Biology subjects

Eeckhoute, J.

Publications and source records attributed to Eeckhoute, J..

3 recordsLinked to original sources

bioRxiv2023

Time-of-day-dependent variation of the hepatic transcriptome and metabolome is disrupted in non-alcoholic fatty liver disease patients

Liver homeostasis is ensured in part by time-of-day-dependent processes, many of them being paced by the molecular circadian clock. Liver functions are compromised in non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), and clock disruption increases susceptibility to non-alcoholic fatty liver disease (NAFLD) progression in rodent models. We therefore investigated whether time-of-day-dependent transcriptome and metabolome are significantly altered in human NAFL and NASH livers. Liver biopsies, collected within an 8 hour- window from a carefully phenotyped cohort of 290 patients and histologically diagnosed to be either normal, NAFL or NASH hepatic tissues, were analyzed by RNA sequencing and unbiased metabolomic approaches. Time-of-day-dependent gene expression patterns and metabolomes were identified and compared between histologically normal, NAFL and NASH livers. We provide here a first-of-its-kind report of a daytime-resolved human liver transcriptome-metabolome and associated alterations in NAFLD. Transcriptomic analysis showed a robustness of core molecular clock components in NAFL and NASH livers. It also revealed stage-specific, time-of-day- dependent alterations of hundreds of transcripts involved in cell-to-cell communication, intra- cellular signaling and metabolism. Similarly, rhythmic amino acid and lipid metabolomes were affected in pathological livers. Both TNFa and PPAR{gamma} signaling are predicted as important contributors to altered rhythmicity. NAFLD progression to NASH perturbs time-of-day-dependent processes in human livers, while core molecular clock component differential expression is maintained.

genomics↗

bioRxiv2023

A time- and space-resolved nuclear receptor atlas in mouse liver

The unique functional versatility of the liver is paramount for organismal homeostasis. Both liver development and adult functions are controlled by tightly regulated transcription factor networks, within which nuclear receptors regulate essential functions of parenchymal and non-parenchymal cells. Acting as transcription factors sensitive to extracellular cues such as steroidal hormones, lipid metabolites, xenobiotics... and modulated by intracellular signaling pathways, nuclear receptors orchestrate many aspects of hepatic physiology. While liver functional zonation and adaptability to fluctuating conditions are known to rely on a sophisticated cellular architecture, a comprehensive knowledge of nuclear receptor functions in the different liver cell types is still lacking. As a first step toward the accurate mapping of nuclear receptor functions in mouse liver, we characterized their levels of expression in whole liver as a function of time and diet, and explored nuclear receptor isoform expression in hepatocytes, cholangiocytes, Kupffer cells, hepatic stellate cells and liver sinusoidal cells. In addition, we leveraged liver single cell RNAseq studies to provide here an up-to-date compendium of nuclear receptor expression in mouse liver in space and time.

molecular biology↗

bioRxiv2022

The HDAC inhibitor trichostatin A impairs pancreatic β-cell function through an epigenome-wide reprogramming

ObjectiveThe pancreatic islets of Langerhans contain distinct cell subtypes including insulin-producing {beta} cells. Although their cell-specific gene expression pattern defines their identity, the underlying molecular network driving this transcriptional specificity is not fully understood. Among the numerous transcriptional regulators, histone deacetylases (HDAC) enzymes are potent chromatin modifiers which directly regulate gene expression through deacetylation of lysine residues within specific histone proteins. The precise molecular mechanisms underlying HDAC effects on cellular plasticity and {beta}-cell identity are currently unknown. MethodsThe pharmacological inhibition of HDAC activity by trichostatin A (TSA) was studied in the mouse Min6 and human EndocBH1 cell lines, as well as primary mouse sorted {beta} cells and human pancreatic islets. The molecular and functional effects of treating these complementary {beta}-cell models with TSA was explored at the epigenomic and transcriptomic level through next-generation sequencing of chromatin immunoprecipitation (ChIP) assays (ChIP-seq) and RNA sequencing (RNA-seq) experiments, respectively. ResultsWe showed that TSA alters insulin secretion associated with {beta}-cell specific transcriptome programming in both mouse and human {beta}-cell lines, as well as on human pancreatic islets. We also demonstrated that this alternative {beta}-cell transcriptional program in response to HDAC inhibition is related to an epigenome-wide remodeling at both promoters and enhancers. ConclusionsTaken together, our data indicate that full HDAC activity is required to safeguard the epigenome, to protect against loss of {beta}-cell identity with unsuitable expression of genes associated with alternative cell fates.

genomics↗