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, Amaia; Söderholm, Simon; Weiss, Tamina; Nordin, Anna; Ghezzi, Valeria; Brütsch, Salome M.; Pagella, Pierfrancesco; van de Grift, Yorick; Zambanini, Gianluca; Ulisse, Jacopo; Mattia, Alessandro; Deviatiiarov, Ruslan; Faustini, Elena; Moparthi, Lavanya; Lottersberger, Francisca; Koch, Stefan; Moor, Andreas E.; Sun, Xiao-Feng; von Castelmur, Eleonore; Sheng, Guojun; Cantù, Claudio

doi:10.1101/2023.12.18.571901

Cited by 2 publications

(1 citation statement)

References 118 publications

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“…To explore how ICEBERG would perform on another target, we applied it to map the binding pattern of the developmental transcription factor TBX3 in CRC cells ( 59 ). Here we also performed 25 replicates, all of which showed high signal to noise ratio and peaks at positive control loci that matched our previous ChIP-seq performed with a different antibody ( 60 ) ( Supplementary Figure S3A ).…”

Section: Resultsmentioning

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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Section: Resultsmentioning

confidence: 99%

Exhaustive identification of genome-wide binding events of transcriptional regulators

Nordin,

Pagella,

Zambanini

et al. 2024

Nucleic Acids Research

Self Cite

View full text Add to dashboard Cite

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The Transcription Factor Binding Landscape of Mouse Development

Nordin,

Zambanini,

Jonasson

et al. 2024

Preprint

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Gene regulators physically associate to the genome, in a combinatorial fashion, to drive tissue-specific gene expression programs. Uncovering the genome-wide activity of all gene regulators across tissues is therefore needed to understand how the genome is regulated during development. Here, we take a first step forward towards achieving this goal. Using CUT&RUN, we systematically measured the genome-wide binding profiles of key transcription factors and cofactors that mediate the activity of ontogenetically relevant signaling pathways in select mouse tissues at two developmental stages. Computation of the numerous genome-wide binding datasets unveiled a large degree of tissue and time-specific activity for each gene regulator, and several factor-specific idiosyncrasies. Moreover, we identified 'popular' regulatory regions that are bound by a multitude of pathway regulators. Popular regions tend to be more evolutionarily conserved, implying their essentiality. Consistently, they lie in the proximity of genes whose dysregulation causes early embryonic lethality in the mouse. Moreover, the human homologs of these regions are also bound by many gene regulators and are highly conserved in human populations, indicating that they retain functional relevance for human development. This work constitutes a decisive step towards under-standing how the genome is simultaneously read and used by gene regulators in a holistic fashion and unveils multiple genomic mechanisms that drive embryonic development.

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

Cited by 2 publications

References 118 publications

Exhaustive identification of genome-wide binding events of transcriptional regulators

Exhaustive identification of genome-wide binding events of transcriptional regulators

The Transcription Factor Binding Landscape of Mouse Development

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