bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2024–10–06
two papers selected by
Alessandro Carrer, Veneto Institute of Molecular Medicine
  1. Cpt1a Drives primed-to-naïve pluripotency transition through lipid remodeling.
  2. Inhibition of O-GlcNAc transferase activates type I interferon-dependent antitumor immunity by bridging cGAS-STING pathway.
  1. Commun Biol. 2024 Sep 30. 7(1): 1223
    Cpt1a Drives primed-to-naïve pluripotency transition through lipid remodeling.
    Zhaoyi Ma, Xingnan Huang, Junqi Kuang, Qiannan Wang, Yue Qin, Tao Huang, Zechuan Liang, Wei Li, Yu Fu, Pengli Li, Yixin Fan, Ziwei Zhai, Xiaomin Wang, Jin Ming, Chengchen Zhao, Bo Wang, Duanqing Pei.
      Metabolism has been implicated in cell fate determination, particularly through epigenetic modifications. Similarly, lipid remodeling also plays a role in regulating cell fate. Here, we present comprehensive lipidomics analysis during BMP4-driven primed to naive pluripotency transition or BiPNT and demonstrate that lipid remodeling plays an essential role. We further identify Cpt1a as a rate-limiting factor in BiPNT, driving lipid remodeling and metabolic reprogramming while simultaneously increasing intracellular acetyl-CoA levels and enhancing H3K27ac at chromatin open sites. Perturbation of BiPNT by histone acetylation inhibitors suppresses lipid remodeling and pluripotency transition. Together, our study suggests that lipid remodeling promotes pluripotency transitions and further regulates cell fate decisions, implicating Cpt1a as a critical regulator between primed-naive cell fate control.
    DOI:  https://doi.org/10.1038/s42003-024-06874-3
  2. Elife. 2024 Oct 04. pii: RP94849. [Epub ahead of print]13
    Inhibition of O-GlcNAc transferase activates type I interferon-dependent antitumor immunity by bridging cGAS-STING pathway.
    Jianwen Chen, Bao Zhao, Hong Dong, Tianliang Li, Xiang Cheng, Wang Gong, Jing Wang, Junran Zhang, Gang Xin, Yanbao Yu, Yu L Lei, Jennifer D Black, Zihai Li, Haitao Wen.
      The O-GlcNAc transferase (OGT) is an essential enzyme that mediates protein O-GlcNAcylation, a unique form of posttranslational modification of many nuclear and cytosolic proteins. Recent studies observed increased OGT and O-GlcNAcylation levels in a broad range of human cancer tissues compared to adjacent normal tissues, indicating a universal effect of OGT in promoting tumorigenesis. Here, we show that OGT is essential for tumor growth in immunocompetent mice by repressing the cyclic GMP-AMP synthase (cGAS)-dependent DNA sensing pathway. We found that deletion of OGT (Ogt-/-) caused a marked reduction in tumor growth in both syngeneic mice tumor models and a genetic mice colorectal cancer (CRC) model induced by mutation of the Apc gene (Apcmin). Pharmacological inhibition or genetic deletion of OGT induced a robust genomic instability (GIN), leading to cGAS-dependent production of the type I interferon (IFN-I) and IFN-stimulated genes (ISGs). As a result, deletion of Cgas or Sting from Ogt-/- cancer cells restored tumor growth, and this correlated with impaired CD8+ T-cell-mediated antitumor immunity. Mechanistically, we found that OGT-dependent cleavage of host cell factor C1 (HCF-1) is required for the avoidance of GIN and IFN-I production in tumors. In summary, our results identify OGT-mediated genomic stability and activate cGAS-STING pathway as an important tumor-cell-intrinsic mechanism to repress antitumor immunity.
    Keywords:  OGT; STING; cGAS; cancer biology; colorectal cancer; immunology; inflammation; mouse; tumor immunity
    DOI:  https://doi.org/10.7554/eLife.94849
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