Biology subjects

Murtuza Baker, S.

Publications and source records attributed to Murtuza Baker, S..

5 recordsLinked to original sources

bioRxiv2025

Regional Vulnerability of Cardiac Chambers to Radiotherapy: A Multi-Omics Perspective

The heart is highly vulnerable to radiotherapy (RT)-induced injury, leading to molecular and structural remodeling collectively termed radiation-induced cardiac toxicity (RICT). Although several biological pathways have been implicated, the regional, cardiac-specific molecular responses to radiation exposure remain incompletely understood. Here, a multi-omics approach was adopted to longitudinally characterise the unique responses to radiation of the heart base (including ventricular base and right atrium), or the heart apex. Ventricular base irradiation induced a cardiomyopathy phenotype, with pronounced molecular perturbations in metabolism and electrical conduction, while changes related to tissue structure were predominant following apex-directed RT. In the right atrium, irradiation drives fibrotic tissue remodelling, leading to an increased propensity for atrial fibrillation, underpinned by changes in sarcomere organisation. This study represents a comprehensive characterisation of differential spatiotemporal radiation effects in the heart and highlights biological and functional pathways that are potentially clinically actionable for cardiac radioprotection and monitoring.

cell biology↗

bioRxiv2025

Spatial transcriptomic profiling reveals distinct signatures in acute versus chronic wounds through hypergraph modelling and transcriptomic entropy analysis.

IntroductionThe financial burden of wounds to healthcare systems continues to increase, with little progression on advanced treatment options. Single cell RNA sequencing studies have predominantly focused on phenotypically different cell types and are generally descriptive in their analyses. Coordination within the transcriptome can be modelled using hypergraphs, which quantify higher order interactions (coordination between two or more genes) in transcriptomic data. Hypergraph modelling and analysis of transcriptomic entropy of wound samples will further elucidate differences between healing and non-healing wounds. MethodsSpatial transcriptomic analysis (Visium Spatial Gene Expression) was performed on three acute wounds, three chronic wounds and two healthy, unwounded skin samples. Standard transcriptomic analyses were performed in Python using the packages Scanpy and Squidpy. Hypergraph modelling and transcriptomic entropy analyses were performed in R. ResultsAcross the samples, twenty-nine Leiden clusters were defined, with keratinocytes, fibroblasts and adipocytes subclusters present. Fifteen marker genes for acute and chronic wounds were identified, with pathway analysis identifying immune responses and cellular homeostasis present in acute wounds, whilst in chronic wounds, pathways included immune responses and extracellular matrix structure. Spatial transcriptomics allowed for a descriptive analysis of the Leiden clusters within the samples, with each tissue sample being divided up into upper, middle and lower layer for this purpose. Hypergraph analyses of the whole transcriptome from the pathology groups and the independent transcriptomic Leiden clustering, revealed differences in underlying transcriptomic coordination. The top 1000 highly connected genes from each pathology group were analysed by Over Representation Analysis, with integrated stress response signalling, maintenance of cell number and myeloid and mononuclear cell differentiation pathways present in acute samples (all FDR <0.05) compared to regulation of vasculature development, mononuclear cell differentiation and epithelial cell proliferation (all FDR <0.05) in the chronic samples. Analysis of transcriptomic entropy identified further differences between acute and chronic wounds, with decreasing entropy from control to acute to chronic samples (all p-adjusted <0.001). When comparing Leiden clusters that were present in at least two sample groups, there was a statistically significant difference in entropy, although Leiden clusters varied in high or low entropy between acute and chronic wound samples (all p< 2.2 x 10-16). By mapping high and low entropy values to spatial images of each sample, lower transcriptomic entropy within the wound bed was identified compared to the rest of the tissue sample. ConclusionsSpatial transcriptomic analysis allowed for distinct spatial patterning to be observed which delineated acute and chronic wounds. Analysis of higher order interactions within the wound sample transcriptome identified key pathways that were not identified using traditional analyses. Transcriptomic entropy analysis further highlighted the differences between the wound samples. This work has implications for the future development of biomarkers of chronic wounds.

physiology↗

bioRxiv2023

A cell atlas of the human outflow tract of the heart and its adult derivatives

The outflow tract (OFT) of the heart carries blood away from the heart into the great arteries. During embryogenesis, the OFT divides to form the aorta and pulmonary trunk, creating the double circulation present in mammals. Defects in this area account for one-third of all congenital heart defect cases. Here, we present comprehensive transcriptomic data on the developing OFT at two distinct timepoints (embryonic and fetal) and its adult derivatives, the aortic valves, and use spatial transcriptomics to define the distribution of cell populations. We uncover that distinctive embryonic signatures persist in adult cells and can be used as labels to retrospectively attribute relationships between cells separated by a large time scale. Single-cell regulatory network inference identifies GATA6, a transcription factor linked to common arterial trunk and bicuspid aortic valve, as a key regulator of valve precursor cells. Its downstream network reveals candidate drivers of human cardiac defects and illuminates the molecular mechanisms of both normal and pathological valve development. Our findings define the cellular and molecular signatures of the human OFT and its distinct cell lineages, which is critical for understanding congenital heart defects and developing cardiac tissue for regenerative medicine.

developmental biology↗

bioRxiv2023

CD82 expression marks the endothelium to hematopoietic transition at the onset of blood specification in human

SUMMARYDuring embryonic development, all blood progenitors are initially generated from endothelial cells that acquire a hemogenic potential. Blood progenitors emerge through an endothelial-to-hematopoietic transition regulated by the transcription factor RUNX1. To date, we still know very little about the molecular characteristics of hemogenic endothelium and the molecular changes underlying the transition from endothelium to hematopoiesis. Here, we analysed at the single cell level a human embryonic stem cell-derived endothelial population containing hemogenic potential. RUNX1-expressing endothelial cells, which harbour enriched hemogenic potential, show very little molecular differences to their endothelial counterpart suggesting priming toward hemogenic potential rather than commitment. Additionally, we identify CD82 as a marker of the endothelium-to-hematopoietic transition. CD82 expression is rapidly upregulated in newly specified blood progenitors then rapidly downregulated as further differentiation occurs. Together our data suggest that endothelial cells are first primed toward hematopoietic fate, then rapidly undergo the transition from endothelium to blood.

developmental biology↗

bioRxiv2018

ZIC3 controls the transition from naïve to primed pluripotency.

Embryonic stem cells (ESCs) are pluripotent in nature, meaning that they have the capacity to differentiate into any cell in the body. However, to do so they must transition through a series of intermediate cell states before becoming terminally differentiated. A lot is known about how ESCs maintain their pluripotent state but comparatively less about how they exit this state and begin the transition towards differentiated cells. Here we investigated the earliest events in this transition by determining the changes in the open chromatin landscape as naive mouse ESCs transition to epiblast-like cells (EpiLCs). Motif enrichment analysis of the newly opening regions coupled with expression analysis identified ZIC3 as a potential regulator of this cell fate transition. Chromatin binding and genome-wide transcriptional profiling confirmed ZIC3 as an important regulatory transcription factor and among its targets are genes encoding a number of transcription factors. Among these is GRHL2 which acts through enhancer switching to maintain the expression of a subset of genes from the ESC state. Our data therefore place ZIC3 at the top of a cascade of transcriptional regulators and provide an important advance in our understanding of the regulatory factors governing the earliest steps in ESC differentiation.\n\nHighlightsO_LIThe transcription factor ZIC3 drives gene expression changes in the ESC to EpiLC transition.\nC_LIO_LIExtensive changes occur in the open chromatin landscape as ESCs progress to EpiLCs.\nC_LIO_LIZIC3 activates the expression of a network of transcription factors.\nC_LIO_LIZIC3 activated genes in EpiLCs are upregulated in the post-implantation epiblast.\nC_LI

developmental biology↗