Abstract
Genome-wide association studies (GWAS) have recurrently associated sequence variation nearby LIN28B with pubertal timing, growth and disease. However, the biology linking LIN28B with these traits is still poorly understood. With our study, we sought to elucidate the mechanisms behind the LIN28B associations, with a special focus on studying LIN28B function at the hypothalamic-pituitary (HP) axis that is ultimately responsible for pubertal onset. Using CRISPR-Cas9 technology, we first generated lin28b knockout (KO) zebrafish. Compared to controls, the lin28b KO fish showed both accelerated growth tempo, reduced adult size and increased expression of mitochondrial genes during larval development. Importantly, data from the knockout zebrafish models and adult humans imply that LIN28B expression has potential to affect gene expression in the HP axis. Specifically, our results suggest that LIN28B expression correlates positively with the expression of ESR1 in the hypothalamus and POMC in the pituitary. Moreover, we show how the pubertal timing advancing allele (T) for rs7759938 at the LIN28B locus associates with higher testosterone levels in the UK Biobank data. Overall, we provide novel evidence that LIN28B contributes to the regulation of sex hormone pathways, which might help explain why the gene associates with several distinct traits.
Highlights
Genome-wide association studies (GWAS) have recurrently associated sequence variation nearby LIN28B with pubertal timing, growth and disease
Since the different mutational strains were phenotypically indistinguishable, both exon[1] and exon[3] mutants were used in parallel to produce data for the study. cDNA sequencing further confirmed lin28b RNA expressed in the mutants likely yields truncated protein that is prone to undergo non-sense mediated decay (NMD) (Supplementary data 1 and Supplementary Fig. 1)
The results from our study suggest that LIN28B has widespread effects on gene expression at the HP axis, and LIN28B-induced changes in sex steroid signalling might contribute to many of the phenotypes associated with the gene in the human studies
Summary
Genome-wide association studies (GWAS) have recurrently associated sequence variation nearby LIN28B with pubertal timing, growth and disease. Data from the knockout zebrafish models and adult humans imply that LIN28B expression has potential to affect gene expression in the HP axis. Data from adult humans indicate that the genetic variants linked to pubertal timing affect LIN28B expression mainly in the hypothalamus www.nature.com/scientificreports and the pituitary, indicating that LIN28B primarily may impact on pubertal timing and related phenotypes through these tissues[11]. We have combined zebrafish knockout models with human data to address the genetic mechanisms whereby LIN28B might affect growth and development, with a special focus on LIN28B function at the HP axis. We report how the pubertal timing advancing alleles in the LIN28B locus associate with higher serum testosterone levels in the UK Biobank data, highlighting a general mechanism whereby LIN28B could affect several of the phenotypes associated with the gene
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
