bims-meprid 2021-02-07 papers

BMC Dev Biol. 2021 Feb 01. 21(1): 5

Etomoxir regulates the differentiation of male germ cells by specifically reducing H3K27ac level.

BACKGROUND: Fatty acid oxidation plays an important role in a variety of developing and mature organ systems. However, the role of this metabolic pathway in different stages of testis development remains unknown. Here, we elucidate the mechanisms by which fatty acid oxidation regulates the maintenance and differentiation of gonocytes and spermatogonial stem cells.
RESULTS: During E13.5-E15.5, male germ cells gradually enter the mitotic arrest phase, while the expression of CPT1A, a rate-limiting enzyme for fatty acid oxidation, gradually increases. Therefore, we treated pregnant mice (E13.5 to E15.5) with etomoxir, which is an inhibitor of CPT1A. Etomoxir-treated mice showed no difference in embryonic morphology; however, etomoxir-treated male gonocytes exited mitotic arrest, and cells of the gonad underwent apoptosis. In addition, etomoxir-treated mice at P7 displayed impaired homing of spermatogonia and increased cell apoptosis. We further demonstrated that inhibition of fatty acid oxidation in gonads was associated with gonocyte differentiation events and the histone modification H3K27ac.
CONCLUSIONS: Inhibiting fatty acid oxidation can specifically reduce the level of H3K27ac in the reproductive crest, which may be the cause of the down-regulation of male differentiation-specific gene expression, which ultimately leads to the male primordial germ cells exited from mitotic arrest. Our work uncovers metabolic reprogramming during male gonadal development, revealing that it plays an important role in the maintenance of gonocytes in a differentiated and quiescent state during foetal testis development.

Keywords: CPT1A; Differentiation; Etomoxir; Gonocytes; H3K27ac; Primordial germ cells; Proliferation

DOI: https://doi.org/10.1186/s12861-020-00237-x

Proc Natl Acad Sci U S A. 2021 Feb 09. pii: e2016742118. [Epub ahead of print]118(6):

Histone H3Q5 serotonylation stabilizes H3K4 methylation and potentiates its readout.

Shuai Zhao, Kelly N Chuh, Baichao Zhang, Barbara E Dul, Robert E Thompson, Lorna A Farrelly, Xiaohui Liu, Ning Xu, Yi Xue, Robert G Roeder, Ian Maze, Tom W Muir, Haitao Li.

Serotonylation of glutamine 5 on histone H3 (H3Q5ser) was recently identified as a permissive posttranslational modification that coexists with adjacent lysine 4 trimethylation (H3K4me3). While the resulting dual modification, H3K4me3Q5ser, is enriched at regions of active gene expression in serotonergic neurons, the molecular outcome underlying H3K4me3-H3Q5ser crosstalk remains largely unexplored. Herein, we examine the impact of H3Q5ser on the readers, writers, and erasers of H3K4me3. All tested H3K4me3 readers retain binding to the H3K4me3Q5ser dual modification. Of note, the PHD finger of TAF3 favors H3K4me3Q5ser, and this binding preference is dependent on the Q5ser modification regardless of H3K4 methylation states. While the activity of the H3K4 methyltransferase, MLL1, is unaffected by H3Q5ser, the corresponding H3K4me3/2 erasers, KDM5B/C and LSD1, are profoundly inhibited by the presence of the mark. Collectively, this work suggests that adjacent H3Q5ser potentiates H3K4me3 function by either stabilizing H3K4me3 from dynamic turnover or enhancing its physical readout by downstream effectors, thereby potentially providing a mechanism for fine-tuning critical gene expression programs.

Keywords: H3K4me3; H3Q5 serotonylation; designer chromatin; histone modification; modification crosstalk

DOI: https://doi.org/10.1073/pnas.2016742118

Liver Int. 2021 Feb 02.

Maternal High-Fat Diet Disrupted One-Carbon Metabolism in Offspring, contributing to Nonalcoholic Fatty Liver Disease.

Hui Peng, Huiting Xu, Jie Wu, Jiangyuan Li, Yi Zhou, Zehuan Ding, Stefan K Siwko, Xianglin Yuan, Kevin L Schalinske, Gianfranco Alpini, Ke K Zhang, Linglin Xie.

BACKGROUND & AIMS: Pregnant women may transmit their metabolic phenotypes to their offspring, enhancing the risk for nonalcoholic fatty liver disease (NAFLD); however, the molecular mechanisms remain unclear.
METHODS: Prior to pregnancy female mice were fed either a maternal normal-fat diet (NF-group, "no effectors"), or a maternal high-fat diet (HF-group, "persistent effectors"), or were transitioned from a HF to a NF diet before pregnancy (H9N-group, "effectors removal"), followed by pregnancy and lactation, and then offspring were fed high-fat diets after weaning. Offspring livers were analyzed by functional studies, as well as next-generation sequencing for gene expression profiles and DNA methylation changes.
RESULTS: The HF, but not the H9N offspring, displayed glucose intolerance and hepatic steatosis. The HF offspring also displayed a disruption of lipid homeostasis associated with an altered methionine cycle and abnormal one-carbon metabolism that caused DNA hypermethylation and L-carnitine depletion associated with deactivated AMPK signaling and decreased expression of PPAR-α and genes for fatty acid oxidation. These changes were not present in H9N offspring. In addition, we identified maternal HF diet-induced genes involved in one-carbon metabolism that were associated with DNA methylation modifications in HF offspring. Importantly, the DNA methylation modifications and their associated gene expression changes were reversed in H9N offspring livers.
CONCLUSIONS: Our results demonstrate for the first time that maternal HF diet disrupted the methionine cycle and one-carbon metabolism in offspring livers which further altered lipid homeostasis. CpG islands of specific genes involved in one-carbon metabolism modified by different maternal diets were identified.

Keywords: DNA methylation; SAM transferase; fatty acid oxidation; methionine; obesity

DOI: https://doi.org/10.1111/liv.14811