2. Academic Validation
  3. Histone phosphorylation integrates the hepatic glucagon-PKA-CREB gluconeogenesis program in response to fasting

Histone phosphorylation integrates the hepatic glucagon-PKA-CREB gluconeogenesis program in response to fasting

  • Mol Cell. 2023 Feb 22;S1097-2765(23)00102-8. doi: 10.1016/j.molcel.2023.02.007.
Yongxu Zhao 1,  Shuang Li 2,  Yanhao Chen 2,  Yuchen Wang 2,  Yuda Wei 3,  Tingting Zhou 2,  Yuwei Zhang 2,  Yuanyuan Yang 2,  Lanlan Chen 2,  Yan Liu 2,  Cheng Hu 4,  Ben Zhou 2,  Qiurong Ding 5
Affiliations

Affiliations

  • 1 CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: [email protected].
  • 2 CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
  • 3 Department of Clinical Laboratory, Linyi People's Hospital, Xuzhou Medical University, Shandong 276000, China.
  • 4 Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
  • 5 CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: [email protected].
PMID: 36863348 DOI: 10.1016/j.molcel.2023.02.007
Abstract

The glucagon-PKA signal is generally believed to control hepatic gluconeogenesis via the CREB transcription factor. Here we uncovered a distinct function of this signal in directly stimulating histone phosphorylation for gluconeogenic gene regulation in mice. In the fasting state, CREB recruited activated PKA to regions near gluconeogenic genes, where PKA phosphorylated histone H3 serine 28 (H3S28ph). H3S28ph, recognized by 14-3-3ζ, promoted recruitment of RNA polymerase II and transcriptional stimulation of gluconeogenic genes. In contrast, in the fed state, more PP2A was found near gluconeogenic genes, which counteracted PKA by dephosphorylating H3S28ph and repressing transcription. Importantly, ectopic expression of phosphomimic H3S28 efficiently restored gluconeogenic gene expression when liver PKA or CREB was depleted. These results together highlight a different functional scheme in regulating gluconeogenesis by the glucagon-PKA-CREB-H3S28ph cascade, in which the hormone signal is transmitted to chromatin for rapid and efficient gluconeogenic gene activation.

Keywords

14-3-3ζ; chromatin remodeling; gene activation; glucagon-PKA-CREB cascade; hepatic gluconeogenesis; histone H3 serine 28; histone phosphorylation; protein phosphatase 2A.

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