A5028282738- Pluripotent Stem Cells Research
- CRISPR and Genetic Engineering
- Epigenetics and DNA Methylation
- Genomics and Chromatin Dynamics
- Renal and related cancers
- RNA modifications and cancer
- RNA Research and Splicing
- Telomeres, Telomerase, and Senescence
- Cancer-related Molecular Pathways
- Sirtuins and Resveratrol in Medicine
- Neurogenesis and neuroplasticity mechanisms
- Single-cell and spatial transcriptomics
- Prion Diseases and Protein Misfolding
- FOXO transcription factor regulation
- Ubiquitin and proteasome pathways
- Immune Cell Function and Interaction
- Amino Acid Enzymes and Metabolism
- 3D Printing in Biomedical Research
- Alzheimer's disease research and treatments
- Erythrocyte Function and Pathophysiology
- Research on Leishmaniasis Studies
- Cancer-related molecular mechanisms research
- Autophagy in Disease and Therapy
- Pancreatic function and diabetes
- Hemoglobinopathies and Related Disorders
Granta Design (United Kingdom)
2024
University of York
2006-2024
Institute for Research in Biomedicine
2018-2023
Spanish National Cancer Research Centre
2012-2020
Institute for Research in Biomedicine
2020
Centro de Investigación del Cáncer
2018
The mechanisms responsible for the transcriptional silencing of pluripotency genes in differentiated cells are poorly understood. We have observed that lacking tumor suppressor p27 can be reprogrammed into induced pluripotent stem (iPSCs) absence ectopic Sox2. Interestingly, and tissues from null mice, including brain, lung, retina, present an elevated basal expression Sox2, suggesting contributes to repression Furthermore, iPSCs fail fully repress Sox2 upon differentiation. Mechanistically,...
In the mouse embryonic forebrain, developmentally distinct oligodendrocyte progenitor cell populations and their progeny, oligodendrocytes, emerge from three regions in a spatiotemporal gradient ventral to dorsal. However, functional importance of this developmental heterogeneity is unknown. Using genetic strategy ablate dorsally derived lineage cells (OLCs), we show here that areas which OLCs normally reside adult central nervous system become populated myelinated by origin. These ectopic...
Cell identity is orchestrated through an interplay between transcription factor (TF) action and genome architecture. The mechanisms used by TFs to shape three-dimensional (3D) organization remain incompletely understood. Here we present evidence that the lineage-instructive TF CEBPA drives extensive chromatin compartment switching promotes formation of long-range hubs during induced B cell-to-macrophage transdifferentiation. Mechanistically, find intrinsically disordered region (IDR)...
After reprogramming to naive pluripotency, human pluripotent stem cells (PSCs) still exhibit very low ability make interspecies chimeras. Whether this is because they are inherently devoid of the attributes chimeric competency or PSCs cannot colonize embryos from distant species remains be elucidated. Here, we have used different types mouse, human, and rhesus monkey analyzed their rabbit cynomolgus embryos. Mouse embryonic (ESCs) remained mitotically active efficiently colonized host In...
Differentiated cells can be converted into pluripotent stem by expressing the transcription factors OCT4, SOX2, KLF4, and MYC (OSKM) in a process known as reprogramming. Here, using single-cell RNA sequencing of pancreas undergoing reprogramming, we identify markers along trajectory from acinar cell identity to pluripotency. These allow direct situ visualization dedifferentiation acquiring features early advanced intermediate We also find that fraction do not dedifferentiate upon OSKM...
Background The NAD-dependent deacetylase SIRT1 is a nutrient-sensitive coordinator of stress-tolerance, multiple homeostatic processes and healthspan, while p53 stress-responsive transcription factor our paramount tumour suppressor. Thus, SIRT1-mediated inhibition has been identified as key node in the common biology cancer, metabolism, development ageing. However, precisely how integrates such diverse remains to be elucidated. Methodology/Principal Findings Here we report that alternatively...
The ectopic expression of the transcription factors OCT4, SOX2, KLF4 and MYC (OSKM) enables reprogramming differentiated cells into pluripotent embryonic stem cells. Methods based on partial reversible in vivo are a promising strategy for tissue regeneration rejuvenation. However, little is known about barriers that impair an context. We report natural killer (NK) significantly limit reprogramming, both vitro vivo. Cells tissues intermediate states upregulate NK-activating ligands, such as...
The RNA polymerase II-associated protein 1 (RPAP1) is conserved across metazoa and required for stem cell differentiation in plants; however, very little known about its mechanism of action or role mammalian cells. Here, we report that RPAP1 essential the expression identity genes viability. Depletion triggers de-differentiation, facilitates reprogramming toward pluripotency, impairs differentiation. Mechanistically, show interaction between II (RNA Pol II) Mediator, as well recruitment...
Abstract Embryonic stem cells (ESCs) can be maintained in the naïve state through inhibition of Mek1/2 and Gsk3 (2i). A relevant effect 2i is Cdk8/19, which are negative regulators Mediator complex, responsible for activity enhancers. Inhibition Cdk8/19 (Cdk8/19i) stimulates enhancers and, similar to 2i, stabilizes ESCs state. Here, we use mass spectrometry describe molecular events (phosphoproteome, proteome, metabolome) triggered by Cdk8/19i on ESCs. Our data reveal widespread...
Abstract A disordered to β-sheet transition was thought drive the functional switch of Q/N-rich prions, similar pathogenic amyloids. However, recent evidence indicates a critical role for coiled-coil (CC) regions within yeast prion domains in amyloid formation. We show that many human prion-like (PrLDs) contain CC overlap with polyQ tracts. Most proteins bearing these are transcriptional coactivators, including Mediator complex subunit 15 (MED15) involved bridging enhancers and promoters....
Abstract The Leishmania donovani species complex (LdSC) causes visceral leishmaniasis (VL), is present in Africa, Europe, the Middle East, Asia and Americas, 20-40,000 fatalities per year. Previous analyses concluded that dispersal of this occurred 1-10 million years ago. Using updated methods data, we show a ten-thousand year old East African population dispersed globally only within last 2,000 years, consistent with human migration, war colonisation as driving factors.
Summary Differentiated cells can be converted to pluripotent stem (iPSCs) upon ectopic expression of transcription factors OCT4, SOX2, KLF4 and MYC (OSKM) in a process known as reprogramming. Great efforts have been made dissect intermediate states vitro reprogramming how they are affected by culture conditions, while the roadmap vivo remains unexplored. Here, we use single cell RNA sequencing capture undergoing adult pancreas. We identify markers along trajectory from acinar identity...
Summary After reprogramming to naïve pluripotency, human pluripotent stem cells (PSCs) still exhibit very low ability make interspecies chimeras. Whether this is because they are inherently devoid of the attributes chimeric competency or PSCs cannot colonize embryos from distant species remains be elucidated. Here, we have used different types mouse, and rhesus monkey analyzed their rabbit cynomolgus embryos. Mouse embryonic (ESCs) remained mitotically active efficiently colonized host In...
Abstract Lysinuric Protein Intolerance (LPI) is an inborn error of metabolism resulting from SLC7A7 deficiency that causes diminished plasma concentration cationic amino acids. The clinical picture highly heterogeneous among patients, who commonly present intolerance to protein intake and more severe complications such as hematological abnormalities kidney failure. Although current treatments aim address the metabolic defects LPI, they have been unsatisfactory when treating most symptoms....
Pluripotent stem cells can be stabilized in vitro at different developmental states by the use of specific chemicals and soluble factors. The naïve primed are best characterized pluripotency states. Naïve pluripotent (PSCs) correspond to early pre-implantation blastocyst and, mice, constitute optimal starting state for subsequent applications. However, stabilization human PSCs remains challenging because, after short-term culture, most current methods result karyotypic abnormalities,...
Keywords: pluripotency; naïve; stem; imprinting; primordial germ cells; trophoblast; CDK8; Mediator; enhancers.