LIN28B affects gene expression at the hypothalamic-pituitary axis and serum testosterone levels.
Alleles
Animals
Animals, Genetically Modified
CRISPR-Cas Systems
/ genetics
Computational Biology
Datasets as Topic
Estrogen Receptor alpha
/ metabolism
Female
Gene Expression Regulation, Developmental
Gene Knockdown Techniques
Gene Knockout Techniques
Humans
Hypothalamo-Hypophyseal System
/ metabolism
Hypothalamus
/ metabolism
Male
Models, Animal
Pituitary Gland
/ metabolism
Polymorphism, Single Nucleotide
Pro-Opiomelanocortin
/ metabolism
RNA-Binding Proteins
/ genetics
RNA-Seq
Sexual Maturation
/ genetics
Testosterone
/ blood
Zebrafish
Zebrafish Proteins
/ genetics
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
02 12 2019
02 12 2019
Historique:
received:
15
07
2019
accepted:
14
11
2019
entrez:
4
12
2019
pubmed:
4
12
2019
medline:
12
11
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 31792362
doi: 10.1038/s41598-019-54475-6
pii: 10.1038/s41598-019-54475-6
pmc: PMC6889388
doi:
Substances chimiques
ESR1 protein, human
0
Estrogen Receptor alpha
0
LIN28B protein, human
0
RNA-Binding Proteins
0
Zebrafish Proteins
0
estrogen receptor 1, zebrafish
0
lin28b protein, zebrafish
0
pomca protein, zebrafish
0
Testosterone
3XMK78S47O
Pro-Opiomelanocortin
66796-54-1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
18060Subventions
Organisme : Medical Research Council
ID : MC_PC_12028
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_17228
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_QA137853
Pays : United Kingdom
Références
Nat Genet. 2015 Mar;47(3):284-90
pubmed: 25642633
Am J Hum Genet. 2010 May 14;86(5):773-82
pubmed: 20398887
Gene Expr Patterns. 2008 Feb;8(3):155-60
pubmed: 18077221
Mol Cell Endocrinol. 2019 Jan 5;479:61-70
pubmed: 30196135
Gene Expr Patterns. 2003 Dec;3(6):719-26
pubmed: 14643679
Nat Genet. 2019 Feb;51(2):258-266
pubmed: 30598549
Neuropeptides. 2009 Oct;43(5):341-53
pubmed: 19647870
Proc Natl Acad Sci U S A. 2010 Dec 28;107(52):22693-8
pubmed: 21149719
BMC Bioinformatics. 2009 Feb 03;10:48
pubmed: 19192299
Nat Genet. 2016 Sep;48(9):1031-6
pubmed: 27479909
Nature. 2015 Dec 17;528(7582):405-8
pubmed: 26536110
Sci Rep. 2015 Jun 18;5:11208
pubmed: 26084728
Neuroendocrinology. 2015;102(4):247-255
pubmed: 25968239
Mol Vis. 2009 Nov 13;15:2313-25
pubmed: 19936306
Postgrad Med J. 1975 Apr;51(594):200-8
pubmed: 1197148
Curr Opin Endocrinol Diabetes Obes. 2009 Feb;16(1):16-24
pubmed: 19104234
Trends Genet. 2016 Dec;32(12):815-827
pubmed: 27836208
Hum Mol Genet. 2013 Jul 1;22(13):2735-47
pubmed: 23449627
Hum Mol Genet. 2018 Jun 1;27(11):2025-2038
pubmed: 29659830
Dev Dyn. 2009 Dec;238(12):2975-3015
pubmed: 19891001
Am J Hum Genet. 2012 Dec 7;91(6):1065-72
pubmed: 23176824
Front Genet. 2017 Mar 28;8:31
pubmed: 28400788
Nat Commun. 2019 Jan 11;10(1):163
pubmed: 30635563
Cell. 2011 Sep 30;147(1):81-94
pubmed: 21962509
Endocrinology. 2013 Feb;154(2):942-55
pubmed: 23291449
Nat Genet. 2009 Jun;41(6):734-8
pubmed: 19448622
Front Neuroendocrinol. 2015 Jul;38:73-88
pubmed: 25913220
Mol Cell. 2008 Oct 24;32(2):276-84
pubmed: 18951094
Endocrinology. 2011 Apr;152(4):1661-9
pubmed: 21303958
Ann N Y Acad Sci. 2011 Mar;1220:93-105
pubmed: 21388407
Cell Stem Cell. 2016 Jul 7;19(1):66-80
pubmed: 27320042
PLoS One. 2011;6(7):e21800
pubmed: 21789182
Nature. 2019 Apr;568(7751):193-197
pubmed: 30944477
Gene. 2011 Apr 1;475(1):30-8
pubmed: 21194559
Nat Rev Endocrinol. 2016 Aug;12(8):452-66
pubmed: 27199290
PLoS Genet. 2017 Jul 13;13(7):e1006780
pubmed: 28704371
Nat Genet. 2003 Jul;34(3):267-73
pubmed: 12808457
Bioinformatics. 2010 Jan 1;26(1):139-40
pubmed: 19910308
J Clin Endocrinol Metab. 1999 Jun;84(6):1966-72
pubmed: 10372695
J Endocrinol. 2016 Mar;228(3):179-91
pubmed: 26698568
Nature. 2018 Oct;562(7726):203-209
pubmed: 30305743
Nat Genet. 2010 Jul;42(7):626-30
pubmed: 20512147
Science. 1984 Oct 26;226(4673):409-16
pubmed: 6494891
Nat Genet. 2009 Jun;41(6):729-33
pubmed: 19448623
Nat Genet. 2010 Dec;42(12):1077-85
pubmed: 21102462
Nature. 2010 Oct 14;467(7317):832-8
pubmed: 20881960
Endocrinology. 2015 Feb;156(2):589-99
pubmed: 25406015
Biol Reprod. 2018 Sep 1;99(3):565-577
pubmed: 29635430
Science. 2015 May 8;348(6235):648-60
pubmed: 25954001
Cell. 2010 Feb 19;140(4):445-9
pubmed: 20178735