Biology subjects

Fredholm, M.

Publications and source records attributed to Fredholm, M..

5 recordsLinked to original sources

bioRxiv2023

Construction of a multi-tissue cell atlas reveals cell-type-specific regulation of molecular and complex phenotypes in pigs

The systematic characterization of cellular heterogeneity among tissues and cell-type-specific regulation underlying complex phenotypes remains elusive in pigs. Within the Pig Genotype-Tissue Expression (PigGTEx) project, we present a single-cell transcriptome atlas of adult pigs encompassing 229,268 high-quality nuclei from 19 tissues, annotated to 67 major cell types. Besides cellular heterogeneity within and across tissues, we further characterize prominent tissue-specific features and functions of muscle, epithelial, and immune cells. Through deconvoluting 3,921 bulk RNA-seq samples from 17 matching tissues, we dissect thousands of genetic variants with cell-type interaction effects on gene expression (ieQTL). By colocalizing these ieQTL with variants associated with 268 complex traits, we provide new insights into the cellular mechanisms behind these traits. Moreover, we highlight that orthologous genes with cell-type-specific regulation in pigs exhibit significant heritability enrichment for some human complex phenotypes. Altogether, our work provides a valuable resource and highlights novel insights in cellular regulation of complex traits for accelerating pig precision breeding and human biomedical research.

genetics↗

bioRxiv2022

A compendium of genetic regulatory effects across pig tissues

The Farm animal Genotype-Tissue Expression (FarmGTEx, https://www.farmgtex.org/) project has been established to develop a comprehensive public resource of genetic regulatory variants in domestic animal species, which is essential for linking genetic polymorphisms to variation in phenotypes, helping fundamental biology discovery and exploitation in animal breeding and human biomedicine. Here we present results from the pilot phase of PigGTEx (http://piggtex.farmgtex.org/), where we processed 9,530 RNA-sequencing and 1,602 whole-genome sequencing samples from pigs. We build a pig genotype imputation panel, characterize the transcriptional landscape across over 100 tissues, and associate millions of genetic variants with five types of transcriptomic phenotypes in 34 tissues. We study interactions between genotype and breed/cell type, evaluate tissue specificity of regulatory effects, and elucidate the molecular mechanisms of their action using multi-omics data. Leveraging this resource, we decipher regulatory mechanisms underlying about 80% of the genetic associations for 207 pig complex phenotypes, and demonstrate the similarity of pigs to humans in gene expression and the genetic regulation behind complex phenotypes, corroborating the importance of pigs as a human biomedical model.

genomics↗

bioRxiv2022

Body condition score and triglyceride concentrations and their associations with other markers of energy homeostasis in healthy, non-obese dogs

Serum triglyceride concentrations increase in dogs in overweight condition, which is typically assessed by body condition score (BCS). However, their associations with other markers of energy homeostasis are poorly characterized. The present study aimed to evaluate the associations between both BCS and triglyceride levels and other markers of lipid and glucose metabolism in healthy dogs in overweight condition. 534 overweight, but otherwise healthy, client-owned dogs were included. Serum concentrations of cholesterol, free fatty acids, triglycerides, insulin, glucose and fructosamine were measured. Dogs were assigned to lean (BCS: 3-5) or overweight (BCS: 6-7) categories, and linear models were used to assess the differences between BCS categories and the associations between triglycerides and the other variables, correcting for the effect of breed. Globally, "overweight" dogs had greater serum cholesterol (95% CI: 5.3-6.2 mmol/L or 205-237 mg/dL versus 5.1-5.4 mmol/L or 198-210 mg/dl, P = .003), insulin (95% CI: 17.5-22.1 U/ml versus 16.7-18.0 U/ml, P = .036) and were older (95% CI: 4.0-5.3 versus 3.4-3.7 years, P = .002) than lean dogs. Triglyceride concentrations were positively associated with fructosamine (r2 = 0.31, P = .001), cholesterol (r2 = 0.25, P < .001), insulin (r2 = 0.14, P = .003) and glucose (r2 = 0.10, P = .002), and negatively associated with free fatty acids (r2 = 0.11, P < .001). There was no association between triglyceride levels and age. In conclusion, both BCS and triglyceride concentrations were associated with other markers of glucose and lipid metabolism in overweight, but otherwise healthy dogs. Triglyceride concentrations were associated with an increase in insulin and fructosamine that might reflect an early-phase impairment in glucose tolerance which, surprisingly, was concurrent with lower basal free fatty acids.

physiology↗

bioRxiv2022

Investigating the effect of obesity on adipose-derived stem cells (ASCs) using Gottingen Minipigs

Obesity is associated with low grade inflammation, which may adversely impact the biological functions of adipose tissue and consequently of adipose-derived stem cells (ASCs). Studies in humans and rodents have described that obesity alters ASC properties and functionality, compromising their therapeutic prospects. The Gottingen Minipig (GM) is a commonly used obesity model. Nevertheless, there are no studies investigating the effect of obesity on ASCs from GM, which could constitute a valuable addition to both obesity modelling and adult stem cells investigations. In this study, we isolated subcutaneous ASCs from lean and obese GM to investigate the effect of obesity on cell behavior and differentiation capacity. During culturing, we observed an inherent difference in cell morphology between lean and obese ASCs. Upon adipogenic induction, obese-ASCs readily differentiated, developing significantly larger amounts of adipocytes than corresponding lean-ASCs, hinting at a predisposition towards adipogenic differentiation. Expression profiling of obesity-related genes in cell cultures, before and after adipogenic differentiation, revealed a tendency towards up-regulation in differentiated obese-cultures. Altogether, our results indicate that stem cells from obese donors could display different therapeutic properties. In summary, our results point towards GM as a valuable model for future ASCs investigations in healthy and obese states.

cell biology↗

bioRxiv2021

An exon-intron split framework to prioritize transcriptional and post-transcriptional regulatory signals and its application to study energy homeostasis in pigs

The contribution of microRNAs (miRNAs) to mRNA regulation has often been explored by post hoc selection of downregulated genes and determining whether they harbor binding sites for miRNAs of interest. This approach, however, does not discriminate whether these mRNAs are also downregulated at the transcriptional level. Here, we have characterized the transcriptional and post-transcriptional changes of mRNA expression in two porcine tissues: gluteus medius muscle of fasted and fed Duroc gilts and adipose tissue of lean and obese Duroc-Gottingen minipigs. Exon-intron split analysis (EISA) of RNA-seq data allowed us to identify downregulated mRNAs with high post-transcriptional signals in fed or obese states, and we assessed whether they harbor binding sites for upregulated miRNAs in any of these two physiological states. We found 26 downregulated mRNAs with high post-transcriptional signals in the muscle of fed gilts and 21 of these were predicted targets of upregulated miRNAs also in the fed state. For adipose tissue, 44 downregulated mRNAs in obese minipigs displayed high post-transcriptional signals, and 25 of these were predicted targets of miRNAs upregulated in the obese state. These results suggest that the contribution of miRNAs to mRNA repression is more prominent in the skeletal muscle system. Finally, we identified several genes that may play relevant roles in the energy homeostasis of the pig skeletal muscle (DKK2 and PDK4) and adipose (SESN3 and ESRRG) tissues. By differentiating transcriptional from post-transcriptional changes in mRNA expression, EISA provides a valuable view about the regulation of gene expression, complementary to canonical differential expression analyses.

genomics↗