Food for thought

doi:10.1126/science.abb4367

GSTDTAP > 气候变化

DOI	10.1126/science.abb4367
	Food for thought
	Gabor Egervari; Karl M. Glastad; Shelley L. Berger
	2020-11-06
发表期刊	Science
出版年	2020
英文摘要	To drive behaviors essential for survival, numerous pathways have evolved that translate environmental stimuli into gene expression. These include interactions between metabolic and epigenetic regulation, which encompass both predictable indirect connections and unanticipated direct contacts ([ 1 ][1]). Indirect pathways involve metabolites generated from diet and other sources that provide substrates and cofactors for epigenetic enzymes to ensure seamless adaption to nutrient availability. In addition, epigenetic mechanisms regulate the expression of metabolic enzymes, which can in turn produce or deplete various metabolites. The direct metabolic-epigenetic interface, however, represents a paradigm shift in our mechanistic understanding of environmental impacts on gene expression and behavior. Direct communication is mediated by metabolic enzymes—classically thought to reside in mitochondria and cytoplasm—localizing within the nucleus and even binding to chromatin. This surprising relocation enables the generation of metabolite pools that can fuel epigenetic enzymes directly. Classic examples of indirect metabolic-epigenetic interactions are the nuclear receptor superfamily, which bind circulating small molecules, such as steroid and thyroid hormones. The binding of their ligands unleashes nuclear receptors to bind to DNA as transcription factors. They subsequently recruit coactivators and corepressors involved in chromatin modulation, resulting in the activation of new transcriptional programs. These mechanisms translate changes in circulating hormones into specific physiological and behavioral outcomes ([ 2 ][2]). An intriguing alternative model proposes that circulating hormones regulate the activity of certain epigenetic enzymes and thereby alter gene expression and behavior. Specifically, estradiol can increase brain masculinization in mice and rats by reducing DNA methyltransferase activity, which prevents or reverses DNA methylation. This results in de-repression of masculinizing genes in sexually dimorphic brain regions during neonatal development ([ 3 ][3]). Of note, pharmacologic or genetic inhibition of DNA methyltransferases recapitulates the effect of gonadal steroids, resulting in masculinized neuronal markers and male sexual behavior in female rats ([ 3 ][3]). Conversely, epigenetic pathways can determine amounts of circulating hormones, leading to persistent developmental and behavioral changes. Relevant model organisms are ants and other social insects—bees, some wasps, and termites—wherein closely related individuals exhibit dramatic differences in morphology and behavior. For example, in addition to the distinction of the female reproductive queen from sterile workers, some ant species have evolved multiple female worker classes. These so-called castes specialize in either foraging or defense behaviors that are vital for the survival of such complex societies. Recent findings indicate that epigenetic-to-metabolic signaling pathways play a critical role in caste determination in carpenter ants ( Camponotus floridanus ). Juvenile hormone (JH) is pivotal to programming foraging, and repressive epigenetic pathways expressed during brain development establish low expression of enzymes that degrade JH to preserve JH in the adult brain ([ 4 ][4]). Transient experimental manipulation of the brain epigenome in early adulthood of the defense caste promotes long-lasting behavioral reprogramming through stable epigenetic repression of the JH-degrading enzymes, switching behavior to foraging ([ 4 ][4]). Thus, the epigenome “encodes” metabolic information either naturally expressed during development or transiently encountered during vulnerable windows in early life, leading to long-term ossification of adaptive behavioral states. Many social insects can drastically alter their behavioral repertoire over their life span to satisfy colony demands. The precise role of metabolic-epigenetic reprogramming in the regulation of these phenomena later in life is currently unknown. Beyond hormonal regulation, intermediary metabolism also influences epigenetic mechanisms. Metabolites serve as substrates and cofactors for epigenetic enzymes, and their availability and concentration can alter gene expression ([ 1 ][1]). Furthermore, provocative recent findings identified previously unknown histone modifications that can be driven by metabolites. These include, for example, the direct incorporation of lactate into chromatin. Lactate covalently binds to several lysine residues on core histone proteins, in a process potentially regulated by histone acetyltransferases, such as p300 ([ 5 ][5]). Histone lactylation is induced by hypoxia and by bacterial infection in human and mouse cells, helping to reestablish homeostatic gene expression ([ 5 ][5]). Further examples include the deposition of bioamine neurotransmitters serotonin ([ 6 ][6]) and dopamine ([ 7 ][7]) as covalent modifications of histones. Histone serotonylation potentiates binding of transcription factor IID to methylated histones ([ 6 ][6]). Serotonylation is enriched in the brain and gut ([ 6 ][6]), which are the primary sites of serotonin production, raising the intriguing possibility that incorporation into chromatin is dependent on metabolic availability in those tissues. Similarly, histone dopaminylation occurs in dopamine-producing neurons of the ventral tegmental area, a midbrain region involved in reward and motivated behaviors. Dopaminylation accumulates during cocaine withdrawal, leading to transcriptional changes in this brain region. Inhibiting histone dopaminylation rescues cocaine withdrawal-associated phenotypes and attenuates drug-seeking behavior in rats ([ 7 ][7]). Building on these early findings, the extent to which intermediary metabolites are directly incorporated as histone modifications and their precise role in cells and organisms remain to be fully elucidated. Recently, an unanticipated model has arisen for direct interplay between metabolic and epigenetic enzymes (see the figure). Contrary to prevailing dogma that places them exclusively in the mitochondria or cytoplasm, metabolic enzymes can translocate to the nucleus and be recruited to chromatin to regulate local metabolite concentrations in the nucleus or even at specific gene loci. These nuclear metabolic enzymes influence gene expression programs through association with DNA-bound transcription factors, chromatin remodelers, and histone modifiers. Prominent examples are nuclear metabolic enzymes that synthesize acetyl-CoA: acetyl-CoA synthetase (ACSS2) ([ 8 ][8], [ 9 ][9]) and ATP-citrate lyase (ACLY) ([ 10 ][10]). By modulating local acetyl-CoA pools, these nuclear metabolic enzymes regulate histone acetylation. Another example is chromatin-bound fumarase, which affects histone methylation by inhibiting 2-oxoglutarate–dependent lysine demethylases ([ 11 ][11]). ![Figure][12] The metabolic-epigenetic axis and behavior Through direct and indirect metabolic-epigenetic interactions, transient environmental perturbations can influence gene expression programs, leading to long-lasting functional and behavioral adaptations. For example, chromatin-bound metabolic enzymes can facilitate the direct transfer of metabolites between histone residues and increase the local concentration of active metabolite pools in phase-separated chromatin domains. GRAPHIC: C. BICKEL/ SCIENCE These paradigm-shifting mechanisms have profound relevance for health and disease. Direct metabolic-epigenetic interactions regulate autophagy ([ 9 ][9]) and cell differentiation ([ 8 ][8], [ 10 ][10]) and thus can alter the behavior and identity of specific cells. For example, ACLY dynamically regulates histone acetylation in response to growth factor–induced nutrient uptake, thus coordinating cell growth and differentiation with metabolic state ([ 10 ][10]). These changes, in turn, can also lead to impaired organismal function and disease. In many cases, dysregulation of these pathways is linked to cancer. ACSS2-mediated histone acetylation is implicated in brain tumorigenesis, and ACSS2 concentrations in the nucleus correlate with grades of glioma malignancy in humans ([ 9 ][9]). Chromatin-bound fumarase promotes tumor growth under glucose deficiency ([ 11 ][11]). Of particular interest is a nuclear metabolic-epigenetic interface in neurons, where metabolic regulation of histone acetylation serves a key role in spatial learning and memory. Chromatin-bound ACSS2 is enriched at promoters of immediate early genes (IEGs), a set of rapidly induced genes (mostly encoding transcription factors) that drive activity-dependent functional and structural changes in neurons and underlie synaptic plasticity and learning. Reduction of ACSS2 in the hippocampus attenuates long-term spatial memory formation and reconsolidation ([ 8 ][8]). Further, environmental metabolic fluctuations can influence this pathway. Circulating acetate derived from consumed alcohol is captured by ACSS2 in neuronal nuclei and turned into a local pool of acetyl-CoA. This is incorporated into histone acetylation at IEGs, resulting in the activation of transcription programs that underlie associative spatial memory formation ([ 12 ][13]). Through this pathway, direct incorporation of alcohol metabolites into brain histone acetylation may play a critical role in encoding drug-related environmental stimuli, which contribute to craving, relapse, and development of substance use disorders. Future research will expand our understanding of mechanisms that control this metabolic-epigenetic axis. Precise regulation is required to restrict consequences of natural hormonal and metabolic fluctuations that would otherwise change the epigenome, leading to stochastic alterations in transcription. One key regulatory mechanism is the shuttling of metabolic enzymes between the cytoplasm and nucleus. This is gated by phosphorylation or other modifications ([ 9 ][9], [ 11 ][11]), perhaps to regulate interaction with nuclear import factors and epigenetic enzymes. For example, a recent study demonstrates interactions between the folate pathway enzyme methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) and an acetyl-group reader protein, bromodomain-containing 4 (BRD4). This interaction drives recruitment of MTHFD1 to chromatin to regulate the nuclear concentration of one-carbon (methyl group) metabolites required for transcription, thereby driving cancer cell proliferation ([ 13 ][14]). Thus, there are likely to be numerous mechanisms to fine-tune metabolic-epigenetic signaling in specific tissues—including distinct neuronal circuits—in response to environmental stimuli, which is critical for effective regulation of behavioral adaptations. An interesting functional implication of nuclear and chromatin-bound metabolic enzymes is their availability to recycle posttranslational modifications released from histones. This could accomplish dynamic and rapid gene activation. Intriguingly, under oxygen and nutrient limitation, nuclear ACSS2 maintains histone acetylation and gene expression by converting acetate released by histone deacetylases into acetyl-CoA, which is then used by histone acetyltransferases ([ 14 ][15]). Local recapturing of acetate and other metabolites may be essential to maintain or activate new programs of gene expression in nutrient-poor environments. Certain metabolites have profoundly distinct effects on transcription, depending on the histone residue. For example, methyl groups correlate with active [e.g., trimethylated histone H3 lysine 4 (H3K4me)] or repressed (e.g., H3K27me) gene expression. A potential scenario emerges whereby chromatin-bound metabolic enzymes associate with epigenetic enzymes to enable direct transfer of molecules from repressive to activating histone residues (or the reverse) to facilitate rapid transcriptional changes required for cellular and behavioral adaptations. Another possibility is that nuclear metabolic enzymes are required to maintain metabolite concentrations in phase-separated chromatin domains ([ 15 ][16]). Free diffusion of metabolites between liquid phases may be limited, and phase-separated chromatin modifiers might thus be largely segregated from the nuclear and cytoplasmic pools of their substrates. Further, chromatin phase separation is regulated by posttranslational histone modifications, for example, acetylation ([ 15 ][16]), which is under metabolic control. It remains to be seen whether metabolic enzymes phase-separate with epigenetic regulators and whether colocalization to specific phases is required to maintain specific epigenetic signatures. The dialogue between metabolism and epigenetics within the nucleus presents a promising target for future therapeutic interventions. Certain metabolic-epigenetic pathways could be targeted to inhibit tumor formation and growth ([ 9 ][9], [ 13 ][14]) or to attenuate certain forms of unwanted memories (e.g., environmental cues that trigger relapse in substanceuse disorders or flashbacks in posttraumatic stress disorder) ([ 12 ][13]). Hence, continued investigation of the metabolic-epigenetic axis holds an exciting potential to launch future therapies. 1. [↵][17]1. X. Li, 2. G. Egervari, 3. Y. Wang, 4. S. L. Berger, 5. Z. Lu , Nat. Rev. Mol. Cell Biol. 19, 563 (2018). [OpenUrl][18][CrossRef][19][PubMed][20] 2. [↵][21]1. R. M. Evans, 2. D. J. Mangelsdorf , Cell 157, 255 (2014). [OpenUrl][22][CrossRef][23][PubMed][24][Web of Science][25] 3. [↵][26]1. B. M. Nugent et al ., Nat. Neurosci. 18, 690 (2015). [OpenUrl][27][CrossRef][28][PubMed][29] 4. [↵][30]1. K. M. Glastad et al ., Mol. Cell 77, 338 (2020). [OpenUrl][31] 5. [↵][32]1. D. Zhang et al ., Nature 574, 575 (2019). [OpenUrl][33][CrossRef][34][PubMed][35] 6. 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领域	气候变化 ; 资源环境
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引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/301989
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Gabor Egervari,Karl M. Glastad,Shelley L. Berger. Food for thought[J]. Science,2020.
APA	Gabor Egervari,Karl M. Glastad,&Shelley L. Berger.(2020).Food for thought.Science.
MLA	Gabor Egervari,et al."Food for thought".Science (2020).