bims-meprid 2022-01-09 papers

Issue of 2022‒01‒09
six papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine

Mol Cell. 2022 Jan 06. pii: S1097-2765(21)01077-7. [Epub ahead of print]82(1): 60-74.e5

Glucose starvation induces a switch in the histone acetylome for activation of gluconeogenic and fat metabolism genes.

Wen-Chuan Hsieh, Benjamin M Sutter, Holly Ruess, Spencer D Barnes, Venkat S Malladi, Benjamin P Tu.

Acetyl-CoA is a key intermediate situated at the intersection of many metabolic pathways. The reliance of histone acetylation on acetyl-CoA enables the coordination of gene expression with metabolic state. Abundant acetyl-CoA has been linked to the activation of genes involved in cell growth or tumorigenesis through histone acetylation. However, the role of histone acetylation in transcription under low levels of acetyl-CoA remains poorly understood. Here, we use a yeast starvation model to observe the dramatic alteration in the global occupancy of histone acetylation following carbon starvation; the location of histone acetylation marks shifts from growth-promoting genes to gluconeogenic and fat metabolism genes. This reallocation is mediated by both the histone deacetylase Rpd3p and the acetyltransferase Gcn5p, a component of the SAGA transcriptional coactivator. Our findings reveal an unexpected switch in the specificity of histone acetylation to promote pathways that generate acetyl-CoA for oxidation when acetyl-CoA is limiting.

Keywords: Gcn5p; Rpd3p; SAGA; acetyl-CoA; environmental stress response; fat metabolism; gluconeogenesis; glucose starvation; histone acetylation; transcription

DOI: https://doi.org/10.1016/j.molcel.2021.12.015

Mol Cell. 2022 Jan 06. pii: S1097-2765(21)01065-0. [Epub ahead of print]82(1): 8-9

Chromatin as a metabolic organelle: Integrating the cellular flow of carbon with gene expression.

Chen Cheng, Siavash K Kurdistani.

Hsieh et al. (2022) reveal that carbon starvation elicits an unexpected compensatory reallocation of histone acetylation to establish an adaptive gene expression program, demonstrating how chromatin may integrate cellular carbon flow via histone acetylation with gene regulation.

DOI: https://doi.org/10.1016/j.molcel.2021.12.003

Leukemia. 2022 Jan 08.

MYC, mitochondrial metabolism and O-GlcNAcylation converge to modulate the activity and subcellular localization of DNA and RNA demethylases.

An-Ping Lin, Zhijun Qiu, Purushoth Ethiraj, Binu Sasi, Carine Jaafar, Dinesh Rakheja, Ricardo C T Aguiar.

Mitochondria can function as signaling organelles, and part of this output leads to epigenetic remodeling. The full extent of this far-reaching interplay remains undefined. Here, we show that MYC transcriptionally activates IDH2 and increases alpha-ketoglutarate (αKG) levels. This regulatory step induces the activity of αKG-dependent DNA hydroxylases and RNA demethylases, thus reducing global DNA and RNA methylation. MYC, in a IDH2-dependent manner, also promotes the nuclear accumulation of TET1-TET2-TET3, FTO and ALKBH5. Notably, this subcellular movement correlated with the ability of MYC, in an IDH2-dependent manner, and, unexpectedly, of αKG to directly induce O-GlcNAcylation. Concordantly, modulation of the activity of OGT and OGA, enzymes that control the cycling of this non-canonical mono-glycosylation, largely recapitulated the effects of the MYC-IDH2-αKG axis on the subcellular movement of DNA and RNA demethylases. Together, we uncovered a hitherto unsuspected crosstalk between MYC, αKG and O-GlcNAcylation which could influence the epigenome and epitranscriptome homeostasis.

DOI: https://doi.org/10.1038/s41375-021-01489-7

Biosci Rep. 2022 Jan 06. pii: BSR20211558. [Epub ahead of print]

Unconventional metabolites in chromatin regulation.

Liubov Gapa, Huda Alfardus, Wolfgang Fischle.

Chromatin, the complex of DNA and histone proteins, serves as a main integrator of cellular signals. Increasing evidence links cellular functional to chromatin state. Indeed, different metabolites are emerging as modulators of chromatin function and structure. Alterations in chromatin state are decisive for regulating all aspects of genome function and ultimately have the potential to produce phenotypic changes. Several metabolites such as acetyl-CoA, S-adenosyl methionine (SAM) or adenosine triphosphate (ATP) have now been well characterized as main substrates or cofactors of chromatin modifying enzymes. However, there are other metabolites that can directly interact with chromatin influencing its state or that modulate the properties of chromatin regulatory factors. Also, there is a growing list of atypical enzymatic and non-enzymatic chromatin modifications that originate from different cellular pathways that have not been in the limelight of chromatin research. Here, we summarize different properties and functions of uncommon regulatory molecules originating from intermediate metabolism of lipids, carbohydrates and amino acids. Based on the various modes of action on chromatin and the plethora of putative, so far not described chromatin regulating metabolites, we propose that there are more links between cellular functional state and chromatin regulation to be discovered. We hypothesize that these connections could provide interesting starting points for interfering with cellular epigenetic states at a molecular level.

Keywords: DNA; chromatin; epigenetcis; histones; metabolites; regulation

DOI: https://doi.org/10.1042/BSR20211558

J Allergy Clin Immunol. 2021 Dec 30. pii: S0091-6749(21)02745-7. [Epub ahead of print]

A mitochondrial STAT3-methionine metabolism axis promotes ILC2-driven allergic lung inflammation.

Liuhui Fu, Jie Zhao, Jiaoyan Huang, Na Li, Xin Dong, Yao He, Wenyan Wang, Yu Wang, Ju Qiu, Xiaohuan Guo.

BACKGROUND: Group 2 innate lymphoid cells (ILC2s), the innate counterpart of T helper 2 cells (Th2), play a critical role in type 2 immune responses. However, the molecular regulatory mechanisms of ILC2s are still unclear.OBJECTIVE: The aim of this study was to explore the importance of signal transducer and activator of transcription 3 (STAT3) to ILC2 function in allergic lung inflammation.
METHODS: Acute and chronic asthma models were established by intranasal administration of the protease allergen papain in VavicreStat3fl/fl, Il5tdtomato-creStat3fl/fl, and RorccreStat3fl/fl mice to verify the necessity of functional STAT3 for ILC2 allergic response. The intrinsic role of STAT3 in regulating ILC2 function was examined by generation of bone marrow chimera mice. The underlying mechanism was studied through confocal imaging, metabolomics analysis, and chromatin immunoprecipitation quantitative PCR.
RESULTS: STAT3 is essential for ILC2 effector function and promotes ILC2-driven allergic inflammation in the lung. Mechanistically, the alarmin cytokine interleukin (IL)-33 induces a non-canonical STAT3 phosphorylation at serine 727 in ILC2s, leading to translocation of STAT3 into the mitochondria. Mitochondrial STAT3 further facilitates adenosine triphosphate synthesis to fuel the methionine cycle and generation of S-adenosylmethionine, which supports the epigenetic reprogramming of type 2 cytokines in ILC2s. STAT3 deficiency, inhibition of STAT3 mitochondrial translocation, or blockade of methionine metabolism markedly dampened the ILC2 allergic response and ameliorated allergic lung inflammation.
CONCLUSION: The mitochondrial STAT3-methionine metabolism pathway is a key regulator that shapes ILC2 effector function through epigenetic regulation, and the related proteins or metabolites represent potential therapeutic targets for allergic lung inflammation.

Keywords: Allergic lung inflammation; Histone methylation; ILC2; Mitochondria; STAT3; methionine metabolism

DOI: https://doi.org/10.1016/j.jaci.2021.12.783

Neuro Oncol. 2022 Jan 05. pii: noac003. [Epub ahead of print]

IDH Mutated Gliomas Promote Epileptogenesis through D-2-Hydroxyglutarate Dependent mTOR Hyperactivation.

Armin Mortazavi, Islam Fayed, Muzna Bachani, Tyrone Dowdy, Jahandar Jahanipour, Anas Khan, Jemima Owotade, Stuart Walbridge, Sara K Inati, Joseph Steiner, Jing Wu, Mark Gilbert, Chun Zhang Yang, Mioara Larion, Dragan Maric, Alexander Ksendzovsky, Kareem A Zaghloul.

BACKGROUND: Uncontrolled seizures in patients with gliomas have a significant impact on quality of life and morbidity, yet the mechanisms through which these tumors cause seizures remain unknown. Here, we hypothesize that the active metabolite D-2-hydroxyglutarate (D-2-HG) produced by the IDH-mutant enzyme leads to metabolic disruptions in surrounding cortical neurons that consequently promote seizures.METHODS: We use a complementary study of in vitro neuron-glial cultures and electrographically sorted human cortical tissue from patients with IDH-mutant gliomas to test this hypothesis. We utilize micro-electrode arrays for in vitro electrophysiological studies in combination with pharmacological manipulations and biochemical studies in order to better elucidate the impact of D-2-HG on cortical metabolism and neuronal spiking activity.
RESULTS: We demonstrate that D-2-HG leads to increased neuronal spiking activity and promotes a distinct metabolic profile in surrounding neurons, evidenced by distinct metabolomic shifts and increased LDHA expression, as well as upregulation of mTOR signaling. The increases in neuronal activity are induced by mTOR activation and reversed with mTOR inhibition.
CONCLUSION: Together, our data suggest that metabolic disruptions in the surrounding cortex due to D-2-HG may be a driving event for epileptogenesis in patients with IDH-mutant gliomas.

Keywords: D-2-HG; IDH mutated gliomas; Tumor related epilepsy; mTOR

DOI: https://doi.org/10.1093/neuonc/noac003