DOT1L Regulates Thermogenic Adipocyte Differentiation and Function via Modulating H3K79 Methylation

Area of Science:

• Epigenetics
• Metabolic Diseases
• Adipocyte Biology

Background:

• Thermogenic adipocytes (brown and beige) are key targets for treating obesity and metabolic dysfunction.
• Epigenetic modifications play crucial roles in regulating adipocyte differentiation and function.

Purpose of the Study:

• To identify novel epigenetic regulators of thermogenic adipocyte differentiation and function.
• To investigate the role of histone H3 lysine 79 (H3K79) methyltransferase, disruptor of telomeric silencing-1 like (DOT1L), in energy homeostasis.

Main Methods:

• Genetic deletion of DOT1L in thermogenic adipocytes in vivo and in primary preadipocytes in vitro.
• Assessment of metabolic parameters including body weight, glucose homeostasis, and hepatic steatosis.
• Analysis of adipogenesis and thermogenesis markers.
• Investigation of H3K79 methylation (H3K79me2) in regulating gene expression.

Main Results:

• Deletion of DOT1L in thermogenic adipocytes conferred significant protection against diet-induced obesity in mice.
• DOT1L deficiency improved glucose homeostasis, alleviated hepatic steatosis, and enhanced adaptive thermogenesis.
• Loss of DOT1L in primary preadipocytes promoted brown and beige adipogenesis and thermogenesis in vitro.
• DOT1L epigenetically regulates the brown adipose tissue gene program via H3K79 methylation, specifically H3K79me2.

Conclusions:

• DOT1L is a critical epigenetic regulator of thermogenic adipocyte differentiation and function.
• Targeting DOT1L presents a potential therapeutic strategy for obesity and associated metabolic diseases.
• DOT1L plays a significant role in maintaining energy homeostasis through its regulation of thermogenic adipocytes.