Biology subjects

Sexton, T.

Publications and source records attributed to Sexton, T..

9 recordsLinked to original sources

bioRxiv2026

Single-cell analyses reveal a simple multi-gene transcriptomic signature with predictive power in prognosis and therapy effectiveness in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is an aggressive, heterogeneous form of breast cancer with limited specific therapy options, prevalent metastasis and frequent relapse. Re-analysis of single-cell RNA-sequencing data characterizes the diverse cell subtypes within the tumor and microenvironment of TNBC, supporting a luminal progenitor origin for the cancer and providing clues as to the factors involved in progression of the disease. The relative burdens of these subtypes can be deconvolved from bulk RNA-sequencing data, readily identifying the stem-like, mesenchymal and stromal cell subtypes significantly associated with poor survival and enrichment in metastasis. Importantly, these can be simplified to ten-gene signatures with comparable predictive power, notably in response to different therapeutic strategies, which are linked to relative burdens of different subtypes of stromal fibroblasts. The expression level of these signatures could provide a cheap means for selecting therapy strategies in personalized medicine.

cancer biology↗

bioRxiv2025

Enhancers mediate euchromatin hopping at chromatin contact points

Enhancer-mediated gene activation involves the recruitment of chromatin modifiers and RNA polymerase to target promoters, but it is unknown if enhancers influence chromatin beyond their target genes. Euchromatin and heterochromatin associated histone modifications separate the genome into opposing nuclear compartments. Whereas heterochromatin marks are known to spread from one modified nucleosome to another, no such ability has been ascribed to euchromatin. Using mono-allelic enhancer deletions, native ChIP-seq, and an engineered interaction between an enhancer and transcriptionally inert DNA, we show that enhancers mediate the acquisition of euchromatin features at distal regions through chromatin looping. We term this phenomenon euchromatin hopping and found it occurring on average [~]270kb bidirectionally from enhancers, redefining our understanding of enhancer-mediated chromatin architecture with implications on enhancer identification using chromatin features. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=129 SRC="FIGDIR/small/674255v2_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@12c6e9aorg.highwire.dtl.DTLVardef@1165feorg.highwire.dtl.DTLVardef@3f08c8org.highwire.dtl.DTLVardef@598bd3_HPS_FORMAT_FIGEXP M_FIG C_FIG Euchromatin hopping modelFigure showing the proposed euchromatin hopping model. TFs recognize and bind to their binding sites in an active enhancer region. Upon activation enhancers recruit coactivators and RNAPII forming a condensate that supports gene activation. After an abundance of transcriptional machinery and coactivators are recruited, adjacent TF bound sites acquire euchromatin features through physical proximity to the active compartment, we call these regions "bystanders". Upon enhancer deletion, condensate formation is lost and active euchromatin marks are not acquired at the gene promoter or other enhancer chromatin contacts. TFs are displayed in yellow, coactivators in green, RNAPII in pink, and histone modifications in red.

molecular biology↗

bioRxiv2023

Gene-to-Gene Coordinated Regulation of Transcription and Alternative splicing by 3D Chromatin Remodeling upon NF-κB activation

The p65/RelA factor of NF-{kappa}B plays a pivotal role in coordinating gene expression in response to diverse stimuli, including viral infections. At the chromatin level, p65/RelA regulates gene transcription and alternative splicing (AS) through promoter enrichment and genomic exon occupancy, respectively. However, the mechanisms underlying the coordination of these processes across distinct genes remain elusive. In this study, we employed the HTLV-1 Tax oncoprotein, a potent activator of NF-{kappa}B, to investigate the integrative relationship between 3D chromatin architecture, NF-{kappa}B-regulated transcription and AS. Our analysis revealed that Tax induces a pronounced reorganization of the 3D genome, resulting in the formation of multigene complexes that comprise genes regulated either transcriptionally or through AS. Notably, we found that the Tax-induced gene-gene contact between the two master genes NFKBIA and RELA is associated with their differential regulation in gene expression and AS, respectively. Through dCas9-mediated approaches, we demonstrated that NFKBIA-RELA interaction is required for AS regulation and is caused by an intragenic enrichment of p65/RelA on RELA. Our findings shed light on new regulatory mechanisms upon HTLV-1 Tax and underscore the integral role of p65/RelA in coordinated regulation of NF-{kappa}B-responsive genes at both transcriptional and AS levels in the context of the 3D genome.

molecular biology↗

bioRxiv2023

Competition between transcription and loop extrusion modulates promoter and enhancer dynamics

The spatiotemporal configuration of genes with distal regulatory elements, and the impact of chromatin mobility on transcription, remain unclear. Loop extrusion is an attractive model for bringing genetic elements together, but how this functionally interacts with transcription is also largely unknown. We combine live tracking of genomic loci and nascent transcripts with molecular dynamics simulations to assess the 4D arrangement of the Sox2 gene and its enhancer, in response to a battery of perturbations. We find that alterations in chromatin mobility, not promoter-enhancer distance, is more informative about transcriptional status. Active elements display more constrained mobility, consistent with confinement within specialized nuclear sites, and alterations in enhancer mobility distinguish poised from transcribing alleles. Strikingly, we find that whereas loop extrusion and transcription factor-mediated clustering contribute to promoter-enhancer proximity, they have antagonistic effects on chromatin dynamics. This provides an experimental framework for the underappreciated role of chromatin dynamics in genome regulation.

cell biology↗

bioRxiv2022

Context-dependent transcriptional remodeling of TADs during differentiation

Metazoan chromosomes are organized into discrete domains (TADs), believed to contribute to the regulation of transcriptional programs. Despite extensive correlation between TAD organization and gene activity, a direct mechanistic link is unclear, with perturbation studies often showing little effect. To follow TAD dynamics during development, we used Capture Hi-C to interrogate the TADs around key differentially expressed genes during mouse thymocyte maturation, uncovering specific remodeling events. Notably, one TAD boundary was broadened to accommodate RNA polymerase elongation past the border, and sub-domains were formed around some activated genes without changes in CTCF binding. The ectopic induction of one gene was sufficient to recapitulate microdomain formation in embryonic stem cells, providing strong evidence that transcription can directly remodel chromatin structure. These results suggest that transcriptional processes drive complex, but non-universal, chromosome folding patterns that can be important in certain genomic contexts.

genomics↗

bioRxiv2022

Transcriptional regulation and chromatin architecture maintenance are decoupled modular functions at the Sox2 locus

How distal regulatory elements control gene transcription and chromatin topology is not clearly defined, yet these processes are closely linked in lineage specification during development. Through allele-specific genome editing and chromatin interaction analyses of the Sox2 locus in mouse embryonic stem cells, we found a striking disconnection between transcriptional control and chromatin architecture. We trace nearly all Sox2 transcriptional activation to a small number of key transcription factor binding sites, whose deletions have no effect on promoter-enhancer interaction frequencies or topological domain organization. Local chromatin architecture maintenance, including at the topologically associating domain (TAD) boundary downstream of the Sox2 enhancer, is widely distributed over multiple transcription factor-bound regions and maintained in a CTCF-independent manner. Furthermore, disruption of promoter-enhancer interactions by ectopic chromatin loop formation has no effect on Sox2 expression. These findings indicate that many transcription factors are involved in modulating chromatin architecture independently of CTCF.

genetics↗

bioRxiv2021

Precise measurements of chromatin diffusion dynamics by modeling using Gaussian processes

The spatiotemporal organization of chromatin influences many nuclear processes: from chromo-some segregation to transcriptional regulation. To get a deeper understanding of these processes it is essential to go beyond static viewpoints of chromosome structures, and to accurately characterize chromatin mobility and its diffusion properties. Here, we present GP-FBM: a new computational framework based on Gaussian processes and fractional Brownian motion to analyze and extract diffusion properties from stochastic trajectories of labeled chromatin loci. GP-FBM is able to optimally use the higher-order correlations present in the data and therefore outperforms existing methods. Furthermore, GP-FBM is able to extrapolate trajectories from missing data and account for substrate movement automatically. Using our method we show that diffusive chromatin diffusion properties are surprisingly similar in interphase and mitosis in mouse embryonic stem cells. Moreover, we observe surprising heterogeneity in local chromatin dynamics, which correlates with transcriptional activity. We also present GP-Tool, a user-friendly graphical interface to facilitate the use of GP-FBM by the research community for future studies of nuclear dynamics.

systems biology↗

bioRxiv2018

ChiCMaxima: a robust and simple pipeline for detection and visualization of chromatin looping in Capture Hi-C

Capture Hi-C (CHi-C) is a new technique for assessing genome organization, based on chromosome conformation capture coupled to oligonucleotide capture of regions of interest such as gene promoters. Chromatin loop detection is challenging, since existing Hi-C/4C-like analyses, which make different assumptions about the technical biases presented, are often unsuitable. We describe a new approach, ChiCMaxima, which uses local maxima combined with a background model to detect DNA looping interactions, integrating information from biological replicates. ChiCMaxima shows more stringency and robustness compared to previously developed tools. The tool includes a GUI browser for flexible visualization of CHi-C profiles alongside epigenomic tracks.

genomics↗

bioRxiv2017

The Drosophila Dosage Compensation Complex activates target genes by chromosome looping within the active compartment

X chromosome dosage compensation in Drosophila requires chromosome-wide coordination of gene activation. The male-specific-lethal dosage compensation complex (DCC) identifies X chromosomal High Affinity Sites (HAS) from which it boosts transcription. A sub-class of HAS, PionX sites, represent first contacts on the X. Here, we explored the chromosomal interactions of representative PionX sites by high-resolution 4C and determined the global chromosome conformation by Hi-C in sex-sorted embryos. Male and female X chromosomes display similar nuclear architecture, concordant with clustered, constitutively active genes. PionX sites, like HAS, are evenly distributed in the active compartment and engage in short- and long-range interactions beyond compartment boundaries. By de novo induction of DCC in female cells, we monitored the extent of activation surrounding PionX sites. This revealed a remarkable range of DCC action not only in linear proximity, but also at megabase distance if close in space, suggesting that DCC profits from pre-existing chromosome folding to activate genes.

genomics↗