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Reprogramming of Chromatin Accessibility in Somatic Cell Nuclear Transfer Is DNA Replication Independent

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Reprogramming of Chromatin Accessibility in Somatic Cell Nuclear Transfer Is DNA Replication Independent Report Reprogramming of Chromatin Accessibility in Somatic Cell Nuclear Transfer Is DNA Replication Independent Graphical Abstract Authors Mohamed Nadhir Djekidel, Azusa Inoue, SCNT reprogrammed 1cell donor cumulus cell Shogo Matoba, ..., Falong Lu, Lan Jiang, 12 hours Yi Zhang with or without Aphidicolin Correspondence [email protected] Replication-independent reprogramming of DHSs No. of DHS In Brief open closed 14924 Djekidel et al. used low-input DNase-seq to map the chromatin accessibility dynamics of donor cells and SCNT one- closed open cell embryos. They revealed a drastic and 179 fast global DHS reprogramming of donor cells in a DNA replication-independent manner. resemble paternal pronucelus successful reprogramiming open open 524 closed closed resistant 262 somatic memory Highlights Data and Software Availability d Genome-wide DHS maps for donor cumulus cells, one-cell GSE110851 SCNT, and IVF embryos d Rapid and DNA replication-independent DHS reprogramming in SCNT embryos d Transcription factor network switch accompanies DHS reprogramming in SCNT embryos d Loss of donor cell DHSs correlates with suppression of somatic transcription program Djekidel et al., 2018, Cell Reports 23, 1939–1947 May 15, 2018 ª 2018 The Authors. https://doi.org/10.1016/j.celrep.2018.04.036 Cell Reports Report Reprogramming of Chromatin Accessibility in Somatic Cell Nuclear Transfer Is DNA Replication Independent Mohamed Nadhir Djekidel,1,2,3,9 Azusa Inoue,1,2,3,6,9 Shogo Matoba,1,2,3,7 Tsukasa Suzuki,1,2,3 Chunxia Zhang,1,2,3 Falong Lu,1,2,3,8 Lan Jiang,1,2,3 and Yi Zhang1,2,3,4,5,10,* 1Howard Hughes Medical Institute, Boston Children’s Hospital, Boston, MA 02115, USA 2Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA 02115, USA 3Division of Hematology/Oncology, Department of Pediatrics, Boston Children’s Hospital, Boston, MA 02115, USA 4Department of Genetics, Harvard Medical School, Boston, MA 02115, USA 5Harvard Stem Cell Institute, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA 6Present address: RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan 7Present address: RIKEN Bioresource Center, Tsukuba, Ibaraki 305-0074, Japan 8Present address: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China 9These authors contributed equally 10Lead Contact *Correspondence: [email protected] https://doi.org/10.1016/j.celrep.2018.04.036 SUMMARY after the first successful cloning by SCNT (Gurdon, 1962), the molecular mechanisms underlying SCNT-mediated reprogram- Mammalian oocytes have the ability to reset the tran- ming are almost completely unknown. scriptional program of differentiated somatic cells Reprogramming requires change to the chromatin, epige- into that of totipotent embryos through somatic cell netic, and transcriptional landscapes of somatic cells. Many nuclear transfer (SCNT). However, the mechanisms studies have been performed to characterize these changes underlying SCNT-mediated reprogramming are during the induced pluripotent stem cell (iPSC) reprogramming largely unknown. To understand the mechanisms process. These studies used different assays including RNA sequencing (RNA-seq), chromatin immunoprecipitation governing chromatin reprogramming during SCNT, sequencing (ChIP-seq), assays for transposase-accessible we profiled DNase I hypersensitive sites (DHSs) in chromatin using sequencing (ATAC-seq), Hi-C, and prote- donor cumulus cells and one-cell stage SCNT em- omics analyses (Hussein et al., 2014; Knaupp et al., 2017; bryos. To our surprise, the chromatin accessibility Koche et al., 2011; Krijger et al., 2016; Li et al., 2017; Sridharan landscape of the donor cells is drastically changed et al., 2013; Stadhouders et al., 2018). The studies revealed to recapitulate that of the in vitro fertilization (IVF)- the dynamic nature of the chromatin, epigenetics, and tran- derived zygotes within 12 hr. Interestingly, this DHS scriptome during the iPSC generation process and identified reprogramming takes place even in the presence of important factors and molecular events that facilitate or a DNA replication inhibitor, suggesting that SCNT- impede the reprogramming process. While such multi-dimen- mediated DHS reprogramming is independent of sional analyses have been applied to the iPSC reprogramming DNA replication. Thus, this study not only reveals system, only transcriptome analyses have been performed for SCNT reprogramming (Chung et al., 2015; Hormanseder et al., the rapid and drastic nature of the changes in chro- 2017; Inoue et al., 2015; Matoba et al., 2014). Although these matin accessibility through SCNT but also estab- studies revealed that a donor cell transcriptional program is lishes a DNA replication-independent model for largely reprogrammed to an embryonic program by the time studying cellular reprogramming. of zygotic genome activation (ZGA), with the exception of re- programming-resistant regions (Chung et al., 2015; Matoba INTRODUCTION et al., 2014), its molecular basis is still unknown and further study of the chromatin landscape changes during the reprog- Among the currently available systems for cell fate reprogram- ramming process is necessary. ming, somatic cell nuclear transfer (SCNT) is the only one Chromatin accessibility is a good indicator of transcriptional capable of reprogramming terminally differentiated cells to a toti- regulatory elements and can serve as a predictor of gene tran- potent state (Jullien et al., 2011; Mitalipov and Wolf, 2009). SCNT scription activity. It can be identified genome-wide by DNase therefore provides an excellent model for understanding how cell I sequencing or ATAC-seq (Boyle et al., 2008; Buenrostro et al., memory can be fully reprogrammed to generate totipotent cells, 2013). Recent refinements to these techniques have allowed and thus can provide important clues on how to improve other the profiling of the open chromatin landscape using limited num- reprogramming systems. However, despite more than 50 years ber of cells by low-input DNase I sequencing (liDNase-seq) or at Cell Reports 23, 1939–1947, May 15, 2018 ª 2018 The Authors. 1939 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). A C Cumulus cell Cumulus SCNT IVF (Pat) G2 phase Activation OO 12 h SCNT n=3,092 MII oocyte G2 phase IVF 12 h Paternal pronucleus (Pat) B PCA clustering of DHS profiles OC 100 Cumulus1 n=14,924 Cumulus2 RPKM 15 0 10 5 0 Pat3 PC2 (3.13%) −100 rOC Pat1 SCNT1 n=524 rCO Pat2 n=262 −200 SCNT2 CO n=179 5kb 5kb 5kb 5kb 5kb 5kb 5kb 5kb 5kb 5kb 5kb 5kb 5kb 5kb −1600 −1200 −800 −400 PC1 (94.6%) D OO OC rOC rCO CO Wipi1 Mesdc2 Ccdc163 Zyx Fstl3 Mfsd4b4 Scn8a Hivep3 Atxn7 Nav2 350 350 400 400 350 350 150 175 250 150 1 0 0 0 0 0 0 0 0 0 0 2 Cumulus 1 SCNT 2 1 2 IVF(Pat) 5kb 5kb 5kb 5kb 5kb 5kb 2kb 5kb 2kb 5kb Figure 1. Rapid Reprogramming of Donor Cell Chromatin Accessibility in SCNT (A) Schematic illustration of the experimental design for studying the chromatin accessibility dynamics in SCNT and that of the paternal pronucleus from in vitro- fertilized (IVF) zygotes. The collected samples for liDNase-seq analysis are shown inside dotted boxes. (B) PCA of the genome-wide DHS profile of the cumulus, IVF(Pat), and one-cell SCNT samples. Each dot represents one sample. (C) Heatmap showing the DHSs clustered according to their combinatorial enrichment in cumulus, one-cell SCNT, and IVF(Pat) samples. Each row represents a locus (DHS center ± 5 kb), and the red gradient color indicates the liDNase-seq signal intensity. OO, open in cumulus cells, SCNT, and IVF(Pan); OC, open in cumulus cells and closed in SCNT and IVF(Pat); rOC, open in cumulus cells and closed in IVF(Pat), but failed to be closed in SCNT; rCO, closed in cumulus cells and open in IVF(Pat), but failed to be opened in SCNT; CO, closed in cumulus cells and open in IVF(Pat) and SCNT. (D) Genome browser views showing the normalized coverage (per million mapped reads) at representative loci of the different DHS categories. See also Figure S1. the single-cell level by ATAC-seq (Buenrostro et al., 2015; Jin RESULTS AND DISCUSSION et al., 2015; Lu et al., 2016), thereby facilitating the study of chro- matin accessibility in mouse preimplantation embryos (Inoue Fast DNase I Hypersensitive Site Reprogramming upon et al., 2017; Lu et al., 2016; Wu et al., 2016). In this work, we SCNT used liDNase-seq to study chromatin accessibility changes dur- To understand how the chromatin accessibility of somatic donor ing SCNT reprogramming, which revealed the quick and DNA cells is reprogrammed to that of the totipotent one-cell embryo, replication-independent nature of the reprogramming process. we attempted to generate the DNase I hypersensitive site (DHS) 1940 Cell Reports 23, 1939–1947, May 15, 2018 A B Genomic distribution of the different DHS categories Pathway enrichment of genes in proximity of OO DHS OO 0 2 4 6 8 10 12 14 16 18 Cell Cycle, Mitotic 19.56 OC Promoter DNA Replication Exon 16.23 rOC Mitotic M-M/G1 phases 13.50 Intron Gene Expression Intergenic 13.38 rCO Synthesis of DNA 11.83 Formation and Maturation of mRNA Transcript 10.41 CO S Phase 9.61 Mitotic G1-G1/S phases 9.48 0 255075100 Processing of Capped Intron-Containing Pre-mRNA 9.27 Percentage (%) Mitotic G2-G2/M phases 9.15 -log (Binomial p-value) C 10 H3K9me3 enrichment in DHS groups Pathway enrichment of genes in proximity of OC DHS
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