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NANOGP1, a tandem duplicate of NANOG, exhibits partial functional conservation in human naïve pluripotent stem cells

ABSTRACT: NANOGP1, a tandem duplicate of NANOG, exhibits partial functional conservation in human naïve pluripotent stem cells

PROVIDER: PRJNA842743 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR19421418.fastq.gz	Fastqsanger.gz
	SRR19421419.fastq.gz	Fastqsanger.gz
	SRR19421420.fastq.gz	Fastqsanger.gz
	SRR19421421.fastq.gz	Fastqsanger.gz
	SRR19421422.fastq.gz	Fastqsanger.gz

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NANOGP1, a tandem duplicate of NANOG, exhibits partial functional conservation in human naïve pluripotent stem cells

Project description:Gene duplication events are important drivers of evolution by providing genetic material for new gene functions. They also create opportunities for diverse developmental strategies to emerge between species. To study the contribution of duplicated genes to human early development, we examined the evolution and function of NANOGP1, a tandem duplicate of the key transcription factor NANOG. We found that NANOGP1 and NANOG have overlapping but distinct expression profiles, with high NANOGP1 expression restricted to early epiblast cells and naïve-state pluripotent stem cells. Sequence analysis and epitope-tagging of the endogenous locus revealed that NANOGP1 is protein-coding with an intact homeobox domain. NANOGP1 has been retained only in great apes, whereas Old World monkeys have disabled the gene in different ways including point mutations in the homeodomain. NANOGP1 is a strong inducer of naïve pluripotency, however, unlike NANOG, it is not required to maintain the undifferentiated status of human naïve pluripotent cells. By retaining expression, sequence and partial functional conservation with its ancestral copy, NANOGP1 exemplifies how gene duplication and subfunctionalisation can contribute to transcription factor activity in human pluripotency and development.

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Duplicate genes increase expression diversity in closely related species and allopolyploids

Project description:Polyploidy or whole genome duplication (WGD) provides raw genetic materials for sequence and expression evolution of duplicate genes. However, the mode and tempo of expression divergence between WGD duplicate genes in closely relates species and recurrent allopolyploids are poorly understood. Arabidopsis is a suitable system for testing the hypothesis that duplicate genes increase expression diversity and regulatory networks. In Arabidopsis, WGD occurred more than once prior to the split between Arabidopsis thaliana and Arabidopsis arenosa, and both natural and human-made allotetraploids are available. Comparative genomic hybridization analysis indicated that single-copy and duplicate genes after WGD were well preserved in A. thaliana and A. arenosa. Analysis of gene expression microarrays showed that duplicate genes generally had higher levels of expression divergence between two closely related species than single-copy genes. The proportion of the progenitors' duplicate genes that were nonadditively expressed in the resynthesized and natural allotetraploids was significantly higher than that of single-copy genes. Duplicate genes related to environmental stresses tended to be differentially expressed, and multi-copy duplicate genes were likely to diverge expression between progenitors and in the allotetraploids. Compared to single-copy genes, duplicate genes tend to contain TATA boxes and less DNA methylation in the promoter regions, facilitating transcriptional regulation by binding transcription factors and/or cis-and trans- acting proteins. The data suggest an important role of WGD duplicate genes in modulating diverse and novel gene expression changes in response to external environmental cues as well as internal genetic turmoil such as recurrent polyploidy events.

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Nanog-induced intestinal and colonic hyperplasia

Project description:Though expression of the homeobox transcription factor Nanog is generally restricted to pluripotent cells and early germ cells, recent reports have found that Nanog is re-expressed in somatic and germ cell tumors associated with poor differentiation and aggressive disease progression. To elucidate its oncogenic properties, a modified Tet-On system was utilised to generate Nanog-inducible mice. By dexamethasone and doxycycline injection, similar Nanog expression levels as in wild-type embryonic stem cells were obtained in all major organs except for brain. Ectopic Nanog expression resulted in intestinal and colonic epithelium hyperplasia-intestinal villi had doubled in length and hyperplastic epithelium outgrowths were seen after 7 days. The tumor suppressor gene Cdx2 was downregulated at onset of Nanog expression, suggesting that crosstalk between Nanog and Cdx2 is conserved from early embryo development to adulthood. Although the mice died before they could form tumors, Cdx2 repression and intestinal hyperplasia links Nanog to tumor initiation.

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