Metabolism in Pluripotent Stem Cells and Early Mammalian Development

Abstract

Emerging and seminal studies have shown that cell metabolism influences gene expression by modifying the epigenome, which can regulate stem cell pluripotency, differentiation, and somatic cell reprogramming. Core pluripotency factors and developmental regulators reciprocally control the expression of key metabolism genes and their encoded pathways. Recent technological advances enabling sensitive detection methods during early mammalian development revealed the state-specific and context-dependent coordination of signal transduction, histone modifications, and gene expression in developing, resting, and malnourished embryos. Here, we discuss metabolism as a potential driver of earliest cell fate through its influence on the epigenome and gene expression in embryos and their in vitro surrogate pluripotent stem cells.

Lysosomal Signaling Licenses Embryonic Stem Cell Differentiation via Inactivation of Tfe3

“…Blastocyst development and ESC differentiation are associated with shifts in metabolic pathways, but the cause-and-effect relations are mostly unclear (Zhang et al, 2018). Here we show that lysosomal Rag GTPases instruct exit from ESC self-renewal.…”

“…Besides FGF4-elicited mitogen-activated protein kinase signaling and GSK3-dependent disinhibition of the transcriptional repressor Tcf7l1, multiple additional transcriptional and posttranscriptional mechanisms enforce loss of ESC identity (Betschinger, 2017). Among those are metabolic pathways that provide cofactors for chromatin-modifying enzymes and contribute to differentiation-associated epigenetic changes (Zhang et al, 2018). Whether these instruct or permissively facilitate extinction of the ESC state is unclear.…”

Alpha‐ketoglutarate: a “magic” metabolite in early germ cell development

“…Indeed, large knowledge gaps exist for (i) how to assess the contribution of diet to key metabolite levels in both somatic and germ cells, (ii) the responsiveness of epigenetic regulators and cofactors to specific metabolite levels, and (iii) whether metabolite‐influenced epigenome modifications persist and manifest into adulthood and across generations. An impediment to early embryo studies is the paucity of starting materials, with advances in single‐cell methods holding promise to bridge the gap between metabolism, epigenetics, and stem cell fates (Zhang et al , ). Advancing this emerging opportunity in vitro at first, Tischler et al () deploy single‐cell technologies to reveal how targeted metabolic manipulations augment (or potentially retard) dynamic cell state conversions during PCG development.…”

BMAL1 coordinates energy metabolism and differentiation of pluripotent stem cells

“…Collectively, these findings show that BMAL1 is required for proper metabolic dynamics and mitochondrial function of pluripotent ESCs. Taking into account that the balance between glycolysis and OXPHOS is critical for modulating the differentiation potential of pluripotent cells Cliff & Dalton, 2017;Zhang et al, 2018;Dahan et al, 2019), we tested whether reducing OXPHOS activity in Bmal1 KO ESCs could restore the proper expression of lineage specification markers during in vitro differentiation. For this purpose, we used an early differentiation in vitro assay to rapidly induce the expression of genes involved in mesendoderm (ME) lineage choice (Thomson et al, 2011).…”