myocardin-related transcription factor (nMRTF) resistance pathway that amplifies Gli1 activity, but nMRTF cell state and key factors driving its accumulation remain unknown. We have determined that AP-1 and TGFb transcription factor activity is essential to maintain MRTF activation. Here, we treat a murine BCC cell line with small molecule AP-1 and ALK5 inhibitors and analyze transcriptomic profiles.

2020-08-25 | GSE156789 | GEO

Genome-wide chromatin accessibility analysis of MRTF-active subpopulations in human basal cell carcinoma

Project description:Tumor heterogeneity and lack of knowledge about resistant cell states remain a significant barrier to effective targeted cancer therapies. Basal cell carcinomas (BCCs) uniformly depend on Hedgehog (Hh)/Gli signaling for cell growth. We previously identified a nuclear myocardin-related transcription factor (nMRTF) resistance pathway that amplifies Gli1 activity, but nMRTF cell state and key factors driving its accumulation remain unknown. Here, we use three surface markers (LYPD3, TACSTD2, and LY6D) to isolate the nMRTF subpopulation and analyze chromatin accessibility profiles.

2020-08-25 | GSE156853 | GEO

Genome-wide transcriptomic analysis of MRTF-active subpopulations in naïve human basal cell carcinoma

Project description:Tumor heterogeneity and lack of knowledge about resistant cell states remain a significant barrier to effective targeted cancer therapies. Basal cell carcinomas (BCCs) uniformly depend on Hedgehog (Hh)/Gli signaling for cell growth. We previously identified a nuclear myocardin-related transcription factor (nMRTF) resistance pathway that amplifies Gli1 activity, but nMRTF cell state and key factors driving its accumulation remain unknown. Here, we use three surface markers (LYPD3, TACSTD2, and LY6D) to isolate the nMRTF subpopulation and analyze transcriptomic profiles.

2020-08-25 | GSE156790 | GEO

Genomic profiling of metastatic basal cell carcinoma reveals candidate drivers of disease and therapeutic targets

Project description:We assessed the clinicopathologic characteristics of 17 patients with metastatic BCC and pursued whole-exome sequencing of tumor and germline DNA from 8 patients. Genomic profiling revealed aberrant activation of Hedgehog signaling, alterations in regulators of GLI transcriptional activity, in kinases and members of Notch and Hippo signaling. Matched local recurrences of primary BCCs and metastases from three patients provided evidence of a clonal origin in all cases. Mutations in genes associated with YAP inhibition and negative regulation of WNT signaling were found exclusively in hematogenously-spread lung metastases. Metastatic BCCs were enriched for mutations in YAP/TAZ binding domain of TEAD transcriptional factors, RET, HGF and PI3K/AKT signaling compared with an independent cohort of low clinical risk BCCs. Our results implicate Hippo, WNT and PI3K/AKT dysregulation in metastatic progression of BCCs, making these potential therapeutic targets in metastatic disease.

| EGAS00001006148 | EGA

Genome-wide maps of chromatin accessibility in response to Hh signaling in mouse embryonic forelimb buds

Project description:Purpose: The response to Hedgehog signaling in the limb is driven by GLI bound enhancers and the majority of Hh targets in the developing limb bud are regulated solely by the activity of GLI-repressor. Currently, we do not have a comprehensive understanding of how GLI bound enhancers respond to Hedgehog signaling. The goal of this study is to identify how GLI bound enhancers are regulated by Hedgehog signaling and specifically by GLI-repressor. Methods: ATAC-seq was done in embryonic day 10.5 posterior limb buds from control and Shh-null embryos to identify GLI enhancers that change chromatin accessibility in response to Hedgehog signaling. Results: We found that Hedgehog signaling regulates the chromatin accessibility of a subset of GLI binding regions. This subset of GLI bound enhancers has reduced accessibility in the absence of Hedgehog signaling and largely overlaps with GLI enhancers that also have reduced H3K27ac in the absence of Hedgehog signaling.

2020-01-21 | GSE107877 | GEO

Identification of GLI-associated proteins by mass spectrometry

Project description:The Hedgehog signaling pathway is essential for the maintenance and response of several types of stem cells. To study the transcriptional response of stem cells to HH signaling, we searched for proteins binding to GLI proteins, the transcriptional effectors of the HH pathway in mouse embryonic stem (ES) cells. We purified GLI protein complex from an ES cell line that contained a tamoxifen-inducible 3XFLAG-tagged GLI3 repressor allele by anti-FLAG immunoprecipitation and several novel GLI co-factors were identified in the complex by subsequent mass spectrometry analysis.

2016-02-04 | PXD002494 | Pride

Gene expression pattern similarity and differences between hair follicles and basal cell carcinomas

Project description:Hair follicles (HF) and BCCs can be regarded as ordered and disordered skin appendages respectively and may utilize similar molecular mechanisms of growth. We wanted to examine the similarities and differences in gene expression patterns between BCCs and HF to define common growth mechanisms and gene expression patterns that distinguish an ordered skin appendage from a disordered skin growth. Nodular BCCs (n= 8) and non-follicular skin epithelium (n=8) were obtained. Scalp hair follicle root sheath was micro dissected from between the sebaceous gland duct and the lower one third of the HF (n=7). Microarray analysis was performed using 21K cDNA arrays and selected genes were validated using qPCR and histochemistry staining. Two differentially expressed gene sets were identified by significance analysis of microarray (SAM) in BCC and HF verses skin epithelium respectively. Based on these two lists, we conducted multiple signaling pathway analyses. The results indicated that Notch, hedgehog, and WNT signaling pathways were involved in regulating formation of both HF and BCCs. However, Notch signaling, including tumor suppressor genes Notch 1, Notch 2, Jagged ligands (JAG 1, 2), notch signaling inhibitor NUMB, Lunatic Fringe (LFNG), Deltex proteins (DTX 1, 2) which serve as important signaling components downstream of Notch, and Notch target genes HES1 ,RBPSUHL, hairless protein and HES7, all showed selective differential activation in BCCs compared to HF. The components of the notch signaling pathway may be potential new targets in the development of new therapeutic approaches to BCCs.

2008-09-02 | GSE12542 | GEO

Genome wide maps of chromatin modification in response to Hh signaling in mouse embryonic forelimb buds

Project description:Purpose: The response to Hedgehog signaling in the limb is driven by GLI bound enhancers and the majority of Hh targets in the developing limb bud are regulated solely by the activity of GLI-repressor. Currently we do not have a comprehensive understanding of how GLI bound enhancers respond Hedgehog signaling. The goal of this study is to identify how GLI bound enhancers are regulated by Hedgehog signaling and specifically by GLI-repressor. Methods: Histone modification ChIP-sequencing was done in Embryonic day 10.5 limb buds from control and Shh null embryos to identify histone modifications that change in response to Hedgehog signaling. We also did a comparative analysis of histone modificaiton response to Hedgehog stimulation in NIH3T3 cells to assess tissue specificity of GLI bound enhancer response to Hedgehog signaling. Results: We found that Hedgehog signaling specifically regulates the acetylation status of Histone 3 lysine 27 at a subset of GLI binding regions. These regions correlate with both known Hedgehog target genes in the limb bud and with characterized enhancers in the limb. This set of Hedgehog responsive GLI bound enhancers demonstrate enhanced tissue specificity.

2020-01-21 | GSE106948 | GEO

HDAC1 binding regions in mouse embryonic limbs

2020-01-21 | GSE141998 | GEO

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