Biology subjects

Laven-Law, G.

Publications and source records attributed to Laven-Law, G..

4 recordsLinked to original sources

bioRxiv2026

Application of metagenomic sequencing to improve sessile serrated lesion detection using the faecal immunochemical test

Most population colorectal cancer (CRC) screening programs use the faecal immunochemical test (FIT), which quantifies occult haemoglobin in faeces and has proven to be effective in detecting and reducing CRC incidence and mortality. Sessile serrated lesions (SSLs) account for up to 30% of sporadic CRC, yet FIT has low sensitivity to detect them. Faecal microbial biomarkers may improve their detection, but FIT samples have not previously been used to study the SSL microbiome. We asked whether FIT samples preserve the faecal microbiome as accurately as fresh collection, and whether they can reveal a microbial signature of SSL. We first reanalysed a published dataset of paired FIT and fresh faecal samples from the same participants. Donor identity explained 63.5% of compositional variance compared with 16.7% for collection method, indicating that FIT preserves the donor-specific signature on which biomarker discovery depends. We then generated shotgun metagenomes from FIT samples of 24 adults scheduled for diagnostic colonoscopy, twelve with at least one clinically significant SSL and twelve with no neoplasia (NN) and compared each group with a published fresh faeces cohort matched on colonoscopy outcome. Collection method explained 6.3% to 7.6% of variance, and no individual species was significantly differentially abundant between methods. Between SSL and NN FIT samples, community structure did not significantly differ, and conservative differential abundance analysis returned no results. More permissive count-based models suggested a depletion of fermentative commensals in SSL. Functionally, SSL samples encoded significantly fewer KEGG orthologs and less polyamine biosynthesis capacity, while orthologs carried by several Bifidobacterium species were more abundant. Many depleted functions reflected Enterobacteriaceae gene content concentrated in a few control samples. No single feature was diagnostic on its own. A multi-feature signature, confirmed in larger cohorts and applied to samples that screening programs already collect, may increase the detection rate of SSLs.

bioinformatics↗

bioRxiv2025

The transcription factor AP-2β defines active enhancers conferring molecular apocrine cell identity in breast cancer

The transcription factor Activating Protein 2{beta} (TFAP2B; AP-2{beta}) is a candidate marker for the molecular apocrine subtype of breast cancer, which lacks expression of the estrogen receptor alpha (ESR1; ER) but sustains a luminal breast cancer phenotype due to the presence of key luminal lineage transcription factors (GATA3, FOXA1) and activity of the androgen receptor (AR). Our objective was to better understand the expression patterns and molecular function of AP-2{beta} in breast cancer. Using multiple clinical cohorts, we show that high TFAP2B expression was associated with low proliferation in ER positive (ER+) breast cancers of ductal and lobular histology, but with enrichment for lobular tumours. High TFAP2B was also evident in high proliferation tumours lacking ER, with no specific enrichment for lobular histology. Restoring AP-2{beta} expression to highly proliferative ER+ breast cancer cell lines that lack it strongly induced apoptosis. Conversely, reducing AP-2{beta} expression in a molecular apocrine breast cancer cell line model potently inhibited proliferation and cell viability associated with downregulation of MYC oncogene expression. To identify genomic determinants of AP-2{beta} function in molecular apocrine cells in relation to other known transcriptional regulators, we performed chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq) for AP-2{beta}, AR, GATA3, FOXA1, and acetylated lysine 27 in histone 3 (H3K27ac, a marker of active enhancers and promoters). When present alone, AP-2{beta} was preferentially enriched at active promotors. Enhancers bound by AR, GATA3 and FOXA1 were more active when AP-2{beta} was present and genes that define the molecular apocrine phenotype were significantly more likely to have active enhancers co-occupied by all four transcription factors. We conclude that AP-2{beta} plays a context-dependent role in breast cancer and propose that activation of enhancers defining molecular apocrine identity is a key function of AP-2{beta} in the biology of this subtype of breast cancer.

cancer biology↗

bioRxiv2024

Androgen stimulation rapidly reorganizes temporal 3D genome and epigenome states to trigger AR-mediated transcription in prostate cancer.

Androgen receptor (AR)-mediated transcription drives prostate cancer progression and remains a critical therapeutic target. AR activation by androgens triggers nuclear translocation, DNA binding at AR regulatory elements (AREs) and transcription initiation. This process involves co-factors such as FOXA1, epigenetic modifications, and 3D chromatin interactions. However, the temporal coordination of these events during AR-mediated transcription remains poorly understood. Using a time-course androgen stimulation model in prostate cancer cells, we integrated temporal multi-omics data within the MOFA+ framework to dissect AR-mediated transcriptional dynamics. Our analysis revealed that rapid AR binding at gene promoters is crucial for initiating nascent transcription of AR target genes. We identified H3K27 acetylation at flanking AREs, pre-marked by constitutive FOXA1 binding, occurs prior to AR recruitment. Additionally, androgen stimulation induced a temporal early shift in nascent transcription from MYC to AR target genes, associated with transient disruption of 3D chromatin interactions. Finally, we showed that CRISPR-mediated inhibition of AR-associated chromatin contacts suppresses distal linked target genes, demonstrating that dynamic genome architecture is functionally required for AR-driven transcription. Together these findings uncover the dynamic reorganization of 3D chromatin structure and transcription factor binding post-androgen stimulation, resulting in distinct temporal epigenomic states. This work provides new insights into the mechanisms governing AR-mediated transcriptional activation in prostate cancer and highlights the interplay between MYC and AR in regulating transcription in hormone-driven cancers.

genomics↗

bioRxiv2021

Epigenetic therapy suppresses endocrine-resistant breast tumour growth by re-wiring ER-mediated 3D chromatin interactions

Three-dimensional (3D) epigenome remodelling is an important mechanism of gene deregulation in cancer. However, its potential as a target to overcome therapy resistance remains largely unaddressed. Here we show that FDA-approved epigenetic therapy Decitabine (5-Aza-mC) suppresses tumour growth in preclinical metastatic ER+ breast tumour xenograft models. Decitabine-induced genome-wide DNA hypomethylation results in large-scale 3D epigenome deregulation, including de-compaction of higher order chromatin structure and loss of topologically associated domain boundary insulation. Significant DNA hypomethylation at ER-enhancer elements was associated with gain in ER binding, creation of ectopic 3D enhancer-promoter interactions and concordant activation of ER-mediated transcription pathways. Importantly long-term withdrawal of epigenetic therapy partially restores methylation at ER-enhancer elements, resulting in loss of ectopic 3D enhancer-promoter interactions and associated gene repression. Our study illustrates how epigenetic therapy has potential to target ER+ endocrine-resistant breast cancer by DNA methylation-dependent rewiring of 3D chromatin interactions associated with suppression of tumour growth.

molecular biology↗