Biology subjects

Loudon, A. S. I.

Publications and source records attributed to Loudon, A. S. I..

3 recordsLinked to original sources

bioRxiv2021

HNF4A is required to specify glucocorticoid action in the liver

The glucocorticoid receptor (GR) is a nuclear hormone receptor critical to the regulation of energy metabolism and the inflammatory response. The actions of GR are highly dependent on cell type and environmental context. Here, we demonstrate the necessity for liver lineage-determining factor hepatocyte nuclear factor 4A (HNF4A) in defining liver-specificity of GR action. In normal mouse liver, the HNF4 motif lies adjacent to the glucocorticoid response element (GRE) at GR binding sites found within regions of open chromatin. In the absence of HNF4A, the liver GR cistrome is remodelled, with both loss and gain of GR recruitment evident. Lost sites are characterised by HNF4 motifs and weak GRE motifs. Gained sites are characterised by strong GRE motifs, and typically show GR recruitment in non-liver tissues. The functional importance of these HNF4A-regulated GR sites is further demonstrated by evidence of an altered transcriptional response to glucocorticoid treatment in the Hnf4a-null liver.

molecular biology↗

bioRxiv2020

Adipocyte REVERBα dictates adipose tissue expansion during obesity

The circadian clock component REVERB is considered a dominant regulator of lipid metabolism, with global Reverb deletion driving dysregulation of white adipose tissue (WAT) lipogenesis and obesity. However, a similar phenotype is not observed under adipocyte-selective deletion (ReverbFlox2-6AdipoCre), and transcriptional profiling demonstrates that, under basal conditions, direct targets of REVERB regulation are limited, and include the circadian clock and collagen dynamics. Under high-fat diet (HFD) feeding, ReverbFlox2-6AdipoCre mice do manifest profound obesity, yet without the accompanying WAT inflammation and fibrosis exhibited by controls. Integration of the WAT REVERB cistrome with differential gene expression reveals broad control of metabolic processes by REVERB which is unmasked in the obese state. Adipocyte REVERB does not drive an anticipatory daily rhythm in WAT lipogenesis, but rather modulates WAT activity in response to alterations in metabolic state. Importantly, REVERB action in adipocytes is critical to the development of obesity-related WAT pathology and insulin resistance.

physiology↗

bioRxiv2020

A single nuclei transcriptomic analysis of the Atlantic salmon gill through smoltification and seawater transfer

Anadromous salmonids begin life adapted to the freshwater environments of their natal streams before a developmental transition, known as smoltification, transforms them into marine-adapted fish. In the wild, the extending photoperiods of spring stimulates smoltification, typified by radical reprogramming of the gill from an ion-absorbing organ to ion-excreting organ. Prior work has highlighted the role of specialized "mitochondrion-rich" cells in delivering this phenotype. However, transcriptomic studies identify thousands of smoltification-driven differentially regulated genes, indicating that smoltification causes a multifaceted, multicellular change; but direct evidence of this is lacking. Here, we use single-nuclei RNAseq to characterize the Atlantic salmon gill during smoltification and seawater transfer. We identify 20 distinct clusters of nuclei, including known, but also novel gill cell types. These data allow us to isolate cluster-specific, smoltification-induced changes in gene expression. We also show how cellular make-up of the gill changes through smoltification. As expected, we noted an increase in the proportion of seawater mitochondrion-rich cells, however, we also identify a reduction of several immune-related cells. Overall, our results provide unrivaled detail of the cellular complexity in the gill and suggest that smoltification triggers unexpected immune reprogramming directly preceding seawater entry.

molecular biology↗