A5086923541- Genomics and Chromatin Dynamics
- RNA Research and Splicing
- RNA and protein synthesis mechanisms
- Ocular Surface and Contact Lens
- RNA modifications and cancer
- Epigenetics and DNA Methylation
- Single-cell and spatial transcriptomics
- Chromosomal and Genetic Variations
- Surfactants and Colloidal Systems
- Genomics and Phylogenetic Studies
- Cancer-related gene regulation
- Advancements in Transdermal Drug Delivery
- Peptidase Inhibition and Analysis
- Cancer-related molecular mechanisms research
- Lipid Membrane Structure and Behavior
- Hemoglobinopathies and Related Disorders
- CRISPR and Genetic Engineering
- Biochemical and Molecular Research
- Cancer Research and Treatments
- Genomic variations and chromosomal abnormalities
- Extracellular vesicles in disease
- Molecular Biology Techniques and Applications
- Congenital heart defects research
- Genetic Associations and Epidemiology
- Advanced Drug Delivery Systems
MRC Weatherall Institute of Molecular Medicine
2015-2025
John Radcliffe Hospital
2017-2025
University of Oxford
2015-2022
MRC Laboratory of Molecular Biology
2019
MRC Molecular Haematology Unit
2017-2019
Medical Research Council
2015-2018
University of Southern Denmark
2012-2013
Aalto University
2010-2012
Helsinki Institute of Physics
2009-2010
University of Helsinki
2007-2008
The human genome contains ∼30,000 CpG islands (CGIs). While CGIs associated with promoters nearly always remain unmethylated, many of the ∼9,000 lying within gene bodies become methylated during development and differentiation. Both promoter intragenic may also abnormally as a result rearrangements in malignancy. epigenetic mechanisms by which some but others, same cell, unmethylated these situations are poorly understood. Analyzing specific loci using genome-wide analysis, we show that...
Enhancer elements are a key regulatory feature of many important genes. Several general features including the presence specific histone modifications used to demarcate potentially active enhancers. Here we reveal that putative enhancers marked with H3 lysine 79 (H3K79) di or trimethylation (me2/3) (which name H3K79me2/3 enhancer KEEs) can be found in multiple cell types. Mixed lineage leukemia gene (MLL) rearrangements (MLL-r) such as MLL-AF4 major cause incurable acute lymphoblastic...
Highlights•Profiling chromatin dynamics uncovers complete repertoire of neural crest (NC) enhancers•NC super-enhancers act additively to sustain network robustness•Enhancer clustering reveals early split between neural-NC and canonical NC programs•Global construction cranial gene regulatory networkSummaryPrecise control developmental processes is encoded in the genome form networks (GRNs). Such multi-factorial systems are difficult decode vertebrates owing their complex hierarchies dynamic...
Abstract Mammalian gene expression patterns are controlled by regulatory elements, which interact within topologically associating domains (TADs). The relationship between activation of formation structural chromatin interactions and during development is unclear. Here, we present Tiled-C, a low-input chromosome conformation capture (3C) technique. We use this approach to study architecture at high spatial temporal resolution through in vivo mouse erythroid differentiation. Integrated...
β-Thalassemia is one of the most common inherited anemias, with no effective cure for patients. The pathophysiology reflects an imbalance between α- and β-globin chains excess free α-globin causing ineffective erythropoiesis hemolysis. When α-thalassemia co-inherited β-thalassemia, are reduced significantly ameliorating clinical severity. Here we demonstrate use CRISPR/Cas9 genome editing primary human hematopoietic stem/progenitor (CD34+) cells to emulate a natural mutation, which deletes...
Specific communication between gene promoters and enhancers is critical for accurate regulation of expression. However, it remains unclear how specific interactions multiple regulatory elements contained within a single chromatin domain are coordinated. Recent technological advances which can detect multi-way at alleles provide insights into cooperate or compete transcriptional activation. Here, we use such an approach to investigate the α-globin distributed in mouse model extended include...
Abstract Self-interacting chromatin domains encompass genes and their cis -regulatory elements; however, the three-dimensional form a domain takes, whether this relies on enhancer–promoter interactions, processes necessary to mediate formation maintenance of such domains, remain unclear. To examine these questions, here we use combination high-resolution chromosome conformation capture, non-denaturing fluorescence in situ hybridisation super-resolution imaging study 70 kb encompassing mouse...
Abstract Chromosome conformation capture (3C) provides an adaptable tool for studying diverse biological questions. Current 3C methods generally provide either low-resolution interaction profiles across the entire genome, or high-resolution at limited numbers of loci. Due to technical limitations, generation reproducible has not been achieved genome-wide scale. Here, overcome this barrier, we systematically test each step and report two improvements over current methods. We show that up 30%...
Abstract The chromatin remodeller ATRX interacts with the histone chaperone DAXX to deposit variant H3.3 at sites of nucleosome turnover. is known bind repetitive, heterochromatic regions genome including telomeres, ribosomal DNA and pericentric repeats, many which are putative G-quadruplex forming sequences (PQS). At these plays an ancillary role in a wide range nuclear processes facilitating replication, modification transcription. Here, using improved protocol for immunoprecipitation, we...
We investigate the three-dimensional (3D) conformations of α-globin locus at single-allele level in murine embryonic stem cells (ESCs) and erythroid cells, combining polymer physics models high-resolution Capture-C data. Model predictions are validated against independent fluorescence situ hybridization (FISH) data measuring pairwise distances, Tri-C identifying three-way contacts. The architecture is rearranged during transition from ESCs to associated with activation globin genes. find...
Abstract The α- and β-globin loci harbor developmentally expressed genes, which are silenced throughout post-natal life. Reactivation of these genes may offer therapeutic approaches for the hemoglobinopathies, most common single gene disorders. Here, we address mechanisms regulating embryonically α-like globin, termed ζ-globin. We show that in embryonic erythroid cells, ζ-gene lies within a ~65 kb sub-TAD (topologically associating domain) open, acetylated chromatin interacts with α-globin...
Abstract The transcription factor RUNX1 is a critical regulator of developmental hematopoiesis and frequently disrupted in leukemia. Runx1 large, complex gene that expressed from two alternative promoters under the spatiotemporal control multiple hematopoietic enhancers. To dissect dynamic regulation development, we analyzed its three-dimensional chromatin conformation mouse embryonic stem cell (ESC) differentiation cultures. resides 1.1 Mb topologically associating domain (TAD) demarcated...
The tear fluid protects the corneal epithelium from drying and pathogens it also provides nutrients to these cells. Tear is composed of an aqueous layer as well a lipid that resides at air–tear interface. function lower surface tension probably prevent evaporation. We have studied impact composition on structural dynamical properties film using Langmuir films, X-ray diffraction, coarse-grained molecular dynamics simulations. Based recently published lipidomic data, we selected number model...
The T-box transcription factor (TF) Eomes is a key regulator of cell fate decisions during early mouse development. cis-acting regulatory elements that direct expression in the anterior visceral endoderm (AVE), primitive streak (PS) and definitive (DE) have yet to be defined. Here, we identified three gene-proximal enhancer-like sequences (PSE_a, PSE_b VPE) faithfully activate tissue-specific transgenic embryos. However, targeted deletion experiments demonstrate PSE_a are dispensable, only...
ABSTRACT With decreasing cost of next-generation sequencing (NGS), we are observing a rapid rise in the volume ‘big data’ academic research, healthcare and drug discovery sectors. The present bottleneck for extracting value from these sets is data processing analysis. Considering this, there still lack reliable, automated easy to use tools that will allow experimentalists assess quality sequenced libraries explore first hand, without need investing lot time computational core analysts early...
In the era of genome-wide association studies (GWAS) and personalized medicine, predicting impact single nucleotide polymorphisms (SNPs) in regulatory elements is an important goal. Current approaches to determine potential SNPs depend on inadequate knowledge cell-specific DNA binding motifs. Here, we present Sasquatch, a new computational approach that uses DNase footprint data estimate visualize effects noncoding variants transcription factor binding. Sasquatch performs comprehensive k...
Abstract Many single nucleotide variants (SNVs) associated with human traits and genetic diseases are thought to alter the activity of existing regulatory elements. Some SNVs may also create entirely new elements which change gene expression, but mechanism by they do so is largely unknown. Here we show that a base in an otherwise unremarkable region α-globin cluster creates promoter unidirectional transcript. This SNV downregulates expression causing α-thalassaemia. Of note, lying between...