Biology subjects

Maytum, A.

Publications and source records attributed to Maytum, A..

4 recordsLinked to original sources

bioRxiv2025

The ratio of RUNX1-ETO oncoprotein to normal RUNX1 expression determines the balance between endothelial reprogramming and hematopoietic cell growth

In t(8;21) acute myeloid leukemia (AML) the RUNX1 DNA binding domain is fused to the RUNX1T1 protein producing the RUNX1-ETO onco-fusion protein. We previously showed that t(8;21) leukemic stem cells aberrantly activate endothelial signalling pathways to initiate blast cell proliferation. Here, we employed a human embryonic stem cell (ESC) line expressing an inducible RUNX1-ETO transgene to determine whether RUNX1-ETO directly induces endothelial signalling pathways or whether it is dependent on AML progression. Using single cell analyses we show that RUNX1-ETO induction reprograms ESC-derived myeloid progenitors towards endothelial cells. Integrated data analysis demonstrates (i) that endothelial reprogramming is RUNX1-ETO concentration-dependent and irreversible, (ii) that when RUNX1-ETO and RUNX1 expression levels are equal, a sub-population of blood progenitors escapes reprogramming and (iii) keeps proliferating when co-cultured with endothelial cells. Our experiments provide important insights into the earliest stages of epigenetic reprogramming by oncogenic transcription factors in AML.

cancer biology↗

bioRxiv2025

Application of spatial transcriptomics across organoids: a high-resolution spatial whole-transcriptome benchmarking dataset

Stem cell-derived organoids hold promise to model tissue-specific disease. To enable this, it is crucial to assess how transcriptional signatures, cellular organisation and composition of organoids compare to in vivo counterparts. However, technologies which elucidate regional molecular identity, like spatial transcriptomics, have been challenging to apply to organoids. This study presents the first systematic profiling of multiple stem cell derived organoid models (brain, heart muscle, heart valve, kidney, lung, cartilage, and haematopoietic) with Stereo-seq, a full transcriptome, spatial transcriptomics assay using on-chip in situ RNA capture at subcellular resolution. It describes optimisation of this assay to characterise organoids, use of multiple organoid samples on a single chip, assess differences in RNA capture efficiency compared to reference tissues and its limitations. This study introduces a bespoke analysis method that partitions samples into regions and further characterises them. These findings inform future works to characterise organoids using spatial transcriptomics, providing insights in optimising RNA capture of multiple organoids across a chip and novel methods for regional analysis.

bioinformatics↗

bioRxiv2023

Chromatin priming elements direct tissue-specific gene activity prior to hematopoietic specification

Tissue-specific gene regulation during development involves the interplay between transcription factors and epigenetic regulators binding to enhancer and promoter elements. The pattern of active enhancers defines the cellular differentiation state. However, developmental gene activation involves a previous step called chromatin priming which is not fully understood. We recently developed a genome-wide functional assay that allowed us to functionally identify enhancer elements integrated in chromatin regulating each of five stages spanning the in vitro differentiation of embryonic stem cells to blood. We also measured global chromatin accessibility, histone modifications and transcription factor binding. The integration of these data identified and characterised cis-regulatory elements which become activated prior to the onset of gene expression, some of which are primed in a signalling-dependent fashion. Deletion of such a priming element leads to a delay in the upregulation of its associated gene in development. Our work uncovers the details of a complex network of regulatory interactions with the dynamics of early chromatin opening being at the heart of dynamic tissue-specific gene expression control. Summary blurbIn this manuscript, we exploited a new dataset of functionally characterised enhancer elements active at five stages of differentiation from mouse embryonic stem cells to blood to determine the developmental stages at which these elements are being activated. We show that many enhancer elements are activated at the level of chromatin prior to the activation of their associated genes (priming), which can be associated with signalling events. Elimination of priming elements within a gene locus leads to a delay in cellular development.

genomics↗

bioRxiv2022

A genome-wide relay of signalling-responsive enhancers drives hematopoietic specification

Developmental control of gene expression critically depends on distal cis-regulatory elements including enhancers which interact with promoters to activate gene expression. To date no global experiments have been conducted that identify their cell type and cell stage-specific transcription stimulatory activity within one developmental pathway and in a chromatin context. Here, we describe a high-throughput method that identifies thousands of differentially active cis-elements able to stimulate a minimal promoter at five stages of hematopoietic progenitor development from embryonic stem cells, which can be adapted to any ES cell derived cell type. Exploring this new resource, we show that blood cell-specific gene expression is controlled by the concerted action of thousands of differentiation stage-specific sets of cis-elements which respond to cytokine signals that terminate at signalling responsive transcription factors. Our work presents a major advance in our understanding of developmental gene expression control in the hematopoietic system and beyond.

genomics↗