M6A-eCLIP analysis of mouse BMDM
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE210339 | GEO | 2024/07/01
REPOSITORIES: GEO
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Project description:N6-methyladenosine (m6A) is an abundant modification in eukaryotic mRNA, regulating mRNA dynamics by influencing mRNA stability, splicing, export and translation. Recent studies discovered m6A methyltransferases (?writer?), demethylases (?eraser?) and binding proteins (?reader?), which modulate m6A methylation. However, the precise m6A regulating machinery still remains incompletely understood. Here we demonstrate that ZC3H13, a zinc finger protein, plays an essential role in modulating m6A methylation on polyadenylated RNA in the nucleus. ZC3H13 exists in an evolutionary-conserved macromolecular complex containing WTAP, Virilizer and Hakai. We confirm the interaction among those proteins and demonstrate that knockdown of Zc3h13 in mouse embryonic stem cell (mESC) significantly decreases global m6A level on mRNA, mainly at 3? untranslated regions (3? UTR). Interestingly, fractionation assays show that upon Zc3h13 knockdown a great majority of WTAP, Virilizer and Hakai translocate to the cytoplasm and the nuclear presence of the methyltransferase Mettl3 and Mettl14 also decrease significantly. In contrast, knockdown of WTAP, Virilizer or Hakai does not change the nuclear localization of Zc3h13. This suggests that Zc3h13 is required for nuclear localization of the Zc3h13-WTAP-Virilizer-Hakai complex, which is important for RNA m6A methylation. Finally, Zc3h13 depletion, as does WTAP, Virilizer or Hakai, impairs self-renewal and triggers mESC differentiation. Taken together, our findings demonstrate that Zc3h13 plays an essential role in anchoring WTAP, Virilizer and Hakai in the nucleus to facilitate m6A methylation and to regulate mESC self-renewal.
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Project description:Reyes-Palomares2012 - a combined model hepatic polyamine and sulfur aminoacid metabolism - version2
Mammalian polyamine metabolism consists of a bi-cycle with two required entrances, omithine and S-adenosyl methionine (SAM), and several alternative exists. The relevant regulatory roles of the short half-life enzymes ornithine decarboxylase (ODC), S-adenosyl methione decarboxylase (SAMDC) and spermindine/spermine acetyl transferase (SSAT) in polyamine metabolism are well studied, and has been modelled here.
This model is described in the article:
A combined model of hepatic polyamine and sulfur amino acid metabolism to analyze S-adenosyl methionine availability.
Reyes-Palomares A, Montañez R, Sánchez-Jiménez F, Medina MA
Amino Acids, February 2012, Volume 42, Issue 2-3, pp 597-610
Abstract:
Many molecular details remain to be uncovered concerning the regulation of polyamine metabolism. A previous model of mammalian polyamine metabolism showed that S-adenosyl methionine availability could play a key role in polyamine homeostasis. To get a deeper insight in this prediction, we have built a combined model by integration of the previously published polyamine model and one-carbon and glutathione metabolism model, published by different research groups. The combined model is robust and it is able to achieve physiological steady-state values, as well as to reproduce the predictions of the individual models. Furthermore, a transition between two versions of our model with new regulatory factors added properly simulates the switch in methionine adenosyl transferase isozymes occurring when the liver enters in proliferative conditions. The combined model is useful to support the previous prediction on the role of S-adenosyl methionine availability in polyamine homeostasis. Furthermore, it could be easily adapted to get deeper insights on the connections of polyamines with energy metabolism.
Notes by the author:
This model combines BIOMD0000000190 and BIOMD0000000268 from BioModels Database, both models include corrections respect to their originals publications.
To simulate a MATI/MATIII switch to MATII in proliferating liver:
We set to 0 the Vmax parameters of MATI and MATIII
We included MATII reaction equation.
We add a regulation factor dependent of SAM levels in ODC and SAMDCe rates of synthesis (66.5/[SAM]).
H2O2 was increased in a 50 % according to an initial state ofproliferating and regenerating liver.
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