bims-meprid 2022-01-02 papers

Issue of 2022‒01‒02
two papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine

Free Radic Biol Med. 2021 Dec 27. pii: S0891-5849(21)01169-2. [Epub ahead of print]

Mitochondrial superoxide targets energy metabolism to modulate epigenetic regulation of NRF2-mediated transcription.

Sanjit K Dhar, Timothy Scott, Chi Wang, Teresa W M Fan, Daret K St Clair.

Mitochondria are central to the metabolic circuitry that generates superoxide radicals/anions (O2•-) as a by-product of oxygen metabolism. By regulating superoxide levels, manganese superoxide dismutase plays important roles in numerous biochemical and molecular events essential for the survival of aerobic life. In this study, we used MitoParaquat (mPQ) to generate mitochondria-specific O2•- and stable isotope-resolved metabolomics tracing in primary human epidermal keratinocytes to investigate how O2•- generated in mitochondria regulates gene expression. The results reveal that isocitrate is blocked from conversion to α-ketoglutarate and that acetyl-coenzyme A (CoA) accumulates, which is consistent with a reduction in oxygen consumption rate and inactivation of isocitrate dehydrogenase (IDH) activity. Since acetyl-CoA is linked to histone acetylation and gene regulation, we determined the effect of mPQ on histone acetylation. The results demonstrate an increase in histone H3 acetylation at lysines 9 and 14. Suppression of IDH increased histone acetylation, providing a direct link between metabolism and epigenetic alterations. The activity of histone acetyltransferase p300 increased after mPQ treatment, which is consistent with histone acetylation. Importantly, mPQ selectively increased the nuclear levels and activity of the oxidative stress-sensitive nuclear factor erythroid 2-related factor 2. Together, the results establish a new paradigm that recognizes O2•- as an initiator of metabolic reprogramming that activates epigenetic regulation of gene transcription in response to mitochondrial dysfunction.

Keywords: Epigenetics; Metabolism; Mitochondria; Superoxide; TCA cycle; Transcription

DOI: https://doi.org/10.1016/j.freeradbiomed.2021.12.309

Cell Discov. 2021 Dec 28. 7(1): 122

Histone lysine methacrylation is a dynamic post-translational modification regulated by HAT1 and SIRT2.

Kyle Delaney, Minjia Tan, Zhesi Zhu, Jinjun Gao, Lunzhi Dai, Sunjoo Kim, Jun Ding, Maomao He, Levon Halabelian, Lu Yang, Prabakaran Nagarajan, Mark Robert Parthun, Sangkyu Lee, Saadi Khochbin, Yujun George Zheng, Yingming Zhao.

Histone lysine crotonylation is a posttranslational modification with demonstrated functions in transcriptional regulation. Here we report the discovery of a new type of histone posttranslational modification, lysine methacrylation (Kmea), corresponding to a structural isomer of crotonyllysine. We validate the identity of this modification using diverse chemical approaches and further confirm the occurrence of this type of histone mark by pan specific and site-specific anti-methacryllysine antibodies. In total, we identify 27 Kmea modified histone sites in HeLa cells using affinity enrichment with a pan Kmea antibody and mass spectrometry. Subsequent biochemical studies show that histone Kmea is a dynamic mark, which is controlled by HAT1 as a methacryltransferase and SIRT2 as a de-methacrylase. Altogether, these investigations uncover a new type of enzyme-catalyzed histone modification and suggest that methacrylyl-CoA generating metabolism is part of a growing number of epigenome-associated metabolic pathways.

DOI: https://doi.org/10.1038/s41421-021-00344-4