Abstract:

Lifestyle diseases, such as obesity, diabetes, hypertension, dyslipidemia, and heart and kidney diseases, are complex diseases influenced by both genetic and environmental factors. Epigenetic modifications, including DNA methylation and histone modifications like acetylation and methylation, play a crucial role in long-term adaptation to the environment. Inappropriate epigenetic memory is theorized to contribute to the development and worsening of lifestyle diseases. Research indicates that environmental stress can impact the epigenome.

JMJD1A, a histone demethylase, removes mono- and di-methyl groups from lysine-9 of histone 3, a modification known as H3K9 methylation, which is transcriptionally repressive. JMJD1A is involved in normal body weight control and adaptive thermogenesis, particularly in non-shivering thermogenesis in adipose tissue. Activation of JMJD1A occurs through β-adrenergic receptor signaling triggered by environmental stress such as cold exposure and excess calorie consumption. The phosphorylation of a specific serine residue at amino acid position 265 is crucial for JMJD1A activation.

JMJD1A’s histone demethylation activity is not essential for its role in β-adrenergic-dependent brown adipose tissue (BAT) activation. In this context, JMJD1A facilitates higher-order chromatin structural changes, promoting rapid gene transcription (1).. However, during the process of white adipose tissue (WAT) beiging, where cellular identity changes, JMJD1A’s histone demethylation activity becomes indispensable (2). In response to cold exposure and β-adrenergic stimulation, JMJD1A is phosphorylated at S265 and recruited to enhancer regions of thermogenic genes. It removes the repressive histone modification H3K9me2, enabling the expression of these genes. This two-step process involves signal sensing followed by epigenomic reprogramming (1, 2) (also reviewed in (3-5)).  In this lecture, I will present our studies on environmentally regulated epigenomic reprogramming in adipocytes and discuss a potential strategy to prevent obesity and metabolic disorders based on this machinery.

References：

1. Abe et al., JMJD1A is a signal-sensing scaffold that regulates acute chromatin dynamics via SWI/SNF association for thermogenesis. Nat Commun 6, 7052 (2015).
2. Abe et al., Histone demethylase JMJD1A coordinates acute and chronic adaptation to cold stress via thermogenic phospho-switch. Nat Commun 9, 1566 (2018).
3. Inagaki, J. Sakai, S. Kajimura, Transcriptional and epigenetic control of brown and beige adipose cell fate and function. Nat Rev Mol Cell Biol 17, 480-495 (2016).
4. Matsumura, T. F. Osborne, J. Sakai, Epigenetic and environmental regulation of adipocyte function. Journal of Biochemistry 172, 9-16 (2022).
5. Matsumura, F.-Y. Wei, J. Sakai, Epitranscriptomics in metabolic disease. Nat Metab 5, 370-384 (2023).