A5000034708- Reproductive System and Pregnancy
- Endometriosis Research and Treatment
- Pregnancy and preeclampsia studies
- Congenital heart defects research
- Kawasaki Disease and Coronary Complications
- Reproductive Physiology in Livestock
- RNA modifications and cancer
- Animal Genetics and Reproduction
- Estrogen and related hormone effects
- Zebrafish Biomedical Research Applications
- Cancer Cells and Metastasis
- COVID-19 Clinical Research Studies
- MicroRNA in disease regulation
- Single-cell and spatial transcriptomics
- Renal and related cancers
- COVID-19 Impact on Reproduction
- Epigenetics and DNA Methylation
- Inflammasome and immune disorders
- Reproductive Biology and Fertility
- Tissue Engineering and Regenerative Medicine
- TGF-β signaling in diseases
- Endometrial and Cervical Cancer Treatments
- Pluripotent Stem Cells Research
- CRISPR and Genetic Engineering
- Gynecological conditions and treatments
University of Warwick
2015-2024
University Hospitals Coventry and Warwickshire NHS Trust
2017-2020
National Health Service
2017-2020
Temasek Life Sciences Laboratory
2015
National University of Singapore
2015
BC Cancer Agency
2012-2014
University of British Columbia
2009-2012
Terry Fox Research Institute
2009
Montreal Children's Hospital
2004-2007
McGill University
2007
In cycling human endometrium, menstruation is followed by rapid estrogen-dependent growth. Upon ovulation, progesterone and rising cellular cAMP levels activate the transcription factor Forkhead box O1 (FOXO1) in endometrial stromal cells (EnSCs), leading to cell cycle exit differentiation into decidual that control embryo implantation. Here we show FOXO1 also causes acute senescence of a subpopulation decidualizing EnSCs an IL-8 dependent manner. Selective depletion or enrichment this...
During the implantation window, endometrium becomes poised to transition a pregnant state, process driven by differentiation of stromal cells into decidual (DC). Perturbations in this process, termed decidualization, leads breakdown feto-maternal interface and miscarriage, but underlying mechanisms are poorly understood. Here, we reconstructed pathway at single-cell level vitro demonstrate that first mount an acute stress response before emerging as DC or senescent (snDC). In absence immune...
We analyzed 8.55 million LongSAGE tags generated from 72 libraries. Each library was prepared a different mouse tissue. Analysis of the data revealed extensive overlap with existing gene sets and evidence for existence ≈24,000 previously undescribed genomic loci. The visual cortex, pancreas, mammary gland, preimplantation embryo, placenta contain largest number differentially expressed transcripts, 25% which are
Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening disease occurring several weeks after severe acute respiratory coronavirus 2 (SARS-CoV-2) infection. Deep immune profiling showed MIS-C patients had highly activated neutrophils, classical monocytes and memory CD8+ T-cells, with increased frequencies of B-cell plasmablasts double-negative B-cells. Post treatment samples from the same patients, taken during symptom resolution, identified recovery-associated features...
Abstract Pregnancy depends on the wholesale transformation of endometrium, a process driven by differentiation endometrial stromal cells (EnSC) into specialist decidual cells. Upon embryo implantation, impart tissue plasticity needed to accommodate rapidly growing conceptus and invading placenta, although underlying mechanisms are unclear. Here we characterize discrete population highly proliferative mesenchymal (hPMC) in midluteal human coinciding with window implantation. Single-cell...
Spontaneous decidualization of the endometrium in response to progesterone signaling is confined menstruating species, including humans and other higher primates. During this process, endometrial stromal cells (EnSCs) differentiate into specialized decidual that control embryo implantation. We subjected undifferentiated decidualizing human EnSCs an assay for transposase accessible chromatin with sequencing (ATAC-seq) map underlying changes. A total 185,084 open DNA loci were mapped...
In pregnancy, resistance of endometrial decidual cells to stress signals is critical for the integrity fetomaternal interface and, by extension, survival conceptus. O-GlcNAcylation an essential posttranslational modification that links glucose sensing cellular resistance. Unexpectedly, decidualization primary stromal (EnSCs) was associated with a 60% reduction in O-linked β-N-acetylglucosamine (O-GlcNAc)‒modified proteins, reflecting downregulation enzyme adds O-GlcNAc substrates (O-GlcNAc...
We tested the hypothesis that conserved placental mammal-specific microRNAs and their targets facilitate endometrial receptivity to implantation. Expression of miR-340-5p, -542-3p, -671-5p was regulated by exposure epithelial cells progesterone (10 μg/ml) for 24 h coordinate with 1,713 predicted targets. Proteomic analysis transfected miRNA mimic/inhibitor (48 h: n = 3) revealed 1,745 proteins altered miR-340-5p (mimic; 1,369, inhibitor; 376) which 171 were P4-regulated. MiR-542-3p 2,353...
A fundamental question in developmental biology is how the fertilized egg gives rise to all different cell types of an organism. The traditional view that are specified either by intrinsic factors such as fate determinants or via intercellular signalling. In some animals, a cytoplasmic determinant-like substance called germ plasm specifies germline. zebrafish eggs, dispersed form mRNP complexes granules, which enriched at animal pole. After fertilisation distribution granules changes...
Signaling by the transforming growth factor (TGF)-beta superfamily is important during kidney development. Here, we describe spatial and temporal expression patterns of Smads, transcription factors that translate TGF- signals into gene expression. RT-PCR data in situ hybridization analysis showed receptor-regulated (R) Smads (Smad1, -2, -3, -5, -8), common partner Smad (Smad4), inhibitory (I) (Smad6 -7) were all expressed mouse development from embryonic day 12 until end nephrogenesis at...
Valvuloseptal defects are the most common congenital heart defects. Notch signaling-induced endothelial-to-mesenchymal transition (EMT) in atrioventricular canal (AVC) cushions at murine embryonic day (E)9.5 is a required step during early valve development. Insights to transcriptional network that activated endocardial cells (EC) EMT and how these pathways direct maturation lacking.We show E11.5, AVC-EC retain ability undergo Notch-dependent when explanted on collagen. EC-Notch inhibition...
Abstract Embryo implantation requires a hospitable uterine environment. A key metabolic change that occurs during the peri-implantation period, and throughout early pregnancy, is rise in endometrial glycogen content. Glycogen accumulation prior cellular uptake of glucose. Here we show both human murine epithelial cells express high affinity Na + -coupled glucose carrier SGLT1. Ussing chamber experiments revealed electrogenic transport across endometrium wild type ( Slc5a1 +/+ ) but not SGLT1...
Novel approaches for culturing primary human cells in vitro are increasingly needed to study cell and tissue physiology grow replacement regenerative medicine. Conventional 2D monolayer cultures of endometrial epithelial stromal fail replicate the complex 3D architecture tissue. A fully synthetic scaffold that mimics microenvironment endometrium can ultimately provide a robust platform investigating and, hence, take significant steps toward tackling female infertility IVF failure. In this...
Can the accuracy of timing luteal phase endometrial biopsies based on urinary ovulation testing be improved by measuring expression a small number genes and continuous, non-categorical modelling approach?Measuring levels six (IL2RB, IGFBP1, CXCL14, DPP4, GPX3 SLC15A2) is sufficient to obtain substantially more accurate estimates assess reliability for each sample.Commercially available approaches gene require large sets use categorical approach that classifies samples as pre-receptive,...
Abstract DNA transposons and retroviruses are important transgenic tools for genome engineering. An consideration affecting the choice of vector is their insertion site preferences. Previous large-scale analyses Ds transposon integration sites in plants were done on basis reporter gene expression or germ-line transmission, making it difficult to discern vertebrate Here, we compare over 1300 zebrafish with Tol2 retroviral sites. Genome-wide analysis shows that presence absence marker...
Endometrial mesenchymal stem cells (eMSC) drive the extraordinary regenerative capacity of human endometrium. Clinical application eMSC for therapeutic purposes is hampered by spontaneous differentiation and cellular senescence upon large-scale expansion in vitro. A83-01, a selective transforming growth factor-β receptor (TGFβ-R) inhibitor, promotes culture blocking senescence, but underlying mechanisms are incompletely understood. In this study, we combined RNA-seq ATAC-seq to study impact...
Estrogen-dependent proliferation followed by progesterone-dependent differentiation of the endometrium culminates in a short implantation window. We performed single-cell assay for transposase-accessible chromatin with sequencing on endometrial samples obtained across menstrual cycle to investigate regulation temporal gene networks that control embryo implantation. identify uniquely accessible regions all major cellular constituents endometrium, delineate patterns coordinated remodeling...
Abstract Since the sequencing of human reference genome, many disease-related genes have been discovered. However, understanding functions all in genome remains a challenge. The biological activities these are usually investigated model organisms such as mice and zebrafish. Large-scale mutagenesis screens to generate disruptive mutations useful for identifying genes. Here, we report multifunctional system zebrafish using maize Ds transposon. Integration transposable element containing an...
Valve formation during embryonic heart development involves a complex interplay of regional specification, cell transformations, and remodeling events. While many studies have addressed the role specific genes this process, global understanding genetic basis for specification valves is incomplete. We undertaken genome-wide transcriptional profiling developing in mouse. Four Serial Analysis Gene Expression libraries were generated analyzed from mouse atrio-ventricular canal (AVC) at days...
Malformations of the cardiovascular system are most common type birth defect in humans, frequently affecting formation valves and septa. During heart valve septa formation, cells from atrio-ventricular canal (AVC) outflow tract (OFT) regions undergo an epithelial-to-mesenchymal transformation (EMT) invade underlying extracellular matrix to give rise endocardial cushions. Subsequent maturation newly formed mesenchyme leads thin stress-resistant leaflets. TWIST1 is a basic helix-loop-helix...
Inherited bone marrow failure associated with heterozygous mutations in GATA2 predisposes toward hematological malignancies, but the mechanisms remain poorly understood. Here, we investigate mechanistic basis of a zebrafish model deficiency. Single-cell transcriptomics and chromatin accessibility assays reveal that loss gata2a leads to skewing erythroid lineage at expense myeloid cells, cebpa expression decreased PU.1 CEBPA transcription factor hematopoietic stem progenitor cells (HSPCs)....
Abstract Breakdown of the feto-maternal interface in early pregnancy causes miscarriage. The cycling endometrium becomes poised to transition a pregnant state during midluteal implantation window, coinciding with differentiation stromal cells into decidual (DC) and emergence senescent (snDC). Emerging evidence suggests that DC engage uterine natural killer eliminate their counterparts, thus enabling formation robust matrix pregnancy. To examine if failure constrain snDC peri-implantation...