58 results found
Cvetesic N, Leitch H, Borkowska M, et al., 2018, SLIC-CAGE: high-resolution transcription start site mapping using nanogram-levels of total RNA
Cap analysis of gene expression (CAGE) is a methodology for genome-wide quantitative mapping of mRNA 5'ends to precisely capture transcription start sites at a single nucleotide resolution. In combination with high-throughput sequencing, CAGE has revolutionized our understanding of rules of transcription initiation, led to discovery of new core promoter sequence features and discovered transcription initiation at enhancers genome-wide. The biggest limitation of CAGE is that even the most recently improved version (nAnT-iCAGE) still requires large amounts of total cellular RNA (5 micrograms), preventing its application to scarce biological samples such as those from early embryonic development or rare cell types. Here, we present SLIC-CAGE, a Super-Low Input Carrier-CAGE approach to capture 5'ends of RNA polymerase II transcripts from as little as 5-10 ng of total RNA. The dramatic increase in sensitivity is achieved by specially designed, selectively degradable carrier RNA. We demonstrate the ability of SLIC-CAGE to generate data for genome-wide promoterome with 1000-fold less material than required by existing CAGE methods by generating a complex, high quality library from mouse embryonic day (E) 11.5 primordial germ cells.
Hill PWS, Leitch HG, Requena CE, et al., 2018, Epigenetic reprogramming enables the transition from primordial germ cell to gonocyte, NATURE, Vol: 555, Pages: 392-+, ISSN: 0028-0836
Leitch HG, Hajkova P, 2018, MATERNAL OBESITY Eggs sense high-fat diet, NATURE GENETICS, Vol: 50, Pages: 318-319, ISSN: 1061-4036
Leitch HG, Hajkova P, 2018, Publisher Correction: Eggs sense high-fat diet.
In the version of this article originally published, a box was misplaced in Fig. 1. The error has been corrected in the HTML and PDF versions of the article.
Luo C, Hajkova P, Ecker JR, 2018, Dynamic DNA methylation: In the right place at the right time, SCIENCE, Vol: 361, Pages: 1336-1340, ISSN: 0036-8075
McEwen K, Linnett S, Leitch H, et al., 2018, Signalling pathways drive heterogeneity of ground state pluripotency
Pluripotent stem cells (PSCs) can self-renew indefinitely while maintaining the ability to generate all cell types of the body. This plasticity is proposed to require heterogeneity in gene expression, driving a metastable state which may allow flexible cell fate choices. Contrary to this, naive PSC grown in fully defined '2i' environmental conditions, containing small molecule inhibitors of MEK and GSK3 kinases, show homogenous pluripotency and lineage marker expression. However, here we show that 2i induces greater genome-wide heterogeneity than traditional serum-containing growth environments at the population level across both male and female PSCs. This heterogeneity is dynamic and reversible over time, consistent with a dynamic metastable equilibrium of the pluripotent state. We further show that the 2i environment causes increased heterogeneity in the calcium signalling pathway at both the population and single-cell level. Mechanistically, we identify loss of robustness regulators in the form of negative feedback to the upstream EGF receptor. Our findings advance the current understanding of the plastic nature of the pluripotent state and highlight the role of signalling pathways in the control of transcriptional heterogeneity. Furthermore, our results have critical implications for the current use of kinase inhibitors in the clinic, where inducing heterogeneity may increase the risk of cancer metastasis and drug resistance.
Rosic S, Amouroux R, Requena CE, et al., 2018, Evolutionary analysis indicates that DNA alkylation damage is a byproduct of cytosine DNA methyltransferase activity, NATURE GENETICS, Vol: 50, ISSN: 1061-4036
Wyck S, Herrera C, Requena CE, et al., 2018, Oxidative stress in sperm affects the epigenetic reprogramming in early embryonic development, EPIGENETICS & CHROMATIN, Vol: 11, ISSN: 1756-8935
Benesova M, Trejbalova K, Kucerova D, et al., 2017, Overexpression of TET dioxygenases in seminomas associates with low levels of DNA methylation and hydroxymethylation, MOLECULAR CARCINOGENESIS, Vol: 56, Pages: 1837-1850, ISSN: 0899-1987
Ferry L, Fournier A, Tsusaka T, et al., 2017, Methylation of DNA Ligase 1 by G9a/GLP Recruits UHRF1 to Replicating DNA and Regulates DNA Methylation, MOLECULAR CELL, Vol: 67, Pages: 550-+, ISSN: 1097-2765
Izzo A, Ziegler-Birling C, Hill PWS, et al., 2017, Dynamic changes in H1 subtype composition during epigenetic reprogramming, JOURNAL OF CELL BIOLOGY, Vol: 216, Pages: 3017-3028, ISSN: 0021-9525
Wyck S, Herrera C, Requena-Torres C, et al., 2017, Oxidative stress in sperm causes developmental and epigenetic defects during bovine early embryonic development, 21st Annual Conference of the European-Society-for-Domestic-Animal-Reproduction (ESDAR), Publisher: WILEY, Pages: 143-143, ISSN: 0936-6768
Amouroux R, Nashun B, Shirane K, et al., 2016, De novo DNA methylation drives 5hmC accumulation in mouse zygotes, NATURE CELL BIOLOGY, Vol: 18, Pages: 225-+, ISSN: 1465-7392
Eguizabal C, Herrera L, De Onate L, et al., 2016, Characterization of the Epigenetic Changes During Human Gonadal Primordial Germ Cells Reprogramming, STEM CELLS, Vol: 34, Pages: 2418-2428, ISSN: 1066-5099
Leitch HG, Surani MA, Hajkova P, 2016, DNA (De)Methylation: The Passive Route to Naivety?, TRENDS IN GENETICS, Vol: 32, Pages: 592-595, ISSN: 0168-9525
Trejbalova K, Benesova M, Kucerova D, et al., 2016, Aberrant expression of ERVWE1 endogenous retrovirus and overexpression of TET dioxygenases are characteristic features of seminoma, Publisher: BIOMED CENTRAL LTD, ISSN: 1742-4690
Nashun B, Hill PW, Hajkova P, 2015, Reprogramming of cell fate: epigenetic memory and the erasure of memories past., EMBO Journal, Vol: 34, Pages: 1296-1308, ISSN: 0261-4189
Cell identity is a reflection of a cell type-specific gene expression profile, and consequently, cell type-specific transcription factor networks are considered to be at the heart of a given cellular phenotype. Although generally stable, cell identity can be reprogrammed in vitro by forced changes to the transcriptional network, the most dramatic example of which was shown by the induction of pluripotency in somatic cells by the ectopic expression of defined transcription factors alone. Although changes to cell fate can be achieved in this way, the efficiency of such conversion remains very low, in large part due to specific chromatin signatures constituting an epigenetic barrier to the transcription factor-mediated reprogramming processes. Here we discuss the two-way relationship between transcription factor binding and chromatin structure during cell fate reprogramming. We additionally explore the potential roles and mechanisms by which histone variants, chromatin remodelling enzymes, and histone and DNA modifications contribute to the stability of cell identity and/or provide a permissive environment for cell fate change during cellular reprogramming.
Nashun B, Hill PWS, Smallwood SA, et al., 2015, Continuous Histone Replacement by Hira Is Essential for Normal Transcriptional Regulation and De Novo DNA Methylation during Mouse Oogenesis, MOLECULAR CELL, Vol: 60, Pages: 611-625, ISSN: 1097-2765
Amouroux R, McEwen KR, Hajkova P, 2014, Current technological advances in mapping new DNA modifications, Drug Discovery Today: Disease Models, Vol: 12, Pages: 15-26, ISSN: 1740-6757
Hill PS, Amouroux R, Hajkova P, 2014, DNA demethylation, Tet proteins and 5-hydroxymethylcytosine in epigenetic reprogramming: An emerging complex story, GENOMICS, Vol: 104, Pages: 324-333, ISSN: 0888-7543
Supek F, Lehner B, Hajkova P, et al., 2014, Hydroxymethylated Cytosines Are Associated with Elevated C to G Transversion Rates, PLOS GENETICS, Vol: 10, ISSN: 1553-7390
Leitch HG, McEwen KR, Turp A, et al., 2013, Naive pluripotency is associated with global DNA hypomethylation, NATURE STRUCTURAL & MOLECULAR BIOLOGY, Vol: 20, Pages: 311-316, ISSN: 1545-9993
McEwen KR, Leitch HG, Amouroux R, et al., 2013, The impact of culture on epigenetic properties of pluripotent stem cells and pre-implantation embryos, BIOCHEMICAL SOCIETY TRANSACTIONS, Vol: 41, Pages: 711-719, ISSN: 0300-5127
Piccolo FM, Bagci H, Brown KE, et al., 2013, Different Roles for Tet1 and Tet2 Proteins in Reprogramming-Mediated Erasure of Imprints Induced by EGC Fusion, MOLECULAR CELL, Vol: 49, Pages: 1023-1033, ISSN: 1097-2765
Piccolo FM, Bagci H, Brown KE, et al., 2013, Errata to Different roles for tet1 and tet2 proteins in reprogramming-mediated erasure of imprints induced by egc fusion [Molecular Cell, 49 (2013) 1023-1033], Molecular Cell, Vol: 49, ISSN: 1097-2765
Hajkova P, 2011, Epigenetic reprogramming in the germline: towards the ground state of the epigenome, PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES, Vol: 366, Pages: 2266-2273, ISSN: 0962-8436
Hajkova P, 2010, Epigenetic reprogramming - taking a lesson from the embryo, CURRENT OPINION IN CELL BIOLOGY, Vol: 22, Pages: 342-350, ISSN: 0955-0674
Hajkova P, Jeffries SJ, Lee C, et al., 2010, Genome-Wide Reprogramming in the Mouse Germ Line Entails the Base Excision Repair Pathway, SCIENCE, Vol: 329, Pages: 78-82, ISSN: 0036-8075
Surani MA, Hajkova P, 2010, Epigenetic reprogramming of mouse germ cells toward totipotency., Cold Spring Harb Symp Quant Biol, Vol: 75, Pages: 211-218
Primordial germ cells (PGCs), the precursors of sperm and eggs, are the route to totipotency and require establishment of a unique epigenome in this lineage. The genetic program for PGC specification in the mouse also initiates epigenetic reprogramming that continues when PGCs migrate into the developing gonads. Among these later events is active and genome-wide DNA demethylation, which is linked to extensive chromatin remodeling. These extensive epigenetic changes erase most, if not all, of the existing epigenetic information, which resets the epigenome for totipotency. Recent evidence suggests that active DNA demethylation involves a base excision repair (BER) pathway. BER is mechanistically linked to DNA demethylation, but what triggers BER is currently under investigation. The methylated cytosine (5mC) could be modified by deamination or to 5hmC, which could induce BER. Detection of Tet1 expression specifically and coincidentally, at the time of BER in PGCs, suggests that conversion of 5mC to 5hmC might be involved, at least in part, during epigenetic reprogramming and DNA demethylation in germ cells.
Tee W-W, Pardo M, Theunissen TW, et al., 2010, Prmt5 is essential for early mouse development and acts in the cytoplasm to maintain ES cell pluripotency, GENES & DEVELOPMENT, Vol: 24, Pages: 2772-2777, ISSN: 0890-9369
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