Comprehensive characterization of the embryonic factor LEUTX
Lisa Gawriyski,
Eeva-Mari Jouhilahti,
Masahito Yoshihara,
Liangru Fei,
Jere Weltner,
Tomi T. Airenne,
Ras Trokovic,
Shruti Bhagat,
Mari H. Tervaniemi,
Yasuhiro Murakawa,
Kari Salokas,
Xiaonan Liu,
Sini Miettinen,
Thomas R. Bürglin,
Biswajyoti Sahu,
Timo Otonkoski,
Mark S. Johnson,
Shintaro Katayama,
Markku Varjosalo,
Juha Kere
Affiliations
Lisa Gawriyski
Stem Cells and Metabolism Research Program, University of Helsinki, 00290 Helsinki, Finland; Institute of Biotechnology, University of Helsinki, 00790 Helsinki, Finland; Folkhälsan Research Center, 00290 Helsinki, Finland
Eeva-Mari Jouhilahti
Stem Cells and Metabolism Research Program, University of Helsinki, 00290 Helsinki, Finland; Folkhälsan Research Center, 00290 Helsinki, Finland
Masahito Yoshihara
Department of Biosciences and Nutrition, Karolinska Institutet, 14183 Huddinge, Sweden
Liangru Fei
Applied Tumor Genomics Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland
Jere Weltner
Stem Cells and Metabolism Research Program, University of Helsinki, 00290 Helsinki, Finland; Folkhälsan Research Center, 00290 Helsinki, Finland; Department of Clinical Science, Intervention and Technology, Karolinska Institutet, 14186 Stockholm, Sweden; Division of Obstetrics and Gynecology, Karolinska Universitetssjukhuset, 14186 Stockholm, Sweden
Tomi T. Airenne
Structural Bioinformatics Laboratory and InFLAMES Research Flagship Center, Biochemistry, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland
Ras Trokovic
Stem Cells and Metabolism Research Program, University of Helsinki, 00290 Helsinki, Finland
Shruti Bhagat
Department of Biosciences and Nutrition, Karolinska Institutet, 14183 Huddinge, Sweden; RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
Mari H. Tervaniemi
Stem Cells and Metabolism Research Program, University of Helsinki, 00290 Helsinki, Finland; Folkhälsan Research Center, 00290 Helsinki, Finland
Yasuhiro Murakawa
RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Institute for the Advanced Study of Human Biology, Kyoto University, Kyoto, Japan; Department of Medical Systems Genomics, Graduate School of Medicine, Kyoto University, Kyoto, Japan; IFOM-ETS, Milan, Italy
Kari Salokas
Institute of Biotechnology, University of Helsinki, 00790 Helsinki, Finland
Xiaonan Liu
Institute of Biotechnology, University of Helsinki, 00790 Helsinki, Finland
Sini Miettinen
Institute of Biotechnology, University of Helsinki, 00790 Helsinki, Finland
Thomas R. Bürglin
Department of Biomedicine, University of Basel, Basel, Switzerland
Biswajyoti Sahu
Applied Tumor Genomics Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland; Centre for Molecular Medicine Norway (NCMM), University of Oslo, 0349 Oslo, Norway
Timo Otonkoski
Stem Cells and Metabolism Research Program, University of Helsinki, 00290 Helsinki, Finland; Children’s Hospital, Helsinki University Hospital and University of Helsinki, 00290 Helsinki, Finland
Mark S. Johnson
Structural Bioinformatics Laboratory and InFLAMES Research Flagship Center, Biochemistry, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland
Shintaro Katayama
Stem Cells and Metabolism Research Program, University of Helsinki, 00290 Helsinki, Finland; Folkhälsan Research Center, 00290 Helsinki, Finland; Department of Biosciences and Nutrition, Karolinska Institutet, 14183 Huddinge, Sweden
Markku Varjosalo
Institute of Biotechnology, University of Helsinki, 00790 Helsinki, Finland
Juha Kere
Stem Cells and Metabolism Research Program, University of Helsinki, 00290 Helsinki, Finland; Folkhälsan Research Center, 00290 Helsinki, Finland; Department of Biosciences and Nutrition, Karolinska Institutet, 14183 Huddinge, Sweden; Corresponding author
Summary: The paired-like homeobox transcription factor LEUTX is expressed in human preimplantation embryos between the 4- and 8-cell stages, and then silenced in somatic tissues. To characterize the function of LEUTX, we performed a multiomic characterization of LEUTX using two proteomics methods and three genome-wide sequencing approaches. Our results show that LEUTX stably interacts with the EP300 and CBP histone acetyltransferases through its 9 amino acid transactivation domain (9aaTAD), as mutation of this domain abolishes the interactions. LEUTX targets genomic cis-regulatory sequences that overlap with repetitive elements, and through these elements it is suggested to regulate the expression of its downstream genes. We find LEUTX to be a transcriptional activator, upregulating several genes linked to preimplantation development as well as 8-cell-like markers, such as DPPA3 and ZNF280A. Our results support a role for LEUTX in preimplantation development as an enhancer binding protein and as a potent transcriptional activator.
