Biology subjects

Galbraith, K.

Publications and source records attributed to Galbraith, K..

3 recordsLinked to original sources

bioRxiv2025

A developmentally regulated long-range enhancer-promoter contact mediates human neural development

SOX2 is a core pluripotency factor in human embryonic stem cells (hESCs), but upon differentiation to the three germ layers, its expression is preserved selectively in neuroectoderm. The mechanisms regulating SOX2 transcription in distinct developmental stages remain incompletely understood. Here, we demonstrate that a distant enhancer 550 kb from the human SOX2 locus is selectively activated in neural stem cells (NSCs) and establishes long-range contact with the SOX2 gene. CRISPR-Cas9 excision of the enhancer has no effect in hESCs but reduces SOX2 transcription in NSCs and impairs neuroectodermal differentiation and forebrain specification in teratomas and cerebral organoids. CRISPR excision of a CTCF recognition motif adjacent to the enhancer does not affect enhancer activation in neuroectoderm but reduces chromatin looping and SOX2 transcription to partially reproduce phenotypes seen with enhancer deletion. Our findings indicate that the development of the human nervous system depends on a developmentally regulated long-range contact between a distant enhancer and the SOX2 locus.

developmental biology↗

bioRxiv2025

Hi-C for genome-wide detection of enhancer-hijacking rearrangements in routine lymphoid cancer biopsies

Standard techniques for detecting genomic rearrangements in formalin-fixed paraffin-embedded (FFPE) biopsies have important limitations. We performed FFPE-compatible Hi-C on 44 clinical biopsies comprising large B-cell lymphomas (n=18), plasma cell neoplasms (n=14), and other diverse lymphoid cancers, identifying consistent topological differences between malignant B cell and plasma cell states. Hi-C detected expected oncogene rearrangements at high concordance with fluorescence in-situ hybridization (FISH) and supported enhancer-hijacking in recurrent rearrangements of BCL2, CCND1, and MYC, plus unanticipated variants involving homologous loci. Hi-C identified unanticipated non-coding rearrangements involving PD-1 ligand genes and other loci of potential therapeutic relevance, distinguished between functionally divergent classes of BCL6 rearrangements, and provided topological information supporting the interpretation of atypical MYC rearrangements. In biopsies lacking MYC-activating rearrangements, Hi-C revealed differential interactions with functionally-validated disease-specific native MYC locus enhancers. FFPE-compatible Hi-C detects oncogene rearrangements and their topological consequences at genome-wide scale, finding clinically-relevant drivers that are missed by standard approaches.

genomics↗

bioRxiv2023

MetFinder: a neural network-based tool for automated quantitation of metastatic burden in histological sections from animal models

Diagnosis of most diseases relies on expert histopathological evaluation of tissue sections by an experienced pathologist. By using standardized staining techniques and an expanding repertoire of markers, a trained eye is able to recognize disease-specific patterns with high accuracy and determine a diagnosis. As efforts to study mechanisms of metastasis and novel therapeutic approaches multiply, researchers need accurate, high-throughput methods to evaluate effects on tumor burden resulting from specific interventions. However, current methods of quantifying tumor burden are low in either resolution or throughput. Artificial neural networks, which can perform in-depth image analyses of tissue sections, provide an opportunity for automated recognition of consistent histopathological patterns. In order to increase the outflow of data collection from preclinical studies, we trained a deep neural network for quantitative analysis of melanoma tumor content on histopathological sections of murine models. This AI-based algorithm, made freely available to academic labs through a web-interface called MetFinder, promises to become an asset for researchers and pathologists interested in accurate, quantitative assessment of metastasis burden.

cancer biology↗