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Altering metabolism to program cell identity via NAD+ dependent deacetylation [ATAC-seq]

ABSTRACT: Cells change their metabolic profiles in response to an underling gene regulatory network, but how can alterations in metabolism encode specific transcriptional instructions? Here we show that forcing metabolic change in embryonic stem cells (ESCs) promotes a developmental identity that better approximates the inner cell mass (ICM) of the mammalian blastocyst in cultures we refer to as enhanced metabolic ESCs (EMESCs). The creation of EMESCs depends on the inhibition of glycolysis and stimulation of oxidative phosphorylation (OXPHOS), that in turns activates NAD+-dependent deacetlylases of the Sirtuin family. The activation of this pathway leads to the deacetylation of histones and key transcription factors leading to a revised ICM-like gene regulatory network. The exploitation of the NAD+/NADH coenzyme normally coupled to elevated OXPHOS to program lineage specific transcription suggests new paradigms for how cells respond to alterations in their environment.

ORGANISM(S): Mus musculus

PROVIDER: GSE173542 | GEO | 2025/04/01

REPOSITORIES: GEO

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Altering metabolism programs cell identity via NAD+ dependent deacetylation

Project description:Cells change their metabolic profiles in response to an underling gene regulatory network, but how can alterations in metabolism encode specific transcriptional instructions? Here we show that forcing metabolic change in embryonic stem cells (ESCs) promotes a developmental identity that better approximates the inner cell mass (ICM) of the mammalian blastocyst in cultures we refer to as enhanced metabolic ESCs (EMESCs). The creation of EMESCs depends on the inhibition of glycolysis and stimulation of oxidative phosphorylation (OXPHOS), that in turns activates NAD+-dependent deacetlylases of the Sirtuin family. The activation of this pathway leads to the deacetylation of histones and key transcription factors leading to a revised ICM-like gene regulatory network. The exploitation of the NAD+/NADH coenzyme normally coupled to elevated OXPHOS to program lineage specific transcription suggests new paradigms for how cells respond to alterations in their environment.

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Project description:Cells change their metabolic profiles in response to underlying gene regulatory networks, but how can alterations in metabolism encode specific transcriptional instructions? Here, we show that forcing a metabolic change in embryonic stem cells (ESCs) promotes a developmental identity that better approximates the inner cell mass (ICM) of the early mammalian blastocyst in cultures we refer to as enhanced metabolic ESCs (EMESCs). The creation of EMESCs depends on inhibition of glycolysis and stimulation of oxidative phosphorylation (OXPHOS), that in turns activates NAD+-dependent deacetylases of the Sirtuin family, resulting in the deacetylation of histones and key transcription factors to focus enhancer activity while reducing transcriptional noise, that result in a robust enhanced ESC phenotype. This exploitation of a NAD+/NADH coenzyme coupled to OXPHOS as a means of programming lineage specific transcription suggests new paradigms for how cells respond to alterations in their environment, and implies cellular rejuvenation exploits enzymatic activities to for simultaneous activation of a discrete enhancer set alongside silencing genome-wide transcriptional noise.

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Project description:cell activation demands a significant boost in NAD+ levels, often outpacing the capacity of oxidative phosphorylation (OXPHOS). To explore how T cells manage this metabolic stress, we created T cell-specific ADP/ATP translocase-2 knockout (Ant2-/-) mice. Ant2, which is vital for ADP/ATP exchange between the mitochondria and cytoplasm, when deleted, disrupts OXPHOS by limiting ATP synthase function and blocking NAD+ replenishment. Surprisingly, Ant2-/- naïve T cells show increased activation, proliferation, and effector functions compared to wild-type T cells. Through metabolic profiling, we find these cells adopt a metabolic state similar to that of activated T cells, with heightened mitochondrial biogenesis and anabolic processes. Inhibiting ANT pharmacologically in wild-type T cells mirrors the Ant2-/- phenotype and enhances the effectiveness of adoptive T cell therapies in cancer treatment. These results suggest that Ant2-deficient T cells bypass the usual metabolic shifts necessary for activation, leading to greater T cell function and highlighting ANT inhibition as a potential therapeutic strategy for modulating immune responses.

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Continuous suppression of Mek1/2 impairs the developmental potential of mouse embryonic stem cells (H2A.X pattern)

Project description:Simultaneous inhibition of Gsk3α/β and Mek1/2 signaling in the presence of LIF (2i/L) induces a naïve state in mouse embryonic stem cells (ESCs) that resembles the inner cell mass (ICM) of the pre-implantation embryo. Since the ICM exists only transiently in vivo, it remains unclear how continuous propagation of naïve ESCs in vitro affects their stability and functionality. Here, we show that extended culture of male ESCs in 2i/L results in the progressive erosion of genomic imprints, loss of H2A.X binding, and accumulation of chromosomal aberrations. Consistent with these observations, we find that ESCs propagated in 2i/L have an impaired developmental potential. Mechanistically, we demonstrate that Mek1/2 inhibition is predominantly responsible for these effects, in part through downregulation of DNA methyltransferases. We further provide evidence that female ESCs cultured in conventional serum/LIF media phenocopy male ESCs cultured in 2i/L, including the aforementioned epigenetic and developmental abnormalities. Finally, we show that replacement of the Mek1/2 inhibitor with a Src inhibitor preserves the epigenetic and genomic integrity as well as developmental potential of ESCs. Taken together, our data suggest that, while suppression of Mek1/2 in ESCs maintains an ICM-like epigenetic state, continuous suppression results in irreversible changes that compromise their developmental potential.

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Extended suppression of Mek1/2 impairs the developmental potential of mouse embryonic stem cells

Project description:Simultaneous inhibition of Gsk3α/β and Mek1/2 activity in the presence of LIF (2i/L) induces a naïve state in mouse embryonic stem cells (ESCs) that resembles the inner cell mass (ICM) of the pre-implantation embryo. Since the ICM exists only transiently in vivo, it remains unclear how extended propagation of naïve ESCs in vitro affects their stability and functionality. Here we show that extended culture of male ESCs in 2i/L results in the progressive erosion of genomic imprints, loss of H2A.X binding, and accumulation of chromosomal aberrations. Consistent with these observations, we find that the developmental potential of ESCs cultured in 2i/L is impaired. Mechanistically, we demonstrate that Mek1/2 inhibition is predominantly responsible for these effects, in part through downregulation of DNA methyltransferases. Additionally, we demonstrate that female ESCs cultured in conventional serum/LIF media phenocopy male ESCs cultured in 2i/L, including the aforementioned epigenetic and developmental abnormalities. Finally, we show that replacement of the Mek1/2 inhibitor with a Src inhibitor preserves the epigenetic and genomic integrity as well as developmental potential of ESCs. Taken together, our data suggest that, while short-term suppression of Mek1/2 in ESCs maintains an ICM-like epigenetic state, prolonged suppression results in irreversible changes that compromise their developmental potential.

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