A sister of NANOG regulates genes expressed in pre-implantation human development

Thomas L Dunwell,Peter W H Holland

doi:10.1098/rsob.170027

Abstract

The NANOG homeobox gene plays a pivotal role in self-renewal and maintenance of pluripotency in human, mouse and other vertebrate embryonic stem cells, and in pluripotent cells of the blastocyst inner cell mass. There is a poorly studied and atypical homeobox locus close to the Nanog gene in some mammals which could conceivably be a cryptic paralogue of NANOG, even though the loci share only 20% homeodomain identity. Here we argue that this gene, NANOGNB (NANOG Neighbour), is an extremely divergent duplicate of NANOG that underwent radical sequence change in the mammalian lineage. Like NANOG, the NANOGNB gene is expressed in pre-implantation embryos of human and cow; unlike NANOG, NANOGNB expression is restricted to 8-cell and morula stages, preceding blastocyst formation. When expressed ectopically in adult cells, human NANOGNB elicits gene expression changes, including downregulation of a set of genes that have an expression pulse at the 8-cell stage of pre-implantation development. We conclude that gene duplication and massive sequence divergence in mammals generated a novel homeobox gene that acquired new developmental roles complementary to those of Nanog.

Highlights

The Nanog gene was originally described independently by Wang et al [1], Mitsui et al [2] and Chambers et al [3] and has been placed within the ANTP class of homeobox genes
Its evolutionary origins were obscure because, neighbouring the wellknown NANOG gene, the homeodomain of NANOGNB is extremely divergent from any other homeodomain sequence known
We argue that NANOGNB was generated by tandem duplication of the NANOG gene followed by extensive, dramatic, protein sequence divergence

Summary

Introduction

The Nanog gene was originally described independently by Wang et al [1], Mitsui et al [2] and Chambers et al [3] and has been placed within the ANTP class of homeobox genes. The Nanog gene facilitates self-renewal of ESCs in culture and plays a central role in maintaining ESCs in a pluripotent state [2,3,4]. The gene is thought to have an analogous role in the embryo, being essential for maintenance of pluripotency by cells of the inner cell mass [2]. NANOGP1 was independently named NANOG2 by Hart et al [6] and this name was adopted as evidence accumulated that the locus was under selection and produced a protein [6 –8]. An independent duplication of NANOG was reported in chicken [10], and more recently this duplication was found to be prevalent across birds.

Methods

Results

Conclusion