Biology subjects

Seldin, M. M.

Publications and source records attributed to Seldin, M. M..

5 recordsLinked to original sources

bioRxiv2022

Genetic Architecture of Heart Mitochondrial Proteome influencing Cardiac Hypertrophy

Mitochondria play a key role in the normal function of the heart as well as in the pathogenesis of diseases. We report analysis of common genetic variations contributing to mitochondrial and heart functions using an integrative proteomics approach in a panel of inbred mouse strains called the Hybrid Mouse Diversity Panel (HMDP). We performed a whole heart proteomic analysis in the HMDP (72 strains, n=2-3 mice) and retrieved 840 mitochondrial proteins (quantified in [≥]50 strains). High-resolution association mapping on their respective abundance levels identified three trans-acting genetic loci, located on chromosome (chr) 7, chr13 and chr17, that control distinct classes of mitochondrial proteins as well as heart hypertrophy. Follow-up high resolution regional mapping identified NDUFS4, LRPPRC and COQ7 as the candidate genes for chr13, chr17 and chr7 loci, respectively, and both experimental and statistical analyses supported their causal roles. Variations of all three were associated with heart mass in two independent heart stress models, namely, isoproterenol (ISO)-induced heart failure and diet-induced obesity (DIO) models. To identify the aspects of mitochondrial metabolism regulated by these loci, we constructed co-expression protein networks using weighted gene co-expression network analysis (WGCNA). DAVID enrichment analyses of genes regulated by each of the loci revealed that the chr13 locus was highly enriched for complex-I proteins (24 proteins, P = 2.2E-61), the chr17 locus for mitochondrial ribonucleoprotein complex (17 proteins, P = 3.1E-25) and the chr7 locus for ubiquinone biosynthesis (3 proteins, P = 6.9E-05). These results indicate that common variations of certain mitochondrial proteins can act in trans to influence mitochondrial functions and contribute to heart hypertrophy, elucidating mechanisms that may underlie genetic susceptibility to heart failure in human populations.

genetics↗

bioRxiv2022

Proteome-wide systems genetics identifies UFMylation as a regulator of skeletal muscle function

Improving muscle function has great potential to improve the quality of life. To identify novel regulators of skeletal muscle metabolism and function, we performed a proteomic analysis of gastrocnemius muscle from 73 genetically distinct inbred mouse strains, and integrated the data with genomics and >300 molecular/phenotypic traits via quantitative trait loci mapping and correlation network analysis. These data identified thousands of associations between protein abundance and phenotypes and can be accessed online (https://muscle.coffeeprot.com/) to identify regulators of muscle function. We used this resource to prioritize targets for a functional genomic screen in human bioengineered skeletal muscle. This identified several negative regulators of muscle function including UFC1, an E2 ligase for protein UFMylation. We show UFMylation is up-regulated in a mouse model of amyotrophic lateral sclerosis, a disease that involves muscle atrophy. Furthermore, in vivo knockdown of UFMylation increased contraction force, implicating its role as a negative regulator of skeletal muscle function.

systems biology↗

bioRxiv2022

Transcriptional control of adipogenesis by PATZ1

White adipose tissues (WAT) play a central role in lipid storage and systemic energy, lipid, and glucose homeostasis. Understanding the intricacies of adipocyte formation could inform therapies for obesity and metabolic disorders. We have identified the POZ/BTB and AT Hook Containing Zinc Finger 1 (PATZ1) protein as an adipogenic transcription factor through an unbiased high-throughput cDNA screen for modulators of adipogenesis. PATZ1 is expressed by both human and mouse adipocyte precursor cells (APC) and adipocytes, and its expression negatively correlates with obesity. In cell models, PATZ1 expression promotes adipogenesis through a mechanism dependent on protein-protein interaction and DNA binding. Adipose-specific ablation of PATZ1 in mice leads to decreased lipid storage and fat mass and protection from diet-induced obesity. Genome-wide PATZ1 DNA binding analyses using ChIP-Seq suggest that PATZ1 facilitates adipogenesis through interactions with transcription factor machinery at the promoter regions of key adipogenic factors and histone modifiers. Global PATZ1 protein interaction studies using immunoprecipitation-mass spectrometry (IP-MS) suggest that General Transcription Factor 2I (GTF2I) binding to PATZ1 forms a repressive complex, and knockdown of GTF2I augments PATZ1 adipogenic function. Collectively these findings identify PATZ1 as a regulator of the adipocyte differentiation programs and advance our understanding of the complex transcriptional mechanisms underlying adipose tissue development and homeostasis.

molecular biology↗

bioRxiv2022

Genetic variation of human myokine signaling is dominated by biologic sex and sex hormones

Abstract/IntroductionProteins secreted from skeletal muscle, termed myokines, allow muscle to impact systemic physiology and disease. Myokines play critical roles in a variety of processes, including metabolic homeostasis, exercise improvements, inflammation, cancer and cognitive functions1-6. Despite the clear relevance of these factors in mediating a multitude of physiological outcomes, the genetic architecture, regulation and functions of myokines, as well as degree of conservation of these communication circuits remains inadequately understood. Given that biologic sex controls critical aspects of nearly every physiologic outcome, it is essential to consider when relating specific mechanisms to complex genetic and metabolic interactions. Specifically, many metabolic traits impacted by myokines show striking sex differences arising from hormonal7-10, genetic7,11 or gene-by-sex interactions12,13. In this study, we performed a genetic survey of myokine gene regulation and cross-tissue signaling in humans where sex as a biological variable was emphasized. While expression levels of a majority of myokines and cell proportions within skeletal muscle showed little differences between males and females, nearly all significant cross-tissue enrichments operated in a sex-specific or hormone-dependent fashion; in particular, with estrogens. These sex- and hormone-specific effects were consistent across key metabolic tissues: liver, pancreas, hypothalamus, intestine, heart, visceral and subcutaneous adipose tissue. Skeletal muscle estrogen receptor enrichments across metabolic tissues appeared stronger than androgen receptor and, surprisingly, ~3-fold higher in males compared to females. To define the causal roles of estrogen signaling on myokine gene expression and functions, we generated male and female mice which lack estrogen receptor (Esr1) specifically in skeletal muscle and integrated global RNA-Sequencing with human data. These analyses highlighted mechanisms of sex-dependent myokine signaling conserved between species, such as myostatin enriched for divergent substrate utilization pathways between sexes. Several other sex-dependent mechanisms of myokine signaling were uncovered, such as muscle-derived TNF exerting stronger inflammatory signaling in females compared to males and GPX3 as a male-specific link between glycolytic fiber abundance and hepatic inflammation. Collectively, we provide the first genetic survey of human myokines and highlight sex and estrogen receptor signaling as critical variables when assaying myokine functions and how changes in cell composition impact other metabolic organs.

physiology↗

bioRxiv2020

CoffeeProt: An online tool for correlation and functional enrichment of proteome-wide systems genetics

The integration of genomics, proteomics and phenotypic traits across genetically diverse populations is a powerful approach to discover novel biological regulators. The increasing volume of complex data require new and easy-to-use tools accessible to a variety of scientists for the discovery and visualization of functionally relevant associations. To meet this requirement, we developed CoffeeProt, an open-source tool that analyzes genetic variants associated to protein networks and phenotypic traits. CoffeeProt uses proteomics data to perform correlation network analysis and annotates protein-protein interactions and subcellular localizations. It then integrates genetic and phenotypic associations along with variant effect predictions. We demonstrate its utility with the analysis of mouse and human population data enabling the rapid identification of genetic variants associated with protein complexes and clinical traits. We expect CoffeeProt will serve the proteomics and systems genetics communities, leading to the discovery of novel biologically relevant associations. CoffeeProt is available at www.coffeeprot.com.

systems biology↗