Biology subjects

Vaagenso, C.

Publications and source records attributed to Vaagenso, C..

4 recordsLinked to original sources

bioRxiv2026

The human RNA-DNA interactome is cell type-specific and dynamic

More than twenty years ago, the FANTOM consortium uncovered that mammalian genomes are pervasively transcribed, revealing multitudes of RNAs with unknown functions. A subset of these transcripts has since then been linked to transcriptional control and to chromatin organization via their ability to interact with DNA, suggesting that chromatin-associated RNAs could be key players in genome regulation. Although recent technological advances now enable the mapping of genome-wide RNA-DNA contacts, a lack of analyses integrating these methods with other genomic features and across multiple cellular contexts hinders our comprehensive understanding of the principles underlying RNA-DNA interactions and of their biological importance. As part of the FANTOM6 project, we thus generated RNA-DNA interaction maps in 16 different human cell types, then combined these contacts with multiple layers of other genomic data to investigate how patterns of interaction between RNA and DNA relate to chromatin organization and function. We show that the RNA-DNA interactome is highly dynamic yet reproducibly organized in cell-type specific networks, constituted of a great diversity of interactions that vary in function of their distance, the nature of their sources and the chromatin state of their targets. In particular, we detected numerous regulatory elements that exhibit marked changes in activity when differentially bound by transcripts, implying that thousands of RNA-DNA interactions can play a mechanistic role in gene expression. This regulatory function correlates with RNA-protein interactions and significantly associates with cell type-relevant and disorder-related traits. In addition to providing essential resources for future research in RNA-mediated chromatin regulation, cellular biology and human diseases, our study thus establishes the RNA-DNA interactome as a new genome regulatory layer that defines and maintains cellular identity and behavior.

genomics↗

bioRxiv2025

Genome-wide rules of transcription factor cooperativity revealed through in silico binding site ablation

Transcription factor (TF) cooperativity plays a critical role in gene regulation. However, the underlying genomic rules remain unclear, calling for scalable methods to characterize the TF binding site (motif) syntax of regulatory elements. Here, we introduce DeepCompARE, a lightweight model paired with an in silico ablation (ISA) framework for genome-wide analysis of regulatory sequences. Our framework enables precise interpretation of the motif syntax governing chromatin accessibility, enhancer activity, and promoter function. We find that most TF motifs are pairwise independent, indicating a default additive behavior of TFs, and define a cooperativity score to quantify deviations from this baseline. This reveals synergy and redundancy as opposite effects along the same cooperative spectrum. TF redundancy is linked to promoter activity and broad expression, whereas TF synergy is associated with enhancer activity, physical interactions, and cell-type specificity. Our framework provides a quantitative model for TF cooperativity, offering new insights into gene regulatory logic.

bioinformatics↗

bioRxiv2023

MYC enhancer invasion promotes prognostic cancer type-specific gene programs through an epigenetic switch

The transcription factor MYC is overexpressed in most cancers, where it drives multiple hallmarks of cancer progression. MYC is known to promote oncogenic transcription by binding to active promoters. In addition, MYC has also been shown to invade distal enhancers when expressed at oncogenic levels, but this enhancer binding has been proposed to have low gene-regulatory potential. Here, we demonstrate that MYC enhancer binding directly promotes cancer type-specific gene programs predictive of poor patient prognosis. MYC induces transcription of enhancer RNA through recruitment of RNAPII, rather than regulating RNAPII pause-release as is the case at promoters. This is mediated by MYC-induced H3K9 demethylation by KDM3A and acetylation by GCN5, leading to enhancer-specific BRD4 recruitment through its bromodomains, which facilitates RNAPII recruitment. Thus, we propose that MYC drives prognostic cancer type-specific gene programs by promoting RNAPII recruitment to enhancers through induction of an epigenetic switch.

genomics↗

bioRxiv2021

Promoter sequence and architecture determine expression variability and confer robustness to genetic variants

Genetic and environmental exposures cause variability in gene expression. Although most genes are affected in a population, their effect sizes vary greatly, indicating the existence of regulatory mechanisms that could amplify or attenuate expression variability. Here, we investigate the relationship between the sequence and transcription start site architectures of promoters and their expression variability across human individuals. We find that expression variability can be largely explained by a promoters DNA sequence and its binding sites for specific transcription factors. We show that promoter expression variability reflects the biological process of a gene, demonstrating a selective trade-off between stability for metabolic genes and plasticity for responsive genes and those involved in signaling. Promoters with a rigid transcription start site architecture are more prone to have variable expression and to be associated with genetic variants with large effect sizes, while a flexible usage of transcription start sites within a promoter attenuates expression variability and limits genotypic effects. Our work provides insights into the variable nature of responsive genes and reveals a novel mechanism for supplying transcriptional and mutational robustness to essential genes through multiple transcription start site regions within a promoter.

genomics↗