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HDAC1 and HDAC2 in Mouse Oocytes and Preimplantation Embryos: Specificity Versus Compensation

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HDAC1 and HDAC2 in Mouse Oocytes and Preimplantation Embryos: Specificity Versus Compensation Cell Death and Differentiation (2016) 23, 1119–1127 & 2016 Macmillan Publishers Limited All rights reserved 1350-9047/16 www.nature.com/cdd Review HDAC1 and HDAC2 in mouse oocytes and preimplantation embryos: Specificity versus compensation P Ma*,1 and RM Schultz1 Oocyte and preimplantation embryo development entail dynamic changes in chromatin structure and gene expression, which are regulated by a number of maternal and zygotic epigenetic factors. Histone deacetylases (HDACs), which tighten chromatin structure, repress transcription and gene expression by removing acetyl groups from histone or non-histone proteins. HDAC1 and HDAC2 are two highly homologous Class I HDACs and display compensatory or specific roles in different cell types or in response to different stimuli and signaling pathways. We summarize here the current knowledge about the functions of HDAC1 and HDAC2 in regulating histone modifications, transcription, DNA methylation, chromosome segregation, and cell cycle during oocyte and preimplantation embryo development. What emerges from these studies is that although HDAC1 and HDAC2 are highly homologous, HDAC2 is more critical than HDAC1 for oocyte development and reciprocally, HDAC1 is more critical than HDAC2 for preimplantation development. Cell Death and Differentiation (2016) 23, 1119–1127; doi:10.1038/cdd.2016.31; published online 15 April 2016 Facts HDAC1/2-containing complexes in defining steady-state levels of acetylated histones? • HDAC1 and HDAC2 show different expression profiles • What non-histone proteins are deacetylated by HDAC1 and/ during oocyte and preimplantation development. or HDAC2 in oocytes and preimplantation embryos, and what • HDAC1 and HDAC2 regulate oocyte development through are the functional consequences of their deacetylation? transcription in a dosage-dependent manner. • HDAC2 is the major HDAC in mouse oocytes and regulates In eukaryotes, DNA is organized into a highly ordered global DNA methylation and imprinting marks by interacting nucleoprotein assembly called chromatin, whose fundamental with DNMT3A2. unit is the nucleosome. The nucleosome consists of 146 bp of • HDAC2 regulates chromosome segregation and kineto- DNA wrapped around a histone core comprised of two chore function via H4K16 deacetylation during oocyte molecules each of histones H2A, H2B, H3 and H4. Histone maturation. H1 is bound to linker DNA between nucleosomes.1,2 Histones • HDAC1 is the responsible HDAC involved in cell cycle are subject to multiple post-translational modifications regulation and zygotic genomic activation during preim- (PTMs), including acetylation, methylation, ubiquitylation, plantation development. phosphorylation, and sumoylation. These PTMs determine open and closed chromatin conformations, which, in turn, Open Questions regulate the differential access and recruitment of transcription factors and other regulatory chromatin-binding proteins to – • How do HDAC1 and HDAC2 regulate cross-talk between DNA.3 5 Among these histone modifications, histone acetyla- histone acetylation and other epigenetic modifications tion is the most well-studied modification, which occurs at the during oocyte and preimplantation embryo development? ε-amino groups of evolutionarily conserved lysine residues • What is the catalog of chromatin remodeling complexes that located at the N termini. Although all core histones are contain HDAC1 and/or HDAC2 in oocytes and preimplanta- acetylated in vivo, modifications of histones H3 and H4 are tion embryos, and what is the relative contribution of these more extensively characterized than those of H2A and H2B.6 1Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA *Corresponding author: P Ma, Department of Biology, University of Pennsylvania, 205 Lynch Labs, 433 South University Avenue, Philadelphia, PA 19104, USA. Tel: +1 856 375 5239; Fax: +1 215 898 7896; E-mail: [email protected] Abbreviations: HDAC, histone deacetylase; HAT, histone acetyl transferase; PTM, post-translational modification; KDAC, lysine deacetylase; TSA, trichostatin A; NAD+, nicotinamide adenine dinucleotide; HAD, HDAC association domain ; GVBD, germinal vesicle breakdown; ChIP-seq, chromatin immunoprecipitation sequencing; TFIID, transcription factor II D; YY1, yin yang 1; Pol II CTD S2, serine 2 within the RNApolymerase II C-terminal domain; H3K4, lysine 4 of histone 3; H3K9, lysine 9 of histone 3; H4K16, lysine 16 of histone 4; SIRT, NAD-dependent deacetylase sirtuin; TBP2, TATA-binding protein 2; DNMT, DNA methyltransferases; RBAP46, retinoblastoma binding protein P46; RNAi, RNA interference; aa, amino acidic; BrUTP, 5-Bromouridine 5′-triphosphate; qRT-PCR, quantitative reverse transcription polymerase chain reaction; CDK, cyclin-dependent kinase; gDMRs, germline differentially methylated regions; HMTase, histone methyltransferase; SCNT, somatic cell nuclear transfer; ZGA, zygotic genome activation Received 11.1.16; revised 21.2.16; accepted 25.2.16; Edited by M Piacentini; published online 15.4.16 HDAC1 and HDAC2 in oocytes and preimplantation embryos P Ma and RM Schultz 1120 Figure 1 A schematic diagram of mammalian HDAC1 and HDAC2 structures with functional domains and post-translational modifications. HDAC1 and HDAC2 share a highly conserved N-terminal HDAC association domain (HAD) that is essential for homo- and hetero-dimerization. The C-terminal part contains an IAC(E/D)E motif (IACEE in HDAC1 and IACDE in HDAC2) involved in the interaction with the pocket proteins. HDAC1 has a 2-residue Chfr interaction domain and a nuclear localization signal (NLS) at the C terminus. HDAC2 contains a coiled-coil domain at the C terminus. HDAC1 and HDAC2 are regulated by different post-translational modifications, such as phosphorylation, acetylation, nitrosylation, carbonylation, and sumoylation. K, lysine; C, cysteine; S, Serine; Y, tyrosine. Numbers indicate the corresponding amino-acidic (aa) position Histone Deacetylases member of class IV, is homologous to both class I and class II HDACs.17 The multiplicity of histone deacetylases reflects Lysine acetylation of histones is controlled by histone acetyl diversification of functions in different tissues and biological transferases (HATs) and histone deacetylases (HDACs).7 The processes.18 balance between the actions of these enzymes serves as a key regulatory mechanism for gene expression and governs numerous developmental processes and disease states. Structure and Complexes of Mammalian HDAC1 and HATs catalyze the transfer of an acetyl group to lysine HDAC2 residues of histone tails, thereby neutralizing the positive Two highly homologous Class I enzymes, HDAC1 and charge of histones. The decrease in net positive histone HDAC2, are expressed ubiquitously, localized predominantly charge decreases the affinity between histones and DNA, to the nucleus, and display high enzymatic activity toward which relaxes chromatin structure to make it more accessible histone substrates.8,19 The genes for HDAC1 and HDAC2 to transcription factors. Therefore, HATs are considered as originated by gene duplication8,20 and the two proteins exhibit transcription co-activators. In contrast, HDACs remove acetyl ~ 86% amino-acid sequence identity in mice and human, groups from histone tails and are therefore considered as suggesting a high functional redundancy between HDAC1 and 8,9 transcriptional co-repressors. In addition to histones, HDAC2.21 Both HDAC1 and HDAC2 contain several domains HDACs can also deacetylate non-histone proteins, for with defined function (Figure 1). Some domains are common example, transcription factors and a growing list of other to both, whereas other domains are specific for each HDAC.8 8,10 proteins. As a result, HDACs are now also called KDACs, The histone deacetylase domain common to all class I HDACs 11 or lysine deacetylases. is formed by a stretch of more than 300 amino acids that In mammals, 18 HDACs have been identified and are constitute a large portion of the protein.6 An N-terminal HDAC grouped into four classes based on their homology with yeast association domain (HAD; residues 1 to ~ 50) is essential for 12 proteins. Class I, which are homologous to the yeast protein homo- and hetero-dimerization.21 The C-terminal portion RPD3 and ubiquitously expressed in human cell lines and contains an IAC(E/D)E motif (IACEE in HDAC1 and IACDE tissues, include HDAC 1, 2, 3, and 8 that have a nuclear in HDAC2) involved in the interaction with the pocket proteins 6,13 localization. Class II is homologous to yeast Hda1 and can PRb, P107, and P130.8 HDAC1 has a 2-residue Chfr be subdivided into two subclasses: IIa (HDAC 4, 7, and 9) and interaction domain that is essential for the interaction with IIb (HDAC 6 and 10). Class II exhibits tissue-specific Chfr, an ubiquitin ligase regulating protein degradation,22 and expression and can shuttle between the nucleus and a nuclear localization signal at the C terminus.21 A coiled-coil cytoplasm, which suggests that this class of HDACs is domain is only found at the C terminus of HDAC2.8 In addition, involved in acetylation of non-histone proteins.6 Class I and HDAC1 and HDAC2 are not only protein-modifiers but also Class II HDACs are inhibited by trichostatin A (TSA). Class III undergo numerous post-translational modification. These HDACs, or sirtuins (SIRT1-7), are homologous with the yeast modifications can be either chemical moieties (acetylation, SIRT2 family of proteins and require NAD+ as a cofactor.14 phosphorylation, methylation, nitrosylation, ADP-ribosylation,
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