Publications
73 results found
Eguizabal C, Herrera L, De Onate L, et al., 2016, Characterisation of the Epigenetic Changes During Human Gonadal Primordial Germ Cells Reprogramming, Stem Cells, Vol: 34, Pages: 2418-2428, ISSN: 1066-5099
Epigenetic reprogramming is a central process during mammalian germline development. Genome-wide DNA demethylation in primordial germ cells (PGCs) is a prerequisite for the erasure of epigenetic memory, preventing the transmission of epimutations to the next generation. Apart from DNA demethylation, germline reprogramming has been shown to entail reprogramming of histone marks and chromatin remodelling. Contrary to other animal models, there is limited information about the epigenetic dynamics during early germ cell development in humans. Here, we provide further characterization of the epigenetic configuration of the early human gonadal PGCs. We show that early gonadal human PGCs are DNA hypomethylated and their chromatin is characterized by low H3K9me2 and high H3K27me3 marks. Similarly to previous observations in mice, human gonadal PGCs undergo dynamic chromatin changes concomitant with the erasure of genomic imprints. Interestingly, and contrary to mouse early germ cells, expression of BLIMP1/PRDM1 persists in through all gestational stages in human gonadal PGCs and is associated with nuclear lysine-specific demethylase-1. Our work provides important additional information regarding the chromatin changes associated with human PGCs development between 6 and 13 weeks of gestation in male and female gonads.
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: 225-233, ISSN: 1476-4679
Zygotic epigenetic reprogramming entails genome-wide DNA demethylation that is accompanied by Tet methylcytosine dioxygenase 3 (Tet3)-driven oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC; refs ,,,). Here we demonstrate using detailed immunofluorescence analysis and ultrasensitive LC-MS-based quantitative measurements that the initial loss of paternal 5mC does not require 5hmC formation. Small-molecule inhibition of Tet3 activity, as well as genetic ablation, impedes 5hmC accumulation in zygotes without affecting the early loss of paternal 5mC. Instead, 5hmC accumulation is dependent on the activity of zygotic Dnmt3a and Dnmt1, documenting a role for Tet3-driven hydroxylation in targeting de novo methylation activities present in the early embryo. Our data thus provide further insights into the dynamics of zygotic reprogramming, revealing an intricate interplay between DNA demethylation, de novo methylation and Tet3-driven hydroxylation.
Hajkova P, Nashun B, Hill PWS, et al., 2015, Continuous histone replacement by Hira is essential for normal transcriptional regulation and efficient de novo DNA methylation during mouse oogenesis, Molecular Cell, Vol: 60, Pages: 611-625, ISSN: 1097-4164
The integrity of chromatin, which provides a dynamic template for all DNA-related processes in eukaryotes, is maintained through replication-dependent and -independent assembly pathways. To address the role of histone deposition in the absence of DNA replication, we deleted the H3.3 chaperone Hira in developing mouse oocytes. We show that chromatin of non-replicative developing oocytes is dynamic and that lack of continuous H3.3/H4 deposition alters chromatin structure, resulting in increased DNase I sensitivity, the accumulation of DNA damage, and a severe fertility phenotype. On the molecular level, abnormal chromatin structure leads to a dramatic decrease in the dynamic range of gene expression, the appearance of spurious transcripts, and inefficient de novo DNA methylation. Our study thus unequivocally shows the importance of continuous histone replacement and chromatin homeostasis for transcriptional regulation and normal developmental progression in a non-replicative system in vivo.
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.
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
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- Citations: 103
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: 1553-7404
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- Citations: 23
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
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
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- Citations: 21
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 (vol 49, pg 1023, 2013), MOLECULAR CELL, Vol: 49, Pages: 1176-1176, ISSN: 1097-2765
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
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- Citations: 81
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
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- Citations: 366
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
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- Citations: 76
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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- Citations: 246
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
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- Citations: 352
Hajkova P, 2010, Epigenetic reprogramming - taking a lesson from the embryo, CURRENT OPINION IN CELL BIOLOGY, Vol: 22, Pages: 342-350, ISSN: 0955-0674
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- Citations: 38
Surani MA, Hajkova P, 2010, Epigenetic Reprogramming of Mouse Germ Cells toward Totipotency, NUCLEAR ORGANIZATION AND FUNCTION, Vol: 75, Pages: 211-218, ISSN: 0091-7451
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- Citations: 42
Gebert C, Wrenzycki C, Herrmann D, et al., 2009, DNA methylation in the <i>IGF2</i> intragenic DMR is re-established in a sex-specific manner in bovine blastocysts after somatic cloning, GENOMICS, Vol: 94, Pages: 63-69, ISSN: 0888-7543
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- Citations: 51
Tang F, Hajkova P, O'Carroll D, et al., 2008, MicroRNAs are tightly associated with RNA-induced gene silencing complexes <i>in vivo</i>, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, Vol: 372, Pages: 24-29, ISSN: 0006-291X
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- Citations: 24
Hajkova P, Ancelin K, Waldmann T, et al., 2008, Chromatin dynamics during epigenetic reprogramming in the mouse germ line, NATURE, Vol: 452, Pages: 877-U6, ISSN: 0028-0836
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- Citations: 474
Hayashi K, Lopes SMCDS, Kaneda M, et al., 2008, MicroRNA Biogenesis Is Required for Mouse Primordial Germ Cell Development and Spermatogenesis, PLOS ONE, Vol: 3, ISSN: 1932-6203
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- Citations: 382
Surani MA, Durcova-Hills G, Hajkova P, et al., 2008, Germ Line, Stem Cells, and Epigenetic Reprogramming, CONTROL AND REGULATION OF STEM CELLS, Vol: 73, Pages: 9-15, ISSN: 0091-7451
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- Citations: 46
AZIM SURANI, ULRIKE LANGE, PETRA HAJKOVA, et al., 2007, Epigenetic regulatory complex for control of gene expression
An epigenetic regulatory polypeptide complex comprises at least a first domain having site-specific DNA binding activity and at least a second domain having an arginine methyltransferase activity, wherein the second domain is capable of methylating an arginine residue located in the tail region of a histone H2A. The complex is able to regulate gene expression in cells, particularly in mammalian stem cells by controlling the methylation of R3 in the tail regions of histones H2A and H4. The complex is exemplified by a polypeptide complex comprising the DNA binding activity of Blimpi and the arginine methyltransferase activity of Prmt5.
Tang F, Kaneda M, O'Carroll D, et al., 2007, Maternal microRNAs are essential for mouse zygotic development, GENES & DEVELOPMENT, Vol: 21, Pages: 644-648, ISSN: 0890-9369
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- Citations: 444
Surani MA, Hayashi K, Hajkova P, 2007, Genetic and epigenetic regulators of pluripotency, CELL, Vol: 128, Pages: 747-762, ISSN: 0092-8674
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- Citations: 489
Gebert C, Wrenzycki C, Herrmann D, et al., 2006, The bovine <i>IGF2</i> gene is differentially methylated in oocyte and sperm DNA, GENOMICS, Vol: 88, Pages: 222-229, ISSN: 0888-7543
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- Citations: 45
Durcova-Hills G, Hajkova P, Sullivan S, et al., 2006, Influence of sex chromosome constitution on the genomic imprinting of germ cells, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 103, Pages: 11184-11188, ISSN: 0027-8424
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- Citations: 48
Ancelin K, Lange UC, Hajkova P, et al., 2006, Blimp1 associates with Prmt5 and directs histone arginine methylation in mouse germ cells, NATURE CELL BIOLOGY, Vol: 8, Pages: 623-630, ISSN: 1465-7392
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- Citations: 367
Tang FC, Hajkova P, Barton SC, et al., 2006, MicroRNA expression profiling of single whole embryonic stem cells, Nucleic Acids Research, Vol: 34, Pages: 1-7, ISSN: 0305-1048
MicroRNAs (miRNAs) are a class of 17–25 nt non-coding RNAs that have been shown to have critical functions in a wide variety of biological processes during development. Recently developed miRNA microarray techniques have helped to accelerate research on miRNAs. However, in some instances there is only a limited amount of material available for analysis, which requires more sensitive techniques that can preferably work on single cells. Here we demonstrate that it is possible to analyse miRNA in single cells by using a real-time PCR-based 220-plex miRNA expression profiling method. Development of this technique will greatly facilitate miRNA-related research on cells, such as the founder population of primordial germ cells where rapid and dynamic changes occur in a few cells, and for analysing heterogeneous population of cells. In these and similar cases, our method of single cell analysis is critical for elucidating the diverse roles of miRNAs.
Miyoshi N, Barton SC, Kaneda M, et al., 2006, The continuing quest to comprehend genomic imprinting, CYTOGENETIC AND GENOME RESEARCH, Vol: 113, Pages: 6-11, ISSN: 1424-8581
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- Citations: 23
Tang F, Hajkova P, Barton SC, et al., 2006, 220-plex microRNA expression profile of a single cell, NATURE PROTOCOLS, Vol: 1, Pages: 1154-1159, ISSN: 1754-2189
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- Citations: 79
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