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

doi:10.1016/j.isci.2023.106172

Comprehensive characterization of the embryonic factor LEUTX

iScience. 2023 Feb 9;26(3):106172. doi: 10.1016/j.isci.2023.106172. eCollection 2023 Mar 17.

Authors

Lisa Gawriyski^{1

2

3}, Eeva-Mari Jouhilahti^{1

3}, Masahito Yoshihara⁴, Liangru Fei⁵, Jere Weltner^{1

3

6

7}, Tomi T Airenne⁸, Ras Trokovic¹, Shruti Bhagat^{4

9}, Mari H Tervaniemi^{1

3}, Yasuhiro Murakawa^{9

10

11

12}, Kari Salokas², Xiaonan Liu², Sini Miettinen², Thomas R Bürglin¹³, Biswajyoti Sahu^{5

14}, Timo Otonkoski^{1

15}, Mark S Johnson⁸, Shintaro Katayama^{1

3

4}, Markku Varjosalo², Juha Kere^{1

3

4}

Affiliations

¹ Stem Cells and Metabolism Research Program, University of Helsinki, 00290 Helsinki, Finland.
² Institute of Biotechnology, University of Helsinki, 00790 Helsinki, Finland.
³ Folkhälsan Research Center, 00290 Helsinki, Finland.
⁴ Department of Biosciences and Nutrition, Karolinska Institutet, 14183 Huddinge, Sweden.
⁵ Applied Tumor Genomics Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland.
⁶ Department of Clinical Science, Intervention and Technology, Karolinska Institutet, 14186 Stockholm, Sweden.
⁷ Division of Obstetrics and Gynecology, Karolinska Universitetssjukhuset, 14186 Stockholm, Sweden.
⁸ Structural Bioinformatics Laboratory and InFLAMES Research Flagship Center, Biochemistry, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland.
⁹ RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
¹⁰ Institute for the Advanced Study of Human Biology, Kyoto University, Kyoto, Japan.
¹¹ Department of Medical Systems Genomics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
¹² IFOM-ETS, Milan, Italy.
¹³ Department of Biomedicine, University of Basel, Basel, Switzerland.
¹⁴ Centre for Molecular Medicine Norway (NCMM), University of Oslo, 0349 Oslo, Norway.
¹⁵ Children's Hospital, Helsinki University Hospital and University of Helsinki, 00290 Helsinki, Finland.

Abstract

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.

Keywords: Molecular biology; Omics; Reproductive medicine.