A5026072466- Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- DNA Repair Mechanisms
- CRISPR and Genetic Engineering
- Genomics and Chromatin Dynamics
- Animal Genetics and Reproduction
- Chromosomal and Genetic Variations
- Pluripotent Stem Cells Research
- Sperm and Testicular Function
- Microtubule and mitosis dynamics
- Sexual Differentiation and Disorders
- Epigenetics and DNA Methylation
- Reproductive Biology and Fertility
- Single-cell and spatial transcriptomics
- Carcinogens and Genotoxicity Assessment
- Genetics and Neurodevelopmental Disorders
- RNA Research and Splicing
- Mitochondrial Function and Pathology
- Renal and related cancers
- Synthesis of Tetrazole Derivatives
- Chemical Synthesis and Analysis
- Conducting polymers and applications
- MicroRNA in disease regulation
- Cancer-related molecular mechanisms research
- Synthesis and biological activity
- T-cell and B-cell Immunology
The Francis Crick Institute
2015-2025
University College London Hospitals NHS Foundation Trust
2020
University College London
2020
National Hospital for Neurology and Neurosurgery
2020
Medical Research Council
2004-2012
Washington State University
2012
UCB Pharma (United Kingdom)
2008-2012
National Institute for Medical Research
2007-2009
National Institute for Health Research
2000-2008
The mammalian radiation has corresponded with rapid changes in noncoding regions of the genome, but we lack a comprehensive understanding regulatory evolution mammals. Here, track promoters and enhancers active liver across 20 species from six diverse orders by profiling genomic enrichment H3K27 acetylation H3K4 trimethylation. We report that is universal feature genomes. Most recently evolved arise ancestral DNA exaptation, rather than lineage-specific expansions repeat elements. In...
X chromosome inactivation is most commonly studied in the context of female mammalian development, where it performs an essential role dosage compensation. However, another form X-inactivation takes place male,during spermatogenesis, as germ cells enter meiosis. This second X-inactivation, called meiotic sex (MSCI) has emerged a novel paradigm for studying epigenetic regulation gene expression. New studies have revealed that MSCI special example more general mechanism silencing unsynapsed...
CRISPR-Cas9 genome editing is a promising technique for clinical applications, such as the correction of disease-associated alleles in somatic cells. The use this approach has also been discussed context heritable human germ line. However, studies assessing gene early embryos report low efficiency mutation repair, high rates mosaicism, and possibility unintended outcomes that may have pathologic consequences. We developed computational pipelines to assess single-cell genomics transcriptomics...
Chromosome synapsis during zygotene is a prerequisite for the timely homologous recombinational repair of meiotic DNA double-strand breaks (DSBs). Unrepaired DSBs are thought to trigger apoptosis midpachytene male meiosis if fails. An early pachytene response asynapsis silencing unsynapsed chromatin (MSUC), which, in normal males, silences X and Y chromosomes (meiotic sex chromosome inactivation [MSCI]). In this study, we show that MSUC occurs Spo11-null mouse spermatocytes with extensive...
Meiotic crossover formation involves the repair of programmed DNA double-strand breaks (DSBs) and synaptonemal complex (SC) formation. Completion these processes must precede meiotic divisions in order to avoid chromosome abnormalities gametes. Enduring key questions meiosis have been how progression are coordinated, whether inappropriate asynapsis is monitored, elicits prophase arrest via mechanisms that distinct from surveillance unrepaired DSBs. We disrupted meiosis-specific mouse HORMAD2...
In mammals, homologs that fail to synapse during meiosis are transcriptionally inactivated. This process, meiotic silencing, drives inactivation of the heterologous XY bivalent in male germ cells (meiotic sex chromosome [MSCI]) and is thought act as a surveillance mechanism. The checkpoint protein ATM Rad3-related (ATR) localizes unsynapsed chromosomes, but its role initiation maintenance silencing unknown. Here we show ATR has multiple roles silencing. first regulates HORMA (Hop1, Rev7,...
Meiotic synapsis and recombination ensure correct homologous segregation genetic diversity. Asynapsed homologs are transcriptionally inactivated by meiotic silencing, which serves a surveillance function in males drives sex chromosome inactivation. Silencing depends on the DNA damage response (DDR) network, but how DDR proteins engage repressive chromatin marks is unknown. We identify histone H3-lysine-9 methyltransferase SETDB1 as bridge linking to silencing male mice. At onset of X H3K9...
Abstract The Four Core Genotypes (FCG) is a mouse model system used to disentangle the function of sex chromosomes and hormones. We report that copy 3.2 MB region X chromosome has translocated Y Sry- thus increased expression X-linked genes including single-stranded RNA sensor autoimmune disease mediator Tlr7 . This previously-unreported X-Y translocation complicates interpretation studies reliant on C57BL/6J FCG mice.
Meiotic silencing of unsynapsed chromatin (MSUC) is a key mechanism in spermatogenesis and model system to study the dynamics gene silencing. Here we show that MAEL, ortholog Drosophila 's high mobility group box protein Maelstrom, associated not only with silenced XY body, but also autosomes. Characterization MAEL revealed it interacts directly remodeler SNF5/INI1 chromatin-associated SIN3B, which find localized body. This first time has been shown associate whole chromosomes. In addition,...
LRP5 and LRP6 are proteins predicted to contain four six-bladed β-propeller domains both bind the bone-specific Wnt signaling antagonist sclerostin. Here, we report crystal structure of amino-terminal region using NMR show that ability sclerostin this molecule is mediated by central core does not involve amino- carboxyl-terminal flexible arm regions. We structured interacts with via an NXI motif (found in sequence PNAIG) within a loop (loop 2) region. This related closely previously...