Publication Date:
2014-12-10
Description:
The role of cellular metabolism in regulating cell proliferation and differentiation remains poorly understood. For example, most mammalian cells cannot proliferate without exogenous glutamine supplementation even though glutamine is a non-essential amino acid. Here we show that mouse embryonic stem (ES) cells grown under conditions that maintain naive pluripotency are capable of proliferation in the absence of exogenous glutamine. Despite this, ES cells consume high levels of exogenous glutamine when the metabolite is available. In comparison to more differentiated cells, naive ES cells utilize both glucose and glutamine catabolism to maintain a high level of intracellular alpha-ketoglutarate (alphaKG). Consequently, naive ES cells exhibit an elevated alphaKG to succinate ratio that promotes histone/DNA demethylation and maintains pluripotency. Direct manipulation of the intracellular alphaKG/succinate ratio is sufficient to regulate multiple chromatin modifications, including H3K27me3 and ten-eleven translocation (Tet)-dependent DNA demethylation, which contribute to the regulation of pluripotency-associated gene expression. In vitro, supplementation with cell-permeable alphaKG directly supports ES-cell self-renewal while cell-permeable succinate promotes differentiation. This work reveals that intracellular alphaKG/succinate levels can contribute to the maintenance of cellular identity and have a mechanistic role in the transcriptional and epigenetic state of stem cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4336218/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4336218/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Carey, Bryce W -- Finley, Lydia W S -- Cross, Justin R -- Allis, C David -- Thompson, Craig B -- P30 CA008748/CA/NCI NIH HHS/ -- R01 CA105463/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Feb 19;518(7539):413-6. doi: 10.1038/nature13981. Epub 2014 Dec 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, New York 10065, USA. ; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25487152" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Cell Differentiation/drug effects
;
Cell Line
;
Cell Membrane Permeability
;
Cell Proliferation
;
Chromatin/drug effects
;
DNA Methylation/drug effects
;
Embryonic Stem Cells/*cytology/drug effects/metabolism
;
Epigenesis, Genetic/drug effects/genetics
;
Glucose/metabolism
;
Glutamic Acid/metabolism
;
Histones/metabolism
;
Intracellular Space/*metabolism
;
Ketoglutaric Acids/*metabolism/pharmacology
;
Methylation
;
Mice
;
Pluripotent Stem Cells/*cytology/drug effects/metabolism
;
Succinic Acid/metabolism/pharmacology
;
Transcription, Genetic/drug effects
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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