Epigenetics and Human Health Alexander Meissner Jörn Walter Editors Epigenetic Mechanisms in Cellular Reprogramming Tai Lieu Chat Luong Epigenetics and Human Health Series Editors Prof Dr Robert Feil Institute of Molecular Genetics (IGMM) Genomic Imprinting & Development’ laboratory Montpellier France Prof Dr Joărn Walter Universitaăt des Saarlandes FR8.4 Biowissenschaften Dept of Genetics & Epigenetics Saarbruăcken Germany Priv Doz Dr Mario Noyer Weidner Schwaăbische Str Berlin Germany More information about this series at http://www.springer.com/series/8561 Alexander Meissner ã Joărn Walter Editors Epigenetic Mechanisms in Cellular Reprogramming Editors Alexander Meissner Dpt of Stem Cell and Regenerative Biol Harvard University Broad Institute Bauer Laboratory Cambridge Massachusetts USA Joărn Walter Universitaăt des Saarlandes FR84 Biosciences Dept of Genetics & Epigenetics Saarbruăcken Germany ISSN 2191-2262 ISSN 2191-2270 (electronic) ISBN 978-3-642-31973-0 ISBN 978-3-642-31974-7 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Preface During development the genome of the fertilised egg is utilised to create a whole organism with a rich diversity of cell types While the underlying sequence remains unchanged, each cell type and developmental stage is reflected in a unique epigenome This coordinated process of developmental epigenetic programming begins in the germ line (early primordial germs cells, PGCs) and cumulates in the creation of the specialised gametes Post-fertilisation massive epigenetic reprogramming establishes the totipotent zygote and pluripotent cells of the early embryo (inner cell mass, ICM) The latter can be explanted into cell culture and give rise to pluripotent embryonic stem cells (ESCs) that can be maintained over long periods Over the last decade epigenetic reprogramming processes have been widely studied in the zygote, in PGCs and in ESCs The research focused on various aspects of this topic, most of them being reflected in the selected articles of this volume including (1) understanding reprogramming events at the level of DNA and histone modifications, (2) the physiological parameters and enzymes that control the initiation, the entry and exit from pluripotency, and (3) the differences/similarities of epigenetic reprogramming mechanisms in various pluripotent and totipotent cells The detailed knowledge of the underlying reprogramming mechanisms is of great importance for many research areas in human health and disease ranging from stem cell biology to cancer Examples are a controlled understanding of the cell intrinsic reprogramming mechanisms activated during the in vitro generation of induced pluripotent stem cells (iPSCs) from somatic cells and the erroneous reprogramming mechanisms in somatic (stem) cells leading to massive epigenetic changes in cancer This volume compiles a series of articles featuring the current knowledge of molecular events accompanying processes of epigenetic reprogramming The articles focus on mechanisms operating during early embryonic development, the events that are defining the entry into and exit from pluripotency in ESCs and the implications of such mechanisms for aberrant reprogramming in the course of cancer The reader will obtain a detailed view of the molecular changes occurring v vi Preface at various epigenetic levels of histone and DNA modifications All articles feature references to the important discoveries in the field over the last decade A glossary at the end will help the reader to navigate through many of the specific terms used in epigenetic research Cambridge, MA Saarbruăcken, Germany Alex Meissner Joărn Walter Glossary Acetylation The introduction, via an enzymatic reaction, of an acetyl group to an organic compound, for instance to histones or other proteins Agouti gene The agouti gene (A) controls fur colour through the deposition of yellow pigment in developing hairs Several variants of the gene exist, and for one of these (Agouti Variable Yellow, Avy) the expression levels can be heritably modified by DNA methylation Alleles Different variants or copies of a gene For most genes on the chromosomes, there are two copies: one copy inherited from the mother, the other from the father The DNA sequence of each of these copies may be different because of genetic polymorphisms Assisted reproduction technologies (ART) The combination of approaches that are being applied in the fertility clinic, including IVF and ICSI 5-Azacytidine A cytidine analogue in which the carbon of the cytosine ring has been replaced with nitrogen 5-azacytidine is a potent inhibitor of mammalian DNA methyltransferases Bivalent chromatin A chromatin region that is modified by a combination of histone modifications such that it represses gene transcription, but at the same time retains the potential of acquiring gene expression Bisulphite genomic sequencing A procedure in which bisulphite is used to deaminate cytosine to uracil in genomic DNA Conditions are chosen so that 5-methylcytosine is not changed PCR amplification and subsequent DNA sequencing reveal the exact position of cytosines which are methylated in genomic DNA Blastocyst The blastocyst is a structure formed in the early development of mammals It is the last stage of preimplantation development in mammals and it is comprised of outer cell layer—trophoblast, which later develops into placenta, and of inner cell mass (see ICM), which gives rise to the embryonic tissues ICM is vii viii Glossary attached to inner side of the hollow basket-shaped structure, formed by trophectoderm (trophoblast cell layer) Bromo domain Protein motif found in a variety of nuclear proteins including transcription factors and HATs involved in transcriptional activation Bromo domains bind to histone tails carrying acetylated lysine residues Brno nomenclature Regulation of the nomenclature of specific histone modifications formulated at the Brno meeting of the NoE in 2004 Rules are: Example: H3K4me3 ¼ trimethylated lysine-4 on histone H3 Cell fate The programmed path of differentiation of a cell Although all cells have the same DNA, their cell fate can be different For instance, some cells develop into brain, whereas others are the precursors of blood Cell fate is determined in part by the organisation of chromatin—DNA and the histone proteins—in the nucleus Cellular Memory (epigenetic) Specific active and repressive organisations of chromatin can be maintained from one cell to its daughter cells This is called epigenetic inheritance and ensures that specific states of gene expression are inherited over many cell generations ChIP see chromatin immunoprecipitation ChIP on chip After chromatin immunoprecipitation, DNA is purified from the immunoprecipitated chromatin fraction and used to hybridise arrays of short DNA fragments representing specific regions of the genome ChIP Seq Sequencing of the totality of DNA fragments obtained by ChIP to determine their frequency and position on the genome Sequencing is usually preceded by PCR amplification of ChIP-derived DNA to increase its amount Chromatid In each somatic cell generation, the genomic DNA is replicated in order to make two copies of each individual chromosome During M phase of the cell cycle, these copies—called chromatids—are microscopically visible one next to the other, before they get distributed to the daughter cells Chromatin The nucleo-protein complex constituting the chromosomes in eukaryotic cells Structural organisation of chromatin is complex and involves different levels of compaction The lowest level of compaction is represented by an extended array of nucleosomes Chromatin remodelling Locally, the organisation and compaction of chromatin can be altered by different enzymatic machineries This is called chromatin remodelling Several chromatin remodelling proteins move nucleosomes along the DNA and require ATP for their action Glossary ix Chromo domain (chromatin organisation modifier domain) Protein–protein interaction motif first identified in Drosophila melanogaster HP1 and polycomb group proteins Also found in other nuclear proteins involved in transcriptional silencing and heterochromatin formation Chromo domains consist of approx 50 amino acids and bind to histone tails that are methylated at certain lysine residues Chromosomal domain In higher eukaryotes, it is often observed that in a specific cell type, chromatin is organised (e.g by histone methylation) the same way across hundreds to thousands of kilobases of DNA These ‘chromosomal domains’ can comprise multiple genes that are similarly expressed Some chromosomal domains are controlled by genomic imprinting Chromatin immunoprecipitation (ChIP) Incubation of chromatin fragments comprising one to several nucleosomes, with an antiserum directed against particular (histone) proteins or covalent modifications on proteins After ChIP, the genomic DNA is purified from the chromatin fragments brought down by the antiserum and analysed CpG dinucleotide A cytosine followed by a guanine in the sequence of bases of the DNA Cytosine methylation in mammals occurs at CpG dinucleotides CpG island A small stretch of DNA, of several hundred up to several kilobases in size, that is particularly rich in CpG dinucleotides and is also relatively enriched in cytosines and guanines Most CpG islands comprise promoter sequences that drive the expression of genes Cytosine methylation In mammals, DNA methylation occurs at cytosines that are part of CpG dinucleotides As a consequence of the palindromic nature of the CpG sequence, methylation is symmetrical, i.e affects both strands of DNA at a methylated target site When present at promoters, it is usually associated with transcriptional repression Deacetylation The removal of acetyl groups from proteins Deacetylation of histones is often associated with gene repression and is mediated by histone deacetylases (HDACs) DNA demethylation Removal of methyl groups from DNA This can occur ‘actively’, i.e by an 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149–150 Bisulfite sequencing (BS-seq), 182–183 BMI1, haematopoietic stem cells, 128 Branchiostoma floridae homologs of, 147–148 protein lengths, 155 BS-Seq analysis, 79, 80 BX-C gene, 125 C Cancer DNA methylation adding and removing, 202–203 changes in tumorigenesis, 196–201 chromatin-associated factors, 197–200 epigenetic modifications, 195–197 hot spots for, 201–202 in imprinting control regions, 195 Tet proteins, 202–203 glioblastoma, 211 leukemia, 209–210 tumorigenesis cancer stem cells, 207 chromosomal aberrations and chromatin changes, 205–207 epigenetic modifiers, 208–209 prominent histone modifications, 205 target locations, 205 transdifferentiation process, 203–204 Cancer stem cells (CSC), 207 Candidate gene approach chromatin remodeling factors, 18 Glis1, 17 maternal-effect genes, 16 Oct4, 16–17 reprogramming factors, 17 Sox2, 17, 18 5-carboxycytosine (5caC), 169–170 ChIP microarray analysis, 86 Chromatin change, 46–48 pluripotency, 102, 104–107 Chromobox (CBX), 123 Ciona intestinalis homologs of, 147–148 protein lengths, 155 Complex genomic rearrangements (CGR), 206 CpG dinucleotides, 126 Cytosine modifications genome-wide profiling methods affinity purification, 180–181 chemical labeling methods, 181–182 detection and quantification, 177–179 enzyme-based profiling, 179–180 experimental approaches, 178 ingle base pair sequencing, 182–184 next-next-generation sequencing, 184–185 © Springer-Verlag Berlin Heidelberg 2015 A Meissner, J Walter (eds.), Epigenetic Mechanisms in Cellular Reprogramming, Epigenetics and Human Health, DOI 10.1007/978-3-642-31974-7 225 226 Cytosine modifications (cont.) 5-methylcytosine 5-carboxycytosine, 169–170 on chromatin structure and its components, 168–169 DNA demethylation, 170–173 5-formylcytosine, 169–170 5hmC in gene regulation, 177 5-hydroxymethylcytosine, 169–170 Tet enzymes, 174–177 D Danio rerio homologs of, 147–148 protein lengths, 155 DNA demethylation homologous enzymes, 76 5-mC, 77, 170–173 passive, 74 repair-associated proteins, 78 repair-mediated demethylation, 75 replication-independent process, 74 SAM domain, 78 DNA methylation adding and removing, 202–203 changes in tumorigenesis, 196–201 chromatin-associated factors, 197–200 Dnmt1, 81 Dnmt3a/b, 82–83 Dnmt3L, 82–83 Dnmts, 80–81 epigenetic modifications, 195–197 profiles, 69–70 reprogramming, 87–90 global levels of, 46 histone modifications and, 85–87 H3K27me3, 102 hot spots for, 201–202 of imprinted gene, 36 in imprinting control regions, 195 inner cell mass, 108 knockout studies, 102–107 in mammals, 45 methylated histone H3, 36 patterns of, 33 positive regulation of, 86–87 preimplantation development, 79–80 replication-independent process, 74 schematic diagram of, 37–38 in SCNT-derived embryos, 83–84 Tet proteins, 202–203 in vertebrates, 101 Index in zygote, 71–74 DNA methyltransferase (Dnmt) Dnmt1, 81 Dnmt3a/b, 82–83 Dnmt3L, 82–83 embryos, 80–81 knockouts study, 113 pluripotency, 102–104 Drosophila melanogaster PcG proteins, 122, 142 PRC1 and PRC2, 143 protein lengths, 155 E Embryonic gene activation (EGA), 87–88, 90 Embryonic stem cells (ESCs) bivalent states, 144 Ezh2 histone methyltransferase, 109 pluripotency, 102 PRC1 (see Polycomb repressive complex (PRC1)) Tet enzymes role, 109, 111–112 Embryos characteristic of, 59–60 chromatin remodelling mechanisms, 45–46 Dnmts (see DNA methyltransferase (Dnmt)) dynamic localisation during, 56–59 epigenetic reprogramming in, 87–90 Epigenetic profiles, in gametes, 69–70 Epigenetic reprogramming See also Zygotic reprogramming DNA demethylation, 45 in early embryos, 87–90 heterochromatic marks, 46 in mammals, 45 paternal DNA, 46 of zygote, 71 EZH2, 123 F Fe(II)-dependent dioxygenases, 174, 175 5-formylcytosine (5fC), 169–170 Fully grown oocytes (FGOs), 33 G Gametes, epigenetic profiles in, 69–70 Glioblastoma, 211 Glis1, candidate gene approach, 17 Glycosylases flip, 75 Index H H3.3, 51–53 H2A barr body-deficient, 61 macroH2A, 54–55 mouse embryogenesis, 55 X-reactivation, 56 H2A.B, 61 H2A.X analysis of, 60 levels of phosphorylation, 60 role, 59 in Xenopus, 60 H2A.Z acetylation, 57 discovery, 56–57 distribution of, 58 dynamic behaviour of, 59 features of, 59 mouse embryos uses, 58 properties, 57 Xenopus and Drosophila embryos, 59 Heterochromatin global changes in, 52 mouse zygote, 53 in somatic cells, 51 time-lapse analysis, 52 HIPPIE database, 146 Histone lysine methyltransferases (KMTs), 104–106 Histone modification and DNA methylation crosstalk, 85–87 zygotic reprogramming, 34–35 Histone variants chromatin change, development proceeds, 46–48 epigenetic information, regulators of different variants, 48, 49 endogenous profiles, 48, 49 genome-wide incorporation of, 50 heterochromatic regions, 51 mammalian zygote, 49–50 partial removal of, 50 potential role, 48 remodelling of, 50 epigenetic reprogramming (see Epigenetic reprogramming) germline, 53–54 global changes in, 52 H2A macroH2A, 54–55 mouse embryogenesis, 55 X-reactivation, 56 227 H2A.B, 61 H3.3 and De novo, 51–53 H2A.X analysis of, 60 levels of phosphorylation, 60 role, 59 in Xenopus, 60 H2A.Z acetylation, 57 discovery, 56–57 distribution of, 58 dynamic behaviour of, 59 features of, 59 mouse embryos uses, 58 properties, 57 Xenopus and Drosophila embryos, 59 mammalian development, 43–45 schematic representation of, 47, 48 H3K4me3, 85 H3K9me2, 86, 88, 89 H3K9me2,3, 102 H3K27me3, 102, 109 H3K36me3, 85 H3K9 methylation, 86 H3K27 methylation, 102–107 Homologous enzymes, 76 Homo sapiens homologs of, 147–148 protein lengths, 155 5-hydroxymethylcytosine (5hmC) cytosine modifications, 169–170 deamination, 78 in gene regulation, 177 involvement, 34 K Kdm2b, 112 L Leukemia, 209–210 Liquid chromatography-mass spectrometry (LC-MS), 179 M MacroH2A biology of, 55 depletion of, 56 stripping ability, 55 subtypes, 54 Mbd3, 20 228 MBD-isolated Genome Sequencing (MiGS), 180 Methyl-binding domain containing proteins (MBDs), 90 MethylCap-seq, 180 5-methylcytosine (5mC) 5-carboxycytosine, 169–170 on chromatin structure and components, 168–169 demethylation pathway of, 171 DNA demethylation, 170–173 5-formylcytosine, 169–170 in gene regulation, 177 5-hydroxymethylcytosine, 169–170 oxidation, 73–74, 77 protection active loss of, 36 H3K9me2, 36–38 imprinted genes and repetitive sequences, 36 mechanism of, 38–39 Tet enzymes, 174–177 Methyl-sensitive cut counting (MSCC) assay, 170 Mixed lineage leukemia (MLL) gene, 206 N Nanog, 102, 142 NER See Nucleotide excision repair (NER) Next generation sequencing (NGS) technology, 20 Nuclear export signal (NES), 32 Nuclear localization signal (NLS), 32 Nucleotide excision repair (NER), 74–75, 202 O Oct4 candidate gene approach, 16–17 overexpression of, 142 pluripotency, 102, 113, 142 Oocytes candidate gene approach, 16–18 chromatin, 70 DNA, 70 elusive reprogramming factors, 14–15 gene expression in analysis of, 12–13 microarray-based, 13 mouse-based study, 14 young vs aged mouse, 13 molecular searches, 15 proteome analysis biomarkers identification, 21 Index candidate factors, 22–23 cellular function, 21 maternal-effect factors, 22 quantitative methods, 21 semiquantitative MS analysis, 22 qualitative aspects of characteristic traits, chromatin configuration of, 6–9 germinal vesicle-stage, transcriptional activity in, 6, maturation states, 6–9 quantitative aspects of kinetics of reprogramming, 11–12 reprogramming factors, amount of, 10–11 SCNT (see Somatic cell nuclear transfer (SCNT)) screening approaches, 15 transcriptome analysis disadvantage of, 19 gene expression, 18 Mbd3, 20 microarray analysis, 20 NGS technology, 20 uniqueness of, 4–5 Xenopus laevis, 75, 83 Oxidative bisulfite sequencing (oxBS-seq), 183 2-oxoglutarate (2-OG) dioxygenases, 174, 175 P PGCs See Primordial germ cells (PGCs) Pioneer transcription factors, 207 Pleiohomeotic (PHO), 126–127 Pluripotency cell exit, 113–114 chromatin, 102, 104–107 DNA demethylases, 102, 104 DNA methylation, 101–103 ESCs maintain, 110–112 inner cell mass, 108 mouse knockout studies, 102–107 Tet proteins, 109–110 Polycomb group (PcG) proteins ANT-C and BX-C gene, 125 CpG dinucleotides, 126 DNA-binding proteins, 125 enzymatic activities, 124 gene expression, maintenance of, 121–122 H2A ubiquitination role, 124 looping model, 126 mutations in, 122 PRC1, 122–124 PRC2, 123 stem cell maintenance Index bivalent domains, 130 BMI1, 128 dynamic regulation, 127 and dynamics of chromatin marks, 130, 131 genome-wide mapping studies, 128 microarray and sequencing technologies, 129 targets, 125–127 Polycomb repressive complex (PRC1), 122 BCOR and BCORL1, 149–150 components of, 142–144 core pluripotency network, 141–142 in ES cells, 144–146 evolution, 153–155 in factor-driven reprogramming, 157–158 gene expression, 156, 157 and general transcription factors, 123 HIPPIE database, 146 homologs of Drosophila, 146–148 interaction map, 149 mutations in ES cells and mice, 151–152 orthologs in ES cells, 155–157 paralogs of, 146–148 PcG form multimeric complexes, 142–144 Ring1A and Ring1B, 145 and RYBP protein, 145 ubiquitin and histones, 146 Polycomb response element (PRE), 125 Preimplantation development, 79–80 Primordial germ cells (PGCs), 69 Proteome analysis biomarkers identification, 21 candidate factors, 22–23 cellular function, 21 maternal-effect factors, 22 quantitative methods, 21 semiquantitative MS analysis, 22 R Reduced representation bisulfite sequencing (RRBS), 70, 79, 179 Restriction landmark genome scanning (RLGS), 196 Ring1A/B, 145 RYBP definition, 126 ES cell phenotype, 146, 152 S SCNT-derived embryos DNA methylation in, 83–84 229 single-copy targets, 84 Xist genes, 84 Single-molecule real-time sequencing (SMRT-seq), 184–185 Somatic cell nuclear transfer (SCNT) history of, maturation states and chromatin configuration GV-stage, 8–9 interphase zygotes cytoplasm, maturation states, MII-stage, 7–8 M-phase zygotes, proteomic analysis, in zygotes, Sox2 candidate gene approach, 17, 18 ES cells, 142 pluripotency, 102 Stella expression pattern, 32 gene disruption analysis, 32–33 identification, 31–32 5mC protection active loss of, 36 H3K9me2, 36–38 imprinted genes and repetitive sequences, 36 mechanism of, 38–39 T Tet1/2, 109–110, 112 Tet3, 72, 79, 109–110 Tet-assisted bisulfite sequencing (TAB-seq), 183–184 Tet enzymes, 174 Thin layer chromatography (TLC), 177, 179 Thymine DNA glycosylase (TDG) and 5hmU, 78 with Tet oxygenases, 77 TP53 gene, 206 Transcriptome analysis disadvantage of, 19 gene expression, 18 Mbd3, 20 microarray analysis, 20 NGS technology, 20 Transdifferentiation process, 203–204 Trichostatin A (TSA), 84 Tumorigenesis cancer stem cells, 207 chromosomal aberrations and chromatin changes, 205–207 230 Tumorigenesis (cont.) epigenetic modifiers, 208–209 prominent histone modifications, 205 target locations, 205 transdifferentiation process, 203–204 Two-dimensional gel electrophoresis, 196 U Ubiquitin, 146 Uhrf1, 74 X Xenopus laevis, 3, 75, 83 Index Y YAF2, 146 Z Zygotic reprogramming DNA methylation reprogramming in, 71–74 histone modification in, 34–35 5hmC involvement, 34 imprinted genes protection, 34 5mC active loss, 33 repetitive sequences, 34 schematic representation, 72 Tet proteins, 34