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2014 ; 23
(7
): 1700-8
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Functional characterization of SIM1-associated enhancers
#MMPMID24203700
Kim MJ
; Oksenberg N
; Hoffmann TJ
; Vaisse C
; Ahituv N
Hum Mol Genet
2014[Apr]; 23
(7
): 1700-8
PMID24203700
show ga
Haploinsufficiency of the single-minded homology 1 (SIM1) gene in humans and mice
leads to severe obesity, suggesting that altered expression of SIM1, by way of
regulatory elements such as enhancers, could predispose individuals to obesity.
Here, we identified transcriptional enhancers that could regulate SIM1, using
comparative genomics coupled with zebrafish and mouse transgenic enhancer assays.
Owing to the dual role of Sim1 in hypothalamic development and in adult energy
homeostasis, the enhancer activity of these sequences was annotated from
embryonic to adult age. Of the seventeen tested sequences, two SIM1 candidate
enhancers (SCE2 and SCE8) were found to have brain-enhancer activity in
zebrafish. Both SCE2 and SCE8 also exhibited embryonic brain-enhancer expression
in mice, and time course analysis of SCE2 activity showed overlapping expression
with Sim1 from embryonic to adult age, notably in the hypothalamus in adult mice.
Using a deletion series, we identified the critical region in SCE2 that is needed
for enhancer activity in the developing brain. Sequencing this region in obese
and lean cohorts revealed a higher prevalence of single nucleotide polymorphisms
(SNPs) that were unique to obese individuals, with one variant reducing
developmental-enhancer activity in zebrafish. In summary, we have characterized
two brain enhancers in the SIM1 locus and identified a set of obesity-specific
SNPs within one of them, which may predispose individuals to obesity.
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