bims-meprid 2022-06-19 papers

bims-meprid

Biomed News

on Metabolic-dependent epigenetic reprogramming in differentiation and disease

Issue of 2022–06–19
eight papers selected by
Alessandro Carrer, Veneto Institute of Molecular Medicine

Placental sex-dependent spermine synthesis regulates trophoblast gene expression through acetyl-coA metabolism and histone acetylation.
LPS stimulation stabilizes HIF-1α by enhancing HIF-1α acetylation via the PARP1-SIRT1 and ACLY-Tip60 pathways in macrophages.
Hypoxia regulates fibrosis-related genes via histone lactylation in the placentas of patients with preeclampsia.
Fumarate suppresses B-cell activation and function through direct inactivation of LYN.
Glutamate regulates gliosis of BMSCs to promote ENS regeneration through α-KG and H3K9/H3K27 demethylation.
Histone methyltransferase Dot1L recruits O-GlcNAc transferase to target chromatin sites to regulate histone O-GlcNAcylation.
A multi-omics analysis reveals that the lysine deacetylase ABHD14B influences glucose metabolism in mammals.
Global O-GlcNAcylation changes impact desmin phosphorylation and its partition toward cytoskeleton in C2C12 skeletal muscle cells differentiated into myotubes.

Commun Biol. 2022 Jun 15. 5(1): 586

Placental sex-dependent spermine synthesis regulates trophoblast gene expression through acetyl-coA metabolism and histone acetylation.

Irving L M H Aye, Sungsam Gong, Giulia Avellino, Roberta Barbagallo, Francesca Gaccioli, Benjamin J Jenkins, Albert Koulman, Andrew J Murray, D Stephen Charnock-Jones, Gordon C S Smith.

Placental function and dysfunction differ by sex but the mechanisms are unknown. Here we show that sex differences in polyamine metabolism are associated with escape from X chromosome inactivation of the gene encoding spermine synthase (SMS). Female placental trophoblasts demonstrate biallelic SMS expression, associated with increased SMS mRNA and enzyme activity. Polyamine depletion in primary trophoblasts reduced glycolysis and oxidative phosphorylation resulting in decreased acetyl-coA availability and global histone hypoacetylation in a sex-dependent manner. Chromatin-immunoprecipitation sequencing and RNA-sequencing identifies progesterone biosynthesis as a target of polyamine regulated gene expression, and polyamine depletion reduced progesterone release in male trophoblasts. The effects of polyamine depletion can be attributed to spermine as SMS-silencing recapitulated the effects on energy metabolism, histone acetylation, and progesterone release. In summary, spermine metabolism alters trophoblast gene expression through acetyl-coA biosynthesis and histone acetylation, and SMS escape from X inactivation explains some features of human placental sex differences.

DOI: https://doi.org/10.1038/s42003-022-03530-6
FASEB J. 2022 Jul;36(7): e22418

LPS stimulation stabilizes HIF-1α by enhancing HIF-1α acetylation via the PARP1-SIRT1 and ACLY-Tip60 pathways in macrophages.

Qiang Chen, Kun Cui, Zengqi Zhao, Xiang Xu, Yongtao Liu, Yanan Shen, Fan Chen, Kangsen Mai, Qinghui Ai.

  Hypoxia and inflammatory mediators stabilize hypoxia-inducible factor (HIF)-1α through posttranslational modifications, such as phosphorylation and succinylation. Here, we identified sirtuin 1 (SIRT1) and 60 kDa Tat-interactive protein (Tip60)-mediated acetylation as another critical posttranslational modification that regulates HIF-1α protein stability under lipopolysaccharide (LPS) stimulation. Mechanistically, DNA damage induced by excessive reactive oxygen species (ROS) activated poly (ADP-ribose) polymerase 1 (PARP1) to consume oxidized nicotinamide adenine dinucleotide (NAD+ ). Correspondingly, SIRT1 activity was decreased with the decline in NAD+ levels, resulting in increased HIF-1α acetylation. LPS also activated the ATP-citrate lyase (ACLY)-Tip60 pathway to further enhance HIF-1α acetylation. Acetylation contributed to HIF-1α stability and exacerbated LPS-induced inflammation. Thus, inhibiting HIF-1α stability by decreasing its acetylation could partly alleviate LPS-induced inflammation. In conclusion, we revealed the mechanism by which LPS stabilized HIF-1α by increasing its acetylation via the PARP1-SIRT1 and ACLY-Tip60 pathways in fish macrophages. This study may provide novel insights for manipulation of HIF-1α acetylation as a therapeutic strategy against inflammation from the perspective of acetylation in vertebrates.

Keywords:  HIF-1α; LPS; NAD+; ROS; acetylation

DOI:  https://doi.org/10.1096/fj.202200256R
J Hypertens. 2022 Jun 01. 40(6): 1189-1198

Hypoxia regulates fibrosis-related genes via histone lactylation in the placentas of patients with preeclampsia.

Xiang Li, Nana Yang, Yue Wu, Xuegu Wang, Junpei Sun, Lei Liu, Feng Zhang, Yingying Gong, Yan Zhang, Xueting Li, Danli Du, Biao Ding.

BACKGROUND: Histone lactylation, a novel epigenetic modification induced by hypoxia and lactate, plays an important role in regulating gene expression. However, the role of histone lactylation in the pathogenesis of preeclampsia remains unknown.
METHODS: Placentas from preeclamptic patients and control pregnant women were collected for protein immunoassay to detect the expression level of histone lactylation, and two trophoblast cell lines were used to simulate the effect of histone lactylation on genes.
RESULTS: We found that lactate and histone lactylation levels were increased in preeclamptic placentas. In vitro, hypoxia was demonstrated to induce histone lactylation by promoting the production of lactate in human-trophoblast-derived cell line (HTR-8/SVneo) and human first-trimester extravillous trophoblast cell line (TEV-1) cells. In addition, 152 genes were found to be upregulated by both hypoxia exposure and sodium l-lactate treatment in HTR-8/SVneo cells. These genes were mainly enriched in the pathways including the response to hypoxia, cell migration and focal adhesion. Among the 152 genes, nine were upregulated in preeclamptic placentas. Most noteworthy, two upregulated fibrosis-related genes, FN1 and SERPINE1, were promoted by hypoxia through histone lactylation mediated by the production of lactate.
CONCLUSIONS: The present study demonstrated the elevated levels of histone lactylation in preeclamptic placentas and identified fibrosis-related genes that were promoted by histone lactylation induced by hypoxia in trophoblast cells, which provides novel insights into the mechanism of placental dysfunction in preeclampsia.

DOI: https://doi.org/10.1097/HJH.0000000000003129
Nat Chem Biol. 2022 Jun 16.

Fumarate suppresses B-cell activation and function through direct inactivation of LYN.

Jie Cheng, Ying Liu, Jinxin Yan, Lina Zhao, Yinglin Zhou, Xuyang Shen, Yunan Chen, Yining Chen, Xianbin Meng, Xinxiang Zhang, Peng Jiang.

Activated B cells increase central carbon metabolism to fulfill their bioenergetic demands, yet the mechanistic basis for this, as well as metabolic regulation in B cells, remains largely unknown. Here, we demonstrate that B-cell activation reprograms the tricarboxylic acid cycle and boosts the expression of fumarate hydratase (FH), leading to decreased cellular fumarate abundance. Fumarate accumulation by FH inhibition or dimethyl-fumarate treatment suppresses B-cell activation, proliferation and antibody production. Mechanistically, fumarate is a covalent inhibitor of tyrosine kinase LYN, a key component of the BCR signaling pathway. Fumarate can directly succinate LYN at C381 and abrogate LYN activity, resulting in a block to B-cell activation and function in vitro and in vivo. Therefore, our findings uncover a previously unappreciated metabolic regulation of B cells, and reveal LYN is a natural sensor of fumarate, connecting cellular metabolism to B-cell antigen receptor signaling.

DOI: https://doi.org/10.1038/s41589-022-01052-0
Stem Cell Res Ther. 2022 Jun 17. 13(1): 255

Glutamate regulates gliosis of BMSCs to promote ENS regeneration through α-KG and H3K9/H3K27 demethylation.

Mengke Fan, Huiying Shi, Hailing Yao, Weijun Wang, Yurui Zhang, Chen Jiang, Rong Lin.

   BACKGROUND: There is a lack of effective therapies for enteric nervous system (ENS) injury. Our previous study showed that transplanted bone marrow-derived mesenchymal stem cells (BMSCs) play a "glia-like cells" role in initiating ENS regeneration in denervated mice. Cellular energy metabolism is an important factor in maintaining the biological characteristics of stem cells. However, how cellular energy metabolism regulates the fate of BMSCs in the ENS-injured microenvironment is unclear.
METHODS: The biological characteristics, energy metabolism, and histone methylation levels of BMSCs following ENS injury were determined. Then, glutamate dehydrogenase 1 (Glud1) which catalyzes the oxidative deamination of glutamate to α-KG was overexpressed (OE) in BMSCs. Further, OE-Glud1 BMSCs were targeted-transplanted into the ENS injury site of denervated mice to determine their effects on ENS regeneration.
RESULTS: In vitro, in the ENS-injured high-glutamate microenvironment, the ratio of α-ketoglutarate (α-KG) to succinate (P < 0.05), the histone demethylation level (P < 0.05), the protein expression of glial cell markers (P < 0.05), and the gene expression of Glud1 (P < 0.05) were significantly increased. And the binding of H3K9me3 to the GFAP, S100B, and GDNF promoter was enhanced (P < 0.05). Moreover, α-KG treatment increased the monomethylation and decreased the trimethylation on H3K9 (P < 0.01) and H3K27 (P < 0.05) in BMSCs and significantly upregulated the protein expression of glial cell markers (P < 0.01), which was reversed by the α-KG competitive inhibitor D-2-hydroxyglutarate (P < 0.05). Besides, overexpression of Glud1 in BMSCs exhibited increases in monomethylation and decreases in trimethylation on H3K9 (P < 0.05) and H3K27 (P < 0.05), and upregulated protein expression of glial cell markers (P < 0.01). In vivo, BMSCs overexpressing Glud1 had a strong promotion effect on ENS regeneration in denervated mice through H3K9/H3K27 demethylation (P < 0.05), and upregulating the expression of glial cell protein (P < 0.05).
CONCLUSIONS: BMSCs overexpressing Glud1 promote the expression of glial cell markers and ENS remodeling in denervated mice through regulating intracellular α-KG and H3K9/H3K27 demethylation.

Keywords:  Bone marrow-derived mesenchymal stem cells (BMSCs); Glud1 (glutamate dehydrogenase 1); Histone methylation; α-ketoglutarate (α-KG)

DOI:  https://doi.org/10.1186/s13287-022-02936-7
J Biol Chem. 2022 Jun 08. pii: S0021-9258(22)00556-7. [Epub ahead of print] 102115

Histone methyltransferase Dot1L recruits O-GlcNAc transferase to target chromatin sites to regulate histone O-GlcNAcylation.

Bo Xu, Can Zhang, Ao Jiang, Xianhong Zhang, Fenfei Liang, Xueqing Wang, Danni Li, Chenglong Liu, Xiaomei Liu, Jing Xia, Yang Li, Yirong Wang, Zelan Yang, Jia Chen, Yu Zhou, Liang Chen, Hui Sun.

  O-GlcNAc transferase (OGT) is the distinctive enzyme responsible for catalyzing O-GlcNAc addition to the serine or threonine residues of thousands of cytoplasmic and nuclear proteins involved in such basic cellular processes as DNA damage repair, RNA splicing, and transcription preinitiation and initiation complex assembly. However, the molecular mechanism by which OGT regulates gene transcription remains elusive. Using proximity labeling-based mass spectrometry, here we searched for functional partners of OGT and identified interacting protein Dot1L, a conserved and unique histone methyltransferase known to mediate histone H3 Lys79 methylation, which is required for gene transcription, DNA damage repair, cell proliferation, and embryo development. Although this specific interaction with OGT does not regulate the enzymatic activity of Dot1L, we show that it does facilitate OGT-dependent histone O-GlcNAcylation. Moreover, we demonstrate that OGT associates with Dot1L at transcription start sites, and that depleting Dot1L decreases OGT associated with chromatin globally. Notably, we also show that downregulation of Dot1L reduces the levels of histone H2B S112 O-GlcNAcylation and histone H2B K120 ubiquitination in vivo, which are associated with gene transcription regulation. Taken together, these results reveal that O-GlcNAcylation of chromatin is dependent on Dot1L.

Keywords:  Chromatin; Dot1L; O-GlcNAcylation; OGT; histone

DOI:  https://doi.org/10.1016/j.jbc.2022.102115
J Biol Chem. 2022 Jun 11. pii: S0021-9258(22)00569-5. [Epub ahead of print] 102128

A multi-omics analysis reveals that the lysine deacetylase ABHD14B influences glucose metabolism in mammals.

Abinaya Rajendran, Amarendranath Soory, Neha Khandelwal, Girish Ratnaparkhi, Siddhesh S Kamat.

  The sirtuins and histone deacetylases are the best characterized members of the lysine deacetylase (KDAC) enzyme family. Recently, we annotated the "orphan" enzyme ABHD14B (α/β-hydrolase domain containing protein # 14B) as a novel KDAC, showed this enzyme's ability to transfer an acetyl-group from protein lysine residue(s) to coenzyme-A (CoA) to yield acetyl-CoA, expanding the repertoire of this enzyme family. However, the role of ABHD14B in metabolic processes is not fully elucidated. Here, we investigated the role of this enzyme using mammalian cell knockdowns in a combined transcriptomics, and metabolomics analysis. We found from these complementary experiments in vivo, that the loss of ABHD14B results in significantly altered glucose metabolism, specifically the decreased flux of glucose through glycolysis and the citric acid cycle. Further, we show that depleting hepatic ABHD14B in mice, also results in defective systemic glucose metabolism, particularly during fasting. Taken together, our findings illuminate the important metabolic functions that the KDAC ABHD14B plays in mammalian physiology, and poses new questions regarding the role of this hitherto cryptic metabolism-regulating enzyme.

Keywords:  ABHD14B; Glucose Metabolism; Lysine deacetylase; Metabolomics; Transcriptomics

DOI:  https://doi.org/10.1016/j.jbc.2022.102128
Sci Rep. 2022 Jun 14. 12(1): 9831

Global O-GlcNAcylation changes impact desmin phosphorylation and its partition toward cytoskeleton in C2C12 skeletal muscle cells differentiated into myotubes.

Charlotte Claeyssen, Bruno Bastide, Caroline Cieniewski-Bernard.

Desmin is the guardian of striated muscle integrity, permitting the maintenance of muscle shape and the efficiency of contractile activity. It is also a key mediator of cell homeostasis and survival. To ensure the fine regulation of skeletal muscle processes, desmin is regulated by post-translational modifications (PTMs). It is more precisely phosphorylated by several kinases connecting desmin to intracellular processes. Desmin is also modified by O-GlcNAcylation, an atypical glycosylation. However, the functional consequence of O-GlcNAcylation on desmin is still unknown, nor its impact on desmin phosphorylation. In a model of C2C12 myotubes, we modulated the global O-GlcNAcylation level, and we determined whether the expression, the PTMs and the partition of desmin toward insoluble material or cytoskeleton were impacted or not. We have demonstrated in the herein paper that O-GlcNAcylation variations led to changes in desmin behaviour. In particular, our data clearly showed that O-GlcNAcylation increase led to a decrease of phosphorylation level on desmin that seems to involve CamKII correlated to a decrease of its partition toward cytoskeleton. Our data showed that phosphorylation/O-GlcNAcylation interplay is highly complex on desmin, supporting that a PTMs signature could occur on desmin to finely regulate its partition (i.e. distribution) with a spatio-temporal regulation.

DOI: https://doi.org/10.1038/s41598-022-14033-z