iScience (Apr 2022)
DUX4 is a multifunctional factor priming human embryonic genome activation
- Sanna Vuoristo,
- Shruti Bhagat,
- Christel Hydén-Granskog,
- Masahito Yoshihara,
- Lisa Gawriyski,
- Eeva-Mari Jouhilahti,
- Vipin Ranga,
- Mahlet Tamirat,
- Mikko Huhtala,
- Ida Kirjanov,
- Sonja Nykänen,
- Kaarel Krjutškov,
- Anastassius Damdimopoulos,
- Jere Weltner,
- Kosuke Hashimoto,
- Gaëlle Recher,
- Sini Ezer,
- Priit Paluoja,
- Pauliina Paloviita,
- Yujiro Takegami,
- Ai Kanemaru,
- Karolina Lundin,
- Tomi T. Airenne,
- Timo Otonkoski,
- Juha S. Tapanainen,
- Hideya Kawaji,
- Yasuhiro Murakawa,
- Thomas R. Bürglin,
- Markku Varjosalo,
- Mark S. Johnson,
- Timo Tuuri,
- Shintaro Katayama,
- Juha Kere
Affiliations
- Sanna Vuoristo
- Department of Biosciences and Nutrition, Karolinska Institutet, 17177 Huddinge, Sweden; Department of Obstetrics and Gynecology, 00014, University of Helsinki and Helsinki University Hospital, 00290 Helsinki, Finland; Corresponding author
- Shruti Bhagat
- Department of Biosciences and Nutrition, Karolinska Institutet, 17177 Huddinge, Sweden; RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan; Instutute for the Advanced Study of Human Biology, Kyoto University, Kyoto 606-8501, Japan
- Christel Hydén-Granskog
- Reproductive Medicine Unit, Helsinki University Hospital, 00290 Helsinki, Finland
- Masahito Yoshihara
- Department of Biosciences and Nutrition, Karolinska Institutet, 17177 Huddinge, Sweden
- Lisa Gawriyski
- Institute of Biotechnology, University of Helsinki, 00790 Helsinki, Finland
- Eeva-Mari Jouhilahti
- Stem Cells and Metabolism Research Program, University of Helsinki, 00014 Helsinki, Finland
- Vipin Ranga
- Structural Bioinformatics Laboratory, Biochemistry, Faculty of Science and Engineering, Åbo Akademi University, 20520 Turku, Finland
- Mahlet Tamirat
- Structural Bioinformatics Laboratory, Biochemistry, Faculty of Science and Engineering, Åbo Akademi University, 20520 Turku, Finland
- Mikko Huhtala
- Structural Bioinformatics Laboratory, Biochemistry, Faculty of Science and Engineering, Åbo Akademi University, 20520 Turku, Finland
- Ida Kirjanov
- Department of Obstetrics and Gynecology, 00014, University of Helsinki and Helsinki University Hospital, 00290 Helsinki, Finland
- Sonja Nykänen
- Department of Obstetrics and Gynecology, 00014, University of Helsinki and Helsinki University Hospital, 00290 Helsinki, Finland
- Kaarel Krjutškov
- Department of Biosciences and Nutrition, Karolinska Institutet, 17177 Huddinge, Sweden; Stem Cells and Metabolism Research Program, University of Helsinki, 00014 Helsinki, Finland; Competence Centre for Health Technologies, 51010 Tartu, Estonia; University of Tartu, Department of Obstetrics and Gynecology, Institute of Clinical Medicine, 50406 Tartu, Estonia
- Anastassius Damdimopoulos
- Karolinska Institutet, Bioinformatics and Expression Analysis Core Facility, 17177 Huddinge, Sweden
- Jere Weltner
- Stem Cells and Metabolism Research Program, University of Helsinki, 00014 Helsinki, Finland
- Kosuke Hashimoto
- RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan
- Gaëlle Recher
- Laboratoire Photonique Numérique et Nanosciences, CNRS, Institut d’Optique Graduate School, University of Bordeaux, UMR 5298, 33400 Bordeaux, France
- Sini Ezer
- Stem Cells and Metabolism Research Program, University of Helsinki, 00014 Helsinki, Finland; Folkhälsan Research Center, 00290 Helsinki, Finland
- Priit Paluoja
- Competence Centre for Health Technologies, 51010 Tartu, Estonia; Institute of Clinical Medicine, University of Tartu, 50090 Tartu, Estonia; University of Helsinki, Doctoral Program in Population Health, 00014 Helsinki, Finland
- Pauliina Paloviita
- Department of Obstetrics and Gynecology, 00014, University of Helsinki and Helsinki University Hospital, 00290 Helsinki, Finland
- Yujiro Takegami
- K.K. DNAFORM, Yokohama 230-0051, Japan
- Ai Kanemaru
- K.K. DNAFORM, Yokohama 230-0051, Japan
- Karolina Lundin
- Department of Obstetrics and Gynecology, 00014, University of Helsinki and Helsinki University Hospital, 00290 Helsinki, Finland
- Tomi T. Airenne
- Structural Bioinformatics Laboratory, Biochemistry, Faculty of Science and Engineering, Åbo Akademi University, 20520 Turku, Finland
- Timo Otonkoski
- Stem Cells and Metabolism Research Program, University of Helsinki, 00014 Helsinki, Finland; Children’s Hospital, Helsinki University Central Hospital, 00290
- Juha S. Tapanainen
- Department of Obstetrics and Gynecology, 00014, University of Helsinki and Helsinki University Hospital, 00290 Helsinki, Finland; Reproductive Medicine Unit, Helsinki University Hospital, 00290 Helsinki, Finland; Oulu University Hospital, 90220 Oulu, Finland
- Hideya Kawaji
- RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan; RIKEN Preventive Medicine and Diagnosis Innovation Program, Wako 351-0198, Japan; Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan
- Yasuhiro Murakawa
- RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan; Instutute for the Advanced Study of Human Biology, Kyoto University, Kyoto 606-8501, Japan; IFOM, The FIRC Institute of Molecular Oncology, 20139 Milan, Italy; Department of Medical Systems Genomics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
- Thomas R. Bürglin
- Department of Biomedicine, University of Basel, 4031 Basel, Switzerland
- Markku Varjosalo
- Institute of Biotechnology, University of Helsinki, 00790 Helsinki, Finland
- Mark S. Johnson
- Structural Bioinformatics Laboratory, Biochemistry, Faculty of Science and Engineering, Åbo Akademi University, 20520 Turku, Finland
- Timo Tuuri
- Department of Obstetrics and Gynecology, 00014, University of Helsinki and Helsinki University Hospital, 00290 Helsinki, Finland; Reproductive Medicine Unit, Helsinki University Hospital, 00290 Helsinki, Finland
- Shintaro Katayama
- Department of Biosciences and Nutrition, Karolinska Institutet, 17177 Huddinge, Sweden; Stem Cells and Metabolism Research Program, University of Helsinki, 00014 Helsinki, Finland; Folkhälsan Research Center, 00290 Helsinki, Finland
- Juha Kere
- Department of Biosciences and Nutrition, Karolinska Institutet, 17177 Huddinge, Sweden; Stem Cells and Metabolism Research Program, University of Helsinki, 00014 Helsinki, Finland; Folkhälsan Research Center, 00290 Helsinki, Finland; Corresponding author
- Journal volume & issue
-
Vol. 25,
no. 4
p. 104137
Abstract
Summary: Double homeobox 4 (DUX4) is expressed at the early pre-implantation stage in human embryos. Here we show that induced human DUX4 expression substantially alters the chromatin accessibility of non-coding DNA and activates thousands of newly identified transcribed enhancer-like regions, preferentially located within ERVL-MaLR repeat elements. CRISPR activation of transcribed enhancers by C-terminal DUX4 motifs results in the increased expression of target embryonic genome activation (EGA) genes ZSCAN4 and KHDC1P1. We show that DUX4 is markedly enriched in human zygotes, followed by intense nuclear DUX4 localization preceding and coinciding with minor EGA. DUX4 knockdown in human zygotes led to changes in the EGA transcriptome but did not terminate the embryos. We also show that the DUX4 protein interacts with the Mediator complex via the C-terminal KIX binding motif. Our findings contribute to the understanding of DUX4 as a regulator of the non-coding genome.
