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Genomic regulatory regions such as enhancers and silencers serve as key docking sites for transcription factors and coregulators. Their coordinated interactions drive chromatin remodeling and shape the epigenetic landscape that controls gene expression. Disruption of these processes can lead to aberrant gene regulation and disease, for example through mutations in regulatory elements that impair transcription factor binding or altered expression of critical transcription factors and coregulators that rewires transcriptional networks. The Fan lab investigates these mechanisms in the context of metabolic disorders such as type 2 diabetes (T2D), metabolic dysfunction–associated steatotic liver disease (MASLD) and cardiovascular diseases (CVD).
Sex-dimorphic metabolic regulation by sex chromosome-linked epigenetic enzymes. Males and females show distinct susceptibilities to metabolic disorders. Beyond sex hormones, sex chromosomes encode epigenetic enzymes with important regulatory functions, some of which escape X-chromosome inactivation and are therefore expressed at higher levels in females. We identified the X-linked histone demethylase KDM6A as a female-specific regulator of liver cholesterol metabolism. KDM6A is recruited by HNF4A to cholesterol metabolic gene loci, where it establishes an active chromatin state that enables CREBH binding and gene activation. Hepatic loss of KDM6A disrupts bile acid biosynthesis and excretion, leading to cholesterol accumulation, elevated circulating low-density lipoprotein cholesterol, and increased atherosclerosis risk. These findings define a chromatin-based mechanism underlying sex differences in hepatic cholesterol metabolism and cardiometabolic disease risk.
Enhancer and silencer remodelling coordinates macrophage inflammatory response. Using CRISPR KO in the macrophages, along with epigenetic profiling techniques such as ChIP-seq, CUT&Tag and 3C, we identified an enhancer and a silencer at the Ccl2 gene loci in the macrophages. We show that although the enhancer and silencer share very similar epigenetic features, they function differently upon macrophage activation. The silencer releases while enhancer attaches to the promoter to coordinate the transcriptional elevation. It is unclear what the transcription factors involved in this process are, but both enhancer and silencer are bound by similar coactivators, corepressors, mediators, etc. The enhancer appears to be the major docking sites for transcription factors because removal of this region leads to total abrogation of transcription factor binding in both promoter and the silencer. We also observed a much higher transcription activity at the enhancer region with higher eRNA, which facilitates the enhancer/promoter loop formation and is required for the mRNA transcription. We therefore identified a transcription mechanism coordinated by both enhancers and silencers. This study opens up many questions for further investigation. I.e. How to differentiate the functionality of enhancers and silencers and how to identify them from the genome of different tissues.
Corepressor-mediated epigenetic silencing mechanisms in metabolic disorders (Nat Med 2016, FASEB J 2018, Nat Com 2019, Nucleic Acids Res 2023). We have identified the transcriptional corepressor G-protein suppressor 2 (GPS2) as being downregulated in circulating monocytes and adipose tissue macrophages from patients with T2D. In these cells, GPS2 cooperates with transcription factors such as c-JUN and epigenetic enzymes such as HDAC3 and KDM1A to coordinate the pro- and anti-inflammatory gene programs, thereby modulating tissue inflammation and development of T2D. In contrast, in hepatocytes GPS2 interacts with PPARα to inhibit fatty acid oxidation, promoting hepatic lipid accumulation and contributing to MASLD development. Together, these findings illustrate how context-dependent interactions between transcription factors and coregulators orchestrate tissue-specific metabolic and inflammatory responses.
We gratefully acknowledge the generous support of several funding agencies. Their contributions are fundamental to our research operations, allowing us the freedom to pursue innovative scientific inquiries.
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