PUBLICATION
LIN28B affects gene expression at the hypothalamic-pituitary axis and serum testosterone levels
- Authors
- Leinonen, J.T., Chen, Y.C., Pennonen, J., Lehtonen, L., Junna, N., Tukiainen, T., Panula, P., Widén, E.
- ID
- ZDB-PUB-191204-20
- Date
- 2019
- Source
- Scientific Reports 9: 18060 (Journal)
- Registered Authors
- Panula, Pertti
- Keywords
- none
- MeSH Terms
-
- Hypothalamo-Hypophyseal System/metabolism*
- Gene Knockdown Techniques
- Polymorphism, Single Nucleotide
- Datasets as Topic
- CRISPR-Cas Systems/genetics
- Pituitary Gland/metabolism
- Models, Animal
- RNA-Binding Proteins/genetics*
- RNA-Binding Proteins/metabolism*
- Female
- Sexual Maturation/genetics
- RNA-Seq
- Estrogen Receptor alpha/metabolism
- Humans
- Testosterone/blood*
- Testosterone/metabolism
- Computational Biology
- Male
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- Alleles
- Pro-Opiomelanocortin/metabolism*
- Zebrafish
- Hypothalamus/metabolism
- Gene Expression Regulation, Developmental*
- Animals, Genetically Modified
- Gene Knockout Techniques
- Animals
- PubMed
- 31792362 Full text @ Sci. Rep.
Citation
Leinonen, J.T., Chen, Y.C., Pennonen, J., Lehtonen, L., Junna, N., Tukiainen, T., Panula, P., Widén, E. (2019) LIN28B affects gene expression at the hypothalamic-pituitary axis and serum testosterone levels. Scientific Reports. 9:18060.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping