How to tame your genes: mechanisms of inflammatory gene repression by glucocorticoids

FEBS Letters

article

Benjamin A. Strickland¹  Suhail A. Ansari²  Widad Dantoft²  N. Henriette Uhlenhaut¹ 

[1] Metabolic Programming, School of Life Sciences Weihenstephan, ZIEL – Institute for Food and Health, Technische Universitaet Muenchen;Institute for Diabetes and Endocrinology ,(IDE), Helmholtz Center Munich ,(HMGU) and German Center for Diabetes Research

关键词: chromatin;    epigenetic;    gene repression;    glucocorticoid;    glucocorticoid receptor;    inflammation;    macrophage;    phase condensates;    transcription;   

DOI  :  10.1002/1873-3468.14409

来源: John Wiley & Sons Ltd.

【 摘 要 】

Glucocorticoids (GCs) are widely used therapeutic agents to treat a broad range of inflammatory conditions. Their functional effects are elicited by binding to the glucocorticoid receptor (GR), which regulates transcription of distinct gene networks in response to ligand. However, the mechanisms governing various aspects of undesired side effects versus beneficial immunomodulation upon GR activation remain complex and incompletely understood. In this review, we discuss emerging models of inflammatory gene regulation by GR, highlighting GR's regulatory specificity conferred by context-dependent changes in chromatin architecture and transcription factor or co-regulator dynamics. GR controls both gene activation and repression, with the repression mechanism being central to favourable clinical outcomes. We describe current knowledge about 3D genome organisation and its role in spatiotemporal transcriptional control by GR. Looking beyond, we summarise the evidence for dynamics in gene regulation by GR through cooperative convergence of epigenetic modifications, transcription factor crosstalk, molecular condensate formation and chromatin looping. Further characterising these genomic events will reframe our understanding of mechanisms of transcriptional repression by GR.

【 授权许可】

Unknown