Regulation Network of Colorectal-Cancer-Specific Enhancers in the Progression of Colorectal Cancer

Chen, Bohan; Ma, Yuan; Bi, Jinfang; Wang, Wenbin; He, Anshun; Su, Guanghao; Zhao, Zhongfang; Shi, Jiandang; Zhang, Lei

doi:10.3390/ijms22158337

Cited by 8 publications

(8 citation statements)

References 56 publications

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“…We set out to understand which of these changes in RNA abundance could be directly controlled by TBX3. To this aim, we integrated the TBX3 genomic distribution with the network of active CRC-enhancers obtained by HiChIP targeting the marker of open chromatin H3K27ac in HCT116 50 . The 155 differentially expressed CAGE-seq regions were anchored to 230 H3K27ac-mediated DNA-DNA interaction loops (Figure 4C; note that each CAGE-seq region could be anchored to >1 H3K27ac loop), supporting the notion that they correspond to active regulatory elements 51 .…”

Section: Resultsmentioning

confidence: 99%

The Developmental Transcription Factor TBX3 Physically Engages with the Wnt/β-catenin Transcriptional Complex in Human Colorectal Cancer Cells to Regulate Metastasis Genes

Jauregi-Miguel,

Söderholm,

Weiss

et al. 2023

Preprint

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Wnt signaling orchestrates gene expression in a plethora of processes during development and adult cell homeostasis via the action of nuclear β-catenin. Furthermore, neoplasia of the colorectal epithelium begins with aberrant Wnt/β-catenin signaling. Yet, little is known about how β-catenin generates context-specific transcriptional outcomes. We have previously identified the developmental transcription factor TBX3 as a tissue-specific component of the Wnt/β-catenin nuclear complex during mouse forelimb development. In this study, we show that TBX3 is present and functionally active in human colorectal cancers. TBX3’s genomic binding pattern suggests a regulatory role that broadly coincides with that of Wnt/β-catenin. Moreover, proteomics proximity labelling indicated that, during Wnt pathway activation, TBX3 is vicinal to several protein partners, including the transcription factors TCF/LEF and chromatin remodeling complexes which are usually found at Wnt responsive elements. Sequence and structure analysis revealed that TBX3 possesses an exposed Asp-Pro-Phe (NPF) motif predicted by AlphaFold2 Multimer to mediate direct interactions with several Wnt-activated TBX3 partners. Deletion of NPF abrogates TBX3 proximity to these partners and its ability to modulate Wnt-dependent transcription. TBX3 emerges as a key modulator of the oncogenic activity of Wnt/β-catenin in colorectal cancer, and its mechanism of action exposes a novel druggable protein-interaction surface.

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Section: Resultsmentioning

confidence: 99%

The Developmental Transcription Factor TBX3 Physically Engages with the Wnt/β-catenin Transcriptional Complex in Human Colorectal Cancer Cells to Regulate Metastasis Genes

Jauregi-Miguel,

Söderholm,

Weiss

et al. 2023

Preprint

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“…HiChIP of H3K27ac in HCT116 data was performed by Chen et al. ( 53 ). bedpe files containing unfiltered loops downstream of HiChipper were downloaded from GEO GSE173699.…”

Section: Methodsmentioning

confidence: 99%

Exhaustive identification of genome-wide binding events of transcriptional regulators

Nordin,

Pagella,

Zambanini

et al. 2024

Nucleic Acids Research

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Genome-wide binding assays aspire to map the complete binding pattern of gene regulators. Common practice relies on replication—duplicates or triplicates—and high stringency statistics to favor false negatives over false positives. Here we show that duplicates and triplicates of CUT&RUN are not sufficient to discover the entire activity of transcriptional regulators. We introduce ICEBERG (Increased Capture of Enrichment By Exhaustive Replicate aGgregation), a pipeline that harnesses large numbers of CUT&RUN replicates to discover the full set of binding events and chart the line between false positives and false negatives. We employed ICEBERG to map the full set of H3K4me3-marked regions, the targets of the co-factor β-catenin, and those of the transcription factor TBX3, in human colorectal cancer cells. The ICEBERG datasets allow benchmarking of individual replicates, comparing the performance of peak calling and replication approaches, and expose the arbitrary nature of strategies to identify reproducible peaks. Instead of a static view of genomic targets, ICEBERG establishes a spectrum of detection probabilities across the genome for a given factor, underlying the intrinsic dynamicity of its mechanism of action, and permitting to distinguish frequent from rare regulation events. Finally, ICEBERG discovered instances, undetectable with other approaches, that underlie novel mechanisms of colorectal cancer progression.

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“…This raises the prediction that β-catenin binding event probability could be associated with differential functionally relevant regulatory events. To test our prediction, we focused on active cis-regulatory three-dimensional chromatin interactions by employing published HiChIP of H3K27ac in HCT116 31 . This assay uncovers distant regions that are engaging in gene regulation events and that are marked by the open chromatin mark often found in active enhancer regions 31 .…”

Section: Peak Probability Identified By Iceberg Predicts Cis-regulato...mentioning

confidence: 99%

“…To test our prediction, we focused on active cis-regulatory three-dimensional chromatin interactions by employing published HiChIP of H3K27ac in HCT116 31 . This assay uncovers distant regions that are engaging in gene regulation events and that are marked by the open chromatin mark often found in active enhancer regions 31 . We focused on H3K27ac mediated loops that overlap with a βcatenin ICEBERG peak in at least one anchor and assessed the correlation between β-catenin peak detection frequency and 1) number of loops associated to each probability group, 2) loop strength in terms of counts and 3) loop size in terms of linear genomic distance between the two anchors.…”

Section: Peak Probability Identified By Iceberg Predicts Cis-regulato...mentioning

confidence: 99%

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Exhaustive identification of genome-wide binding events of transcriptional regulators with ICEBERG

Cantù

Nordin

Pagella³

et al. 2023

Preprint

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Genome-wide protein interaction assays aspire to map the complete binding pattern of gene regulators. However, common practice relies on replication and high stringency statistics which favor false negatives over false positives, thereby excluding portions of signal which may represent biologically relevant events. Here, we present ICEBERG (Increased Capture of Enrichment By Exhaustive Replicate aGgregation), an experimental and analytical pipeline that harnesses large numbers of CUT&RUN replicates to discover the full set of binding events and chart the line between false positives and false negatives. We employed ICEBERG to map the full set of H3K4me3-marked regulatory regions and β-catenin targets in human colorectal cancer cells. The ICEBERG datasets allow benchmarking of individual replicates, comparison of the performance of peak calling and replication approaches and expose the arbitrary nature of other strategies to identify reproducible peaks. Instead of a static view of genomic targets, ICEBERG established a spectrum of detection probabilities across the genome for a given factor, underlying the intrinsic dynamicity of its mechanism of action, and permitting to distinguish frequent from rare regulation events. Finally, ICEBERG discovered instances, undetectable with other approaches, that might underlie novel mechanisms of colorectal cancer progression.

show abstract

Regulation Network of Colorectal-Cancer-Specific Enhancers in the Progression of Colorectal Cancer

Cited by 8 publications

References 56 publications

The Developmental Transcription Factor TBX3 Physically Engages with the Wnt/β-catenin Transcriptional Complex in Human Colorectal Cancer Cells to Regulate Metastasis Genes

The Developmental Transcription Factor TBX3 Physically Engages with the Wnt/β-catenin Transcriptional Complex in Human Colorectal Cancer Cells to Regulate Metastasis Genes

Exhaustive identification of genome-wide binding events of transcriptional regulators

Exhaustive identification of genome-wide binding events of transcriptional regulators with ICEBERG

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