Research interest:

In the Western world, the excess of food intake is the leading cause of metabolic disorders, such as obesity, type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). Several dietary interventions, including caloric restriction and intermittent fasting, have shown beneficial effects on patients’ metabolic profiles, ultimately improving health- and life- span. The metabolic adaptation occurring in 
disease development and regression is characterized by profound changes in gene expression. The transcriptional control of the metabolic homeostasis is primarily mediated by Nuclear Receptors (NR), a group of transcription factors that act as genomic switches, by directly responding to dietary lipids, hormones, and other intracellular signals. Once activated, NRs bind to specific chromatin loci 
(promoters&enhancers), recruit coregulator complexes, and regulate gene expression through mechanisms that largely depend on the epigenome editing. The p300 acetyltransferase is known to mark all active enhancers and to co-localize with several NRs. By modulating histone acetylation at genomic loci involved in the transcriptional activation of genes belonging to lipid, carbohydrate, and 
amino acid metabolism, the genome-wide map of the p300 complex is a valuable resource to track chromatin dynamics during metabolic disease progression and its regression after dietary intervention. 

Project Title:

Epigenetic and nutritional control of gene networks in hepatic metabolism.  

Project description:

Mammals have evolved to cope with fluctuations in food availability, from excess to deficit of caloric intake. Diet is able to reprogram the epigenome by affecting enhancers’ accessibility and protein composition. The liver as the central organ regulating detoxification, carbohydrate, fat and amino acid metabolism is particularly affected by dietary conditions. To understand how nutritional challenges affect chromatin dynamics and consequently gene expression we aim to identify hepatic-specific loci by tracking the genomic occupancy of the p300 complex. To that end we will use a transgenic mouse line containing an endogenously tagged p300 allele. We will apply Next Generation Sequencing techniques (ChIP- and RNA-seq) to map the ‘diet-sensitive’ enhancers and corresponding target genes. Moreover, taking advantage of the tagged p300 protein, we will be able to purify and define the associated transcriptional complexes, 'enhanceosomes', that respond to the different dietary regimens by proteomics (ChIP-mass spectrometry) analysis. Our integrated approach will uncover diet-specific protein-DNA and protein-protein interactions, and provide new insights on relevant transcriptional pathways. Functional studies will further validate selected target genes either in vivo or in vitro, via reporter assays, siRNA knockdowns/viral-mediated overexpression and, when possible, by use of selective agonists/antagonists. Human translational 
value will be added thanks to the collaboration with the Alberta Diabetes Institute. We expect this project to reveal critical, new information about nutritional responses, and will help to develop new strategies for treating metabolic dysfunctions. 

Publications: 

Cistromic Reprogramming of the Diurnal Glucocorticoid Hormone Response by High-Fat Diet. Quagliarini F, Mir AA, Balazs K, Wierer M, Dyar KA, Jouffe C, Makris K, Hawe J, Heinig M, Filipp FV, Barish GD, Uhlenhaut NH. Mol Cell. 2019 Nov 21;76(4):531-545.e5.

E47 modulates hepatic glucocorticoid action. Hemmer MC, Wierer M, Schachtrup K, Downes M, Hübner N, Evans RM, Uhlenhaut NH. Nat Commun. 2019 Jan 18;10(1):306. doi: 10.1038/s41467-018-08196-5. PMID: 30659202; PMCID: PMC6338785.