Phylogenetic and mutational analyses of human LEUTX, a homeobox gene implicated in embryogenesis

Sci Rep. 2018 Nov 27;8(1):17421. doi: 10.1038/s41598-018-35547-5.

Shintaro Katayama ¹, Vipin Ranga ², Eeva-Mari Jouhilahti ¹ ³, Tomi T Airenne ², Mark S Johnson ², Krishanu Mukherjee ¹ ⁴, Thomas R Bürglin ⁵, Juha Kere ⁶ ⁷ ⁸

Affiliations

1 Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
2 Structural Bioinformatics Laboratory, Biochemistry, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland.
3 Research Programs Unit, Molecular Neurology and Biomedicum Stem Cell Centre, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
4 The Whitney Laboratory for Marine Bioscience, University of Florida, St. Augustine, USA.
5 Department of Biomedicine, University of Basel, Basel, Switzerland. thomas.buerglin@unibas.ch.
6 Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden. juha.kere@ki.se.
7 Folkhälsan Institute of Genetics and Molecular Neurology Research Program, University of Helsinki, Helsinki, Finland. juha.kere@ki.se.
8 School of Basic & Medical Biosciences, King's College London, London, England. juha.kere@ki.se.

PMID: 30479355 DOI: 10.1038/s41598-018-35547-5

Abstract

Recently, human PAIRED-LIKE homeobox transcription factor (TF) genes were discovered whose expression is limited to the period of embryo genome activation up to the 8-cell stage. One of these TFs is LEUTX, but its importance for human embryogenesis is still subject to debate. We confirmed that human LEUTX acts as a TAATCC-targeting transcriptional activator, like Other K50-type PAIRED-LIKE TFs. Phylogenetic comparisons revealed that Leutx proteins are conserved across Placentalia and comprise two conserved domains, the homeodomain, and a Leutx-specific domain containing putative transcriptional activation motifs (9aaTAD). Examination of human genotype resources revealed 116 allelic variants in LEUTX. Twenty-four variants potentially affect function, but they occur only heterozygously at low frequency. One variant affects a DNA-specificity determining residue, mutationally reachable by a one-base transition. In vitro and in silico experiments showed that this LEUTX mutation (alanine to valine at position 54 in the homeodomain) results in a transactivational loss-of-function to a minimal TAATCC-containing promoter and a 36 bp motif enriched in genes involved in embryo genome activation. A compensatory change in residue 47 restores function. The results support the notion that human LEUTX functions as a transcriptional activator important for human embryogenesis.

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