Emerging Functional Connections Between Metabolism and Epigenetic Remodeling in Neural Differentiation

Abstract

Stem cells possess extraordinary capacities for self-renewal and differentiation, making them highly valuable in regenerative medicine. Among these, neural stem cells (NSCs) play a fundamental role in neural development and repair processes. NSC characteristics and fate are intricately regulated by the microenvironment and intracellular signaling. Interestingly, metabolism plays a pivotal role in orchestrating the epigenome dynamics during neural differentiation, facilitating the transition from undifferentiated NSC to specialized neuronal and glial cell types. This intricate interplay between metabolism and the epigenome is essential for precisely regulating gene expression patterns and ensuring proper neural development. This review highlights the mechanisms behind metabolic regulation of NSC fate and their connections with epigenetic regulation to shape transcriptional programs of stemness and neural differentiation. A comprehensive understanding of these molecular gears appears fundamental for translational applications in regenerative medicine and personalized therapies for neurological conditions.

Keywords: Chromatin; Energy metabolism; Epigenetics; Neural stem cells; Neurogenesis; Transcriptional regulation.

Fig. 1

A Metabolism in neural stem and progenitor cells (NS/PC). In a hypoxic niche, neural stem cells (NSCs) maintain a quiescent state and predominantly rely on anaerobic glycolysis for energy production. These cells actively regulate reactive oxygen species (ROS) levels and exhibit immature or non-functional mitochondria. Neural progenitors (NPCs) utilize distinct metabolic pathways, including the pentose phosphate pathway and the folate 1C cycle, to support their proliferation. Furthermore, NPCs facilitate the synthesis of phospholipid membranes in collaboration with cholesterol biosynthesis, accompanied by elevated levels of lipid droplets essential for sustaining stem cell properties. B Metabolism of terminally differentiated neural cells. A notable metabolic reprogramming is evident, characterized by increased activity of glycolytic enzymes, such as hexokinase 1 and pyruvate kinase isoform 1, alongside reduced expression of hexokinase 2 and lactate dehydrogenase A. Simultaneously, pyruvate undergoes efficient conversion to acetyl-CoA for entry into the TCA cycle, where oxidative phosphorylation becomes the primary source of ATP. The upregulation of mitochondrial biogenesis, orchestrated by PGC-1α/ERRα, further accentuates this shift. Concurrently, lipid metabolism, encompassing eicosanoids and fatty acid oxidation, assumes a pivotal role in elevating acetyl-CoA levels, fueling the TCA cycle and augmenting NADH and FADH2 production critical for establishing the proton gradient driving ATP synthase. Concomitantly, elevated mitochondrial activity contributes to heightened ROS levels, playing a crucial role in determining cell fate. Abbreviations: glucose 6-phosphate (G6P); fructose 6-phosphate (F6P); fructose 1,6-bisphosphate (FBP); S-adenosilmetionina (SAM); acetyl-CoA (AcCoA); fatty acid (FA), reduced nicotinamide adenine dinucleotide phosphate (NADPH); polyunsaturated fatty acids (PUFAs); peroxisome proliferator-activated receptor gamma (PPARϒ); hypoxia-inducible factor 1(HIF-1); mammalian target of rapamycin complex 1 (mTORC1); pentose phosphate pathway (PPP); reactive oxygen species (ROS); phosphoenolpyruvic acid (PEP); nicotinamide adenine dinucleotide (NAD.⁺); reduced nicotinamide adenine dinucleotide (NADH); reduced flavin adenine dinucleotide (FADH2); fatty acid oxidation (FAO); oxidative phosphorylation (OxPhos); adenosine triphosphate (ATP); tricarboxylic acid cycle (TCA cycle); peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α); estrogen-related receptor alpha (ERRα). Enzymes: hexokinase 1 (HK1); pyruvate kinase isozymes M1 (PKM1); lactate dehydrogenase A (LDHA); pyruvate dehydrogenase (PDH); pyruvate dehydrogenase kinase (PDK), carnitine palmitoyltransferase 1 (CPT1); acetyl-CoA carboxylase (ACC). Parts of the figure were drawn by using pictures from Servier Medical Art by Servier, licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/)

Fig. 2

The interplay between metabolism and the epigenome in neural stem/progenitor cells and terminally differentiated neural cells. A Metabolism plays a crucial role in establishing and maintaining the epigenetic state that underlies the neural stem/progenitor cell phenotype. Enzyme-mediated post-translational modifications of DNA or histones relying on small metabolites as cofactors contribute to this process. Repressive DNA marks, such as 5mC, catalyzed by DNMTs, and histone methylation marks H3K9me3 and H3K27me3, catalyzed by SAM-dependent KMTs, silence pluripotency genes. Conversely, the presence of H3K9ac, catalyzed by acetyl-CoA-dependent HATs, activates certain genes. The maintenance of the multipotent state is favored by FAD-dependent LSD1 and the KDM5A protein. B In terminally differentiated cells, metabolism, particularly oxidative metabolism, promotes an acetyl-CoA pool, which facilitates the activity of HAT, CBP, and p300, leading to an active transcriptional state for differentiation genes. TIGAR inhibits glycolysis, whereas NaBt promotes mitochondrial biogenesis. Multipotent genes are transcriptionally repressed by DNA and histone repressive marks. In addition, the NAD⁺-dependent deacetylase SIRT1 targets H3K9ac, promoting transcriptional repression at specific genes which determine cell fate. Abbreviations: NAD.⁺, nicotinamide adenine dinucleotide; acetyl-CoA, acetyl coenzyme A; SAM, S-adenosylmethionine; SAH, S-adenosyl-L-homocysteine; FAD, flavin adenine dinucleotide; HAT, histone acetyltransferases; DNMTs, DNA methyltransferases; KMT, lysine methyltransferase; LSD1, lysine-specific demethylase 1; 5mC, 5-methylcytosine; Me, methyl group; SIRT1, NAD-dependent deacetylase sirtuin-1; HDAC, histone deacetylases; ACSS2, acetyl-CoA synthetase 2; ACL, ATP-citrate synthase; TIGAR, TP53-inducible glycolysis and apoptosis regulator; NaBt, sodium butyrate; CREB binding protein (CBP); p300, histone acetyltransferase p300; Ac, acetyl group. Parts of the figure were drawn by using pictures from Servier Medical Art by Servier, licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/)