Primate-specific stress-induced transcription factor POU2F1Z protects human neuronal cells from stress

Alexander G Stepchenko,Bella M Lyanova,Sofia G Georgieva,Ivan A Glukhov,Tatiana N Portseva,Elizaveta V Pankratova,Alina P Kotnova

doi:10.1038/s41598-021-98323-y

Alexander G Stepchenko, Bella M Lyanova + Show 5 more

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https://doi.org/10.1038/s41598-021-98323-y

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Journal: Scientific Reports	Publication Date: Sep 22, 2021
Citations: 3	License type: open-access

Affiliation: Russian Academy of Sciences

Abstract

The emergence of new primate-specific genes is an essential factor in human and primate brain development and functioning. POU2F1/Oct-1 is a transcription regulator in higher eukaryotes which is involved in the regulation of development, differentiation, stress response, and other processes. We have demonstrated that the Tigger2 transposon insertion into the POU2F1 gene which occurred in the primate lineage led to the formation of an additional exon (designated the Z-exon). Z-exon-containing primate-specific Oct-1Z transcript includes a short upstream ORF (uORF) located at its 5’-end and the main ORF encoding the Oct-1Z protein isoform (Pou2F1 isoform 3, P14859-3), which differs from other Oct-1 isoforms by its N-terminal peptide. The Oct-1Z-encoding transcript is expressed mainly in human brain cortex. Under normal conditions, the translation of the ORF coding for the Oct-1Z isoform is repressed by uORF. Under various stress conditions, uORF enables a strong increase in the translation of the Oct-1Z-encoding ORF. Increased Oct-1Z expression levels in differentiating human neuroblasts activate genes controlling stress response, neural cell differentiation, brain formation, and organogenesis. We have shown that the Oct-1Z isoform of the POU2F1/Oct-1 transcription factor is an example of a primate-specific genomic element contributing to brain development and cellular stress defense.

Highlights

The POU2F1/Oct-1/OTF1 transcription factor encoded by the POU2F1 gene belongs to the family of DNA-binding POU domain-containing transcription regulators of higher eukaryotes
The Tigger[2] transposon insertion into the POU2F1 gene of primates gave rise to a novel tran‐ script (Oct‐1Z) which contains the Tigger2‐derived Z‐exon and a short upstream open reading frame (uORF) resulting from its presence
We demonstrate here that the new primate-specific Oct-1Z transcript has emerged as a result of the insertion of the deficient copy of the Tigger[2] mobile element into the POU2F1 gene

Summary

Introduction

The POU2F1/Oct-1/OTF1 transcription factor (further referred to as Oct-1) encoded by the POU2F1 gene belongs to the family of DNA-binding POU domain-containing transcription regulators of higher eukaryotes. Oct-1 controls the expression of a large number of genes involved in development, differentiation, and stress response[1,2,3,4]. Oct-1 plays an important role in the cell-specific and hormonal regulation of GnRH gene transcription in the cell lines, derived from the gonadotropin-releasing hormone (GnRH) neurons of mouse hypothalamus[22]. Oct-1 isoforms reveal similarities and, at the same time, significant differences in the arrays of their targets in human c ells[3,4], suggesting that further study of novel Oct-1isoforms is important for the understanding of the POU2F1 gene functioning. A number of cellular stress-associated genes exhibit altered expression in Oct-1-deficient mouse fibroblasts[31]. The Oct-1 DNA-binding domain is phosphorylated under stress conditions, which results in the altered affinity of the domain to its binding s ites[21]

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