A5068833158- RNA Research and Splicing
- Genomics and Chromatin Dynamics
- RNA and protein synthesis mechanisms
- Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Animal Genetics and Reproduction
- RNA modifications and cancer
- Pluripotent Stem Cells Research
- RNA regulation and disease
- Plant Molecular Biology Research
- Bioinformatics and Genomic Networks
- Chromosomal and Genetic Variations
- Protein Degradation and Inhibitors
- Gene Regulatory Network Analysis
- Microbial Metabolic Engineering and Bioproduction
- Digestive system and related health
- Mitochondrial Function and Pathology
- CRISPR and Genetic Engineering
- Fibroblast Growth Factor Research
- Single-cell and spatial transcriptomics
- Sperm and Testicular Function
- Nuclear Structure and Function
The Francis Crick Institute
2024-2025
University College London
2018-2023
Cancer Institute (WIA)
2023
University of Birmingham
2011-2021
CRUK Lung Cancer Centre of Excellence
2018
Abstract Cohesin and CTCF are master regulators of genome topology. How these ubiquitous proteins contribute to cell-type specific structure is poorly understood. Here, we explore quantitative aspects topologically associated domains (TAD) between pluripotent embryonic stem cells (ESC) lineage-committed cells. ESCs exhibit permissive topological configurations which manifest themselves as increased inter- TAD interactions, weaker intra-TAD a unique connectivity whereby one border makes...
Most studies of cohesin function consider the Stromalin Antigen (STAG/SA) proteins as core complex members given their ubiquitous interaction with ring. Here, we provide functional data to support notion that SA subunit is not a mere passenger in this structure, but instead plays key role localization diverse biological processes and promotes loading at these sites. We show cells acutely depleted for RAD21, remain bound chromatin, cluster 3D interact CTCF, well wide range RNA binding...
The mammalian Y chromosome is essential for male fertility, but which genes regulate spermatogenesis unresolved. We addressed this by generating 13 Y-deletant mouse models. In Eif2s3y , Uty and Zfy2 deletants, was impaired. found that regulates spermatogonial proliferation, revealed a role in promoting meiotic sex pairing, uncovered unexpected effects of on the somatic testis transcriptome. remaining single Y-gene appeared unperturbed, transcription still altered. Multigene deletions,...
Sex chromosomes shape male (XY) - female (XX) differences in development and disease. These can be modelled vitro by comparing XY XX human induced pluripotent stem cells (hiPSCs). However, this system, inter-individual autosomal variation unstable X-dosage compensation confound identification of sex chromosomal effects. Here, we utilise chromosome loss XXY fibroblasts to generate hiPSCs that are autosomally isogenic exhibit stable compensation. We also create X-monosomic (XO) hiPSCs,...
Our understanding of how STAG proteins contribute to cell identity and disease have largely been studied from the perspective chromosome topology protein-coding gene expression. Here, we show that STAG1 is dominant paralog in mouse embryonic stem cells (mESCs) required for pluripotency. mESCs express a wide diversity naturally occurring Stag1 isoforms, resulting complex regulation both levels paralogs proportion their unique terminal ends. Skewing balance these isoforms impacts identity. We...
Ribosomal proteins (RPs) are essential components of ribosomes, but several RPs also present at transcription sites eukaryotic chromosomes. Here, we report a genome-wide ChIP-on-chip analysis the association three representative 60S with in Schizosaccharomyces pombe All tend to bind same subset coding and noncoding loci. The data demonstrate selective RNA-dependent interactions between many suggest that as preassembled multiprotein complex, perhaps or pre-60S subunits. These findings further...
Brain-derived neurotrophic factor (BDNF) promotes neuronal differentiation and survival is implicated in the pathogenesis of many neurological disorders. Here, we identified a novel intergenic enhancer located 170 kb from Bdnf gene, which expression transcript variants during mouse activity. Following activation, enhancer-promoter contacts increase, region moves away repressive nuclear periphery. activity necessary for clustering dendritogenesis vitro, cortical development vivo. Our findings...
The mammalian Y chromosome is essential for male fertility, but how individual genes regulate spermatogenesis poorly understood. To resolve this question, we generate a deletion series of the mouse chromosome, creating thirteen Y-deletant models and conducting exhaustive reproductive phenotyping. Eight genes, including several that are deeply conserved exhibit testis-specific expression, dispensable spermatogenesis. For others, uncover novel functions, role Uty in establishment...
Although the RNA helicase Upf1 has hitherto been examined mostly in relation to its cytoplasmic role nonsense mediated mRNA decay (NMD), here we report high-throughput ChIP data indicating genome-wide association of with active genes Schizosaccharomyces pombe. This is RNase sensitive, correlates Pol II transcription and expression levels. Changes occupancy were detected a deficient (upf1Δ) strain, prevalently at showing high relative wild-type. Additionally, an increased Ser2 signal was all...
Summary Single-cell transcriptomics has revealed conserved and divergent programmes of organogenesis in mammals, but existing studies have focused on eutherians. Marsupials exhibit short gestation complete development externally, necessitating accelerated differentiation anterior features required for locomotion feeding. As such, they represent a unique outgroup with which to understand temporal shifts development, known as heterochrony. Here, we generate the first single-cell transcriptomic...
Sex chromosomes are emerging as key regulators of adult health and disease in males (XY) females (XX), but their impact on embryo development is poorly understood. Using single-cell RNA sequencing (scRNA-seq) wild type aneuploid mouse embryos, we show that sex significantly shape the preimplantation transcriptional landscape. A hierarchy effects identified, distinctly mediated by Y chromosome, dosage X chromosomes, X-chromosome imprinting, Xist, non-coding initiates X-inactivation. The have...
ABSTRACT Most studies of cohesin function consider the Stromalin Antigen (STAG/SA) proteins as core complex members given their ubiquitous interaction with ring. Here, we provide functional data to support notion that SA subunit is not a mere passenger in this structure, but instead plays key role localization diverse biological processes and promotes loading at these sites. We show cells acutely depleted for RAD21, remain bound chromatin, cluster 3D interact CTCF, well wide range RNA...
ABSTRACT Several studies have shown a role for Stag proteins in cell identity. Our understanding of how contribute to identity largely been focused on its roles chromosome topology as part the cohesin complex and impact protein-coding gene expression. Furthermore, several paralogs exist mammalian cells with non-reciprocal structure cohesion functions. Why so many what specific functions each protein performs support given state are poorly understood. Here we reveal that Stag1 is dominant...
Summary Brain derived neurotrophic factor (BDNF) is a critical secreted peptide that promotes neuronal differentiation and survival, its downregulation implicated in many neurological disorders. Here, we investigated the regulation of mouse Bdnf gene cortical neurons identified novel enhancer expression transcript variants during differentiation, increasing total mRNA levels. Enhancer activity contributes to Bdnf-mediated effects on clustering activity-dependent dendritogenesis. During...
Abstract Although the RNA helicase Upf1 has hitherto been examined mostly in relation to its cytoplasmic role nonsense mediated mRNA decay (NMD), here we report high-throughput ChIP data indicating genome-wide association of with active genes Schizosaccharomyces pombe . This is RNase sensitive and it correlates Pol II transcription expression levels. While changes occupancy were detected at only some a Upf1-deficient ( upf1Δ ) strain, there an increased Ser2 signal all highly transcribed by...