Mapping the temporal transcriptional landscape of human white and brown adipogenesis using single-nuclei RNA-seq

Abstract

Adipogenesis is key to maintaining organism-wide energy balance and healthy metabolic phenotype, making it critical to thoroughly comprehend its molecular regulation in humans. By single-nuclei RNA-sequencing (snRNA-seq) of over 20,000 differentiating white and brown preadipocytes, we constructed a high-resolution temporal transcriptional landscape of human white and brown adipogenesis. White and brown preadipocytes were isolated from the neck region of a single individual, thereby eliminating inter-subject variability across two distinct lineages. These preadipocytes were also immortalized to allow for controlled, in vitro differentiation, allowing sampling of distinct cellular states across the spectrum of adipogenic progression. Pseudotemporal cellular ordering revealed the dynamics of ECM remodeling during early adipogenesis, and lipogenic/thermogenic response during late white/brown adipogenesis. Comparison with adipogenic regulation in murine models revealed several targets for potential adipogenic/thermogenic drivers in humans. Key adipogenic and lipogenic markers revealed in our analysis were applied to analyze publicly available scRNA-seq datasets; these confirmed unique cell maturation features in recently discovered murine preadipocytes, and revealed inhibition of adipogenic expansion in humans with obesity. Overall, our study presents a comprehensive molecular description of both white and brown adipogenesis in humans and provides an important resource for future studies of adipose tissue development and function in both health and metabolic disease state.

rs67047829 genotypes of ERV3-1/ZNF117 are associated with lower body mass index in the Polish population

“…The Zinc Finger Protein 117 itself has been suggested to affect subcutaneous obesity and visceral or abdominal-visceral obesity 41 in a study of adipose stem cells and, in a study using preadipocyte single-nuclei RNA sequencing, this was one of the transcription factors found with activity exclusively in brown adipogenesis (and therefore presumably linked to thermogenic response) 42 . Additionally, ZNF117 and ONECUT2 gave the only two transcription factors upregulated in expression-quantitative-trait loci analysis from laser-capture-microdissected pancreatic islet cells from patients with type-2 diabetes 43 .…”

ERV3-1/ZNF117: rs67047829 association with substantial protection against obesity

“…ZNF117 itself has been suggested to affect subcutaneous obesity and visceral or abdominal visceral obesity 41 in a study of adipose stem cells, and in a study using single-nuclei RNA sequencing of white and brown preadipocytes, ZNF117 was one of the transcription factors found with activity exclusively in brown adipogenesis (and therefore presumably linked to the context of thermogenic response). 42…”

A single nuclei atlas of aging human abdominal subcutaneous white adipose tissue

“…The nuclei were split into 5 pseudotemporal bins based on their pseudotime score (<5, 5-10, 10-15, 15-20, >20). Temporally regulated genes were identi ed by performing DGE (logfc > 0.8 & FDR < 0.05) for each bin against the rst and last pseudotemporal bin as previously described 114,115 . Unsupervised hierarchical gene clustering was performed by K-means clustering using R package complex heatmap 116 to identify modules of genes that change throughout the pseudotime.…”