Sex-specific role of epigenetic modification of a leptin upstream enhancer in the adipose tissue

Mueller, L.; Oelkrug, R.; Mittag, J.; Hoffmann, A.; Ghosh, A.; Noe, F.; Wolfrum, C.; Jurado, E. G.; Kloeting, N.; Dietrich, A.; Blueher, M.; Kovacs, P.; Krause, K.; Keller, M.

doi:10.1101/2024.09.30.615808

bioRxiv · 10.1101/2024.09.30.615808

Sex-specific role of epigenetic modification of a leptin upstream enhancer in the adipose tissue

Mueller, L.·Oelkrug, R.·Mittag, J.·Hoffmann, A.·Ghosh, A.·Noe, F.·Wolfrum, C.·Jurado, E. G.·Kloeting, N.·Dietrich, A.·Blueher, M.·Kovacs, P.·Krause, K.·Keller, M.

View original source ↗Export metadata ↓

Abstract

ObjectiveMaternal hormonal status can have long-term effects on offspring metabolic health, likely regulated via epigenetic mechanisms. We elucidated the effect of maternal thyroid hormones on epigenetic regulation of Leptin (Lep) transcription in adipose tissue (AT) and investigated the role of DNA methylation at a Lep upstream enhancer (UE) in adipocyte biology. MethodsPregnant mice were treated with Triiodothyronine (T3). Offspring body composition and adipose tissue were analysed at 6 months (treatment: N = 8, control: N = 12). DNA methylation at the Lep UE and Lep mRNA levels in gonadal white adipose tissue (gWAT) and leptin serum levels were measured. The Lep UE was hypomethylated in murine preadipocytes using a dCas9-SunTag-TET1 system, followed by differentiation. In human visceral AT samples (N = 52) from the Leipzig Obesity BioBank (LOBB) LEP UE methylation and LEP mRNA levels were assessed alongside leptin serum levels and correlated with body fat percentage. Causal relationships were explored using mediation analysis. ResultsHigh maternal T3 levels reduced offspring body weight, total fat, and gWAT mass. Female offspring of T3-treated mothers showed lower Lep mRNA levels and higher Lep UE methylation compared to controls. CRISPR/dCas9 editing reduced Lep UE methylation by [~]20% in preadipocytes without altering Lep expression or lipid accumulation after differentiation. In humans, a mediation of sex-specific difference in body fat percentage via Lep UE methylation was found. ConclusionMaternal thyroid hormones might affect offspring gWAT Lep expression in a sex-specific manner, potentially driven by DNA methylation at the Lep UE, influencing body fat percentage.

Source connections

Published article ↗

Explore related subjects

genetics Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Mueller, L., Oelkrug, R., Mittag, J., Hoffmann, A., Ghosh, A., Noe, F., Wolfrum, C., Jurado, E. G., Kloeting, N., Dietrich, A., Blueher, M., Kovacs, P., Krause, K., Keller, M.. 2024-10-01. Sex-specific role of epigenetic modification of a leptin upstream enhancer in the adipose tissue. https://doi.org/10.1101/2024.09.30.615808

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Utilizing single-cell data for per-cell type eQTL mapping in the human pancreas

Aims/hypothesis The human pancreas is a central organ for metabolic regulation that is comprised of diverse cell types that uniquely contribute to its function. Previous studies have performed expression quantitative trail loci (eQTL) discovery in either whole pancreas or in pancreatic islets, but due to differences between pancreatic cell types, this approach does not reveal cell type-specific effects. In this study, we sought to either implicate the cell type of action for known eQTLs or identify new eQTLs that may have been masked in bulk studies by performing eQTL discovery in individual pancreatic cell types. Methods We clustered 153,018 single-cell RNA sequencing (scRNA-seq) data from 71 pancreatic islet donors from the Human Pancreas Analysis Program (HPAP). We performed eQTL discovery in six pancreatic cell types using this resource directly. We further utilized this single cell resource as a reference to deconvolute bulk pancreatic RNA sequencing data from 305 Genotype Tissue Expression (GTEx) project donors and performed eQTL discovery in four pancreatic cell types. Finally, we performed fine-mapping and co-localization of pancreatic cell type eQTLs with metabolic GWAS to connect our findings to metabolic disease risk. Results From analyzing 71 individuals with single cell profiles, we identified 112 unique eGenes across six pancreatic cell types, 99 of which had been identified previously and 13 unique to this study. From the deconvoluted eQTLs, we identified 3,134 unique eGenes across four pancreatic cell types, 116 of which were unique to our study. Fine-mapping and co-localization of eQTLs with metabolic GWAS yielded key leads that warrant further investigation, such as the association of rs2168101 with LMO1 expression in alpha cells. Conclusions/interpretation We identified new signals that were previously not found in bulk pancreatic eQTL studies and potential cell type of action for several signals that were identified previously. Although there are limitations to the power, and therefore, discoverability of this study, it provides insights into how individual pancreatic cells differently contribute to metabolic disease.

genetics↗

bioRxiv2026

MOD-scTWAS: Leveraging gene co-expression for single-cell transcriptome-wide association studies

Transcriptome-wide association studies (TWAS) provide an effective framework for identifying genes associated with complex traits. Population-scale single-cell transcriptomic data enable genetically regulated expression (GReX) prediction and TWAS analyses at cell-type resolution, but the predictive performance of existing single-cell TWAS methods remains limited. Here, we develop MOD-scTWAS, a module-based method that jointly models GReX for genes within co-expression modules to borrow information across genes. Starting from a generative model for single-cell gene expression, MOD-scTWAS accounts for the heteroscedasticity and cross-gene correlation of individual-level pseudobulk expression in joint GReX prediction. In cross-validation analyses of the OneK1K dataset, MOD-scTWAS achieved higher mean GReX prediction accuracy than scTWAS across all 14 cell types and increased the number of imputable genes. When applied to TWAS analyses of UK Biobank quantitative hematological traits, MOD-scTWAS identified more significant cell type-gene-trait associations than scTWAS. These results demonstrate the potential of leveraging gene co-expression through joint modeling to improve cell-type-specific GReX prediction and TWAS discovery.

genetics↗

bioRxiv2026

Generation of a transgenic cephalopod

Coleoid cephalopods (cuttlefish, octopus, and squid) are marine mollusks with elaborate nervous systems that support a diverse repertoire of complex behaviors. These include the neural control of the color, pattern, and texture of the skin, facilitating both adaptive camouflage and innate patterning that may reflect internal state. The development of transgenic cephalopods expressing fluorescent proteins, optogenetic actuators, and reporters of neural activity would contribute a new and important technology to cephalopod biology. The generation of transgenic cephalopods, however, has remained a major challenge. Here, we report the development of stable transgenic dwarf cuttlefish (Ascarosepion bandense) expressing ubiquitous nuclear-localized mScarlet, a red fluorescent protein. We evaluated multiple strategies for transgenesis, and established cuttlefish lines using both CRISPR and the transposons Sleeping Beauty and Minos. The stable expression of transgenes enabled live imaging of cell dynamics during embryonic development. The Minos transposon emerged as the most efficient transgenesis strategy and is adaptable to promoters and transgenes of choice. These strategies now enable the generation of diverse genetic tools for mechanistic studies of cephalopod biology.

genetics↗