PXD020385

PXD020385 is an original dataset announced via ProteomeXchange.

Title	Metabolic control of DNA methylation and imprinted gene expression in naive pluripotent cells
Description	Naive pluripotent epiblast cells of the preimplantation murine embryo and their in vitro counterpart, embryonic stem (ES) cells, have the capacity to give rise to all cells of the adult. Such developmental plasticity is associated with global genome hypomethylation. It is unclear whether genome methylation is dynamically regulated only via differential expression of DNA methyltransferases (DNMTs) and Ten-eleven Translocation (TET) enzymes, which oxidase methylated DNA. Here we show that LIF/Stat3 signalling induces genomic hypomethylation via metabolic reconfiguration. In Stat3-/- ES cells we observed decreased alpha-ketoglutarate (ɑKG) production from reductive Glutamine metabolism, leading to decreased TET activity, increased Dnmt3a/b expression and to a global increase in DNA methylation. Notably, genome methylation is dynamically controlled by simply modulating αKG availability, mitochondrial activity or Stat3 activation in mitochondria, indicating effective crosstalk between metabolism and the epigenome. Stat3-/- ES cells also show increased methylation at Imprinting Control Regions accompanied with differential expression of >50% of imprinted genes. Single-cell transcriptome analysis of Stat3-/- embryos confirmed dysregulated expression of Dnmt3a/b, Tet2, and imprinted genes in vivo. Our results reveal that the LIF/Stat3 signal bridges the metabolic and epigenetic profiles of naive pluripotent cells, ultimately controlling genome methylation and imprinted gene expression. Several imprinted genes regulate cell proliferation and are often misregulated in tumors. Moreover, a wide range of cancers display Stat3-overactivation, raising the possibility that the molecular module we described here is exploited under pathological conditions.
HostingRepository	PRIDE
AnnounceDate	2020-11-26
AnnouncementXML	Submission_2021-02-03_00:33:38.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Graziano Martello
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2020-07-15 07:52:35	ID requested
1	2020-11-26 00:00:46	announced
⏵ 2	2021-02-03 00:33:39	announced	2021-02-03: Updated publication reference for PubMed record(s): 33526924.

Betto RM, Diamante L, Perrera V, Audano M, Rapelli S, Lauria A, Incarnato D, Arboit M, Pedretti S, Rigoni G, Guerineau V, Touboul D, Stirparo GG, Lohoff T, Boroviak T, Grumati P, Soriano ME, Nichols J, Mitro N, Oliviero S, Martello G, Metabolic control of DNA methylation in naive pluripotent cells. Nat Genet, 53(2):215-229(2021) [pubmed]

submitter keyword: ES, DNA methylation, DNMTs, TET

Graziano Martello
contact affiliation	Department of Molecular Medicine, Medical School, University of Padua, Padua 35121, Italy
contact email	graziano.martello@unipd.it
lab head
Graziano Martello
contact affiliation	Department of Molecular Medicine, Medical School, University of Padua, Padua 35121, Italy.
contact email	graziano.martello@unipd.it
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD020385
     1. Label: PRIDE project
     2. Name: Metabolic control of DNA methylation and imprinted gene expression in naive pluripotent cells