Volume 38 | August 2020
Cover Story
One of the hallmarks of all living beings is their ability to extract energy from their surroundings and use it in a process termed metabolism to grow and reproduce. During evolution, life had to "learn" how to cope with changing environments and exploit even limited and unstable sources of energy. The ability to take up and process energy from diverse sources and adjust their metabolism according to the availability of nutrients is therefore fundamentally engrained in the nature of all living things.
All Articles
Early life lessons: The lasting effects of germline epigenetic information on organismal development
- Abstract
Background
An organism's metabolic phenotype is primarily affected by its genotype, its lifestyle, and the nutritional composition of its food supply. In addition, it is now clear from studies in many different species that ancestral environments can also modulate metabolism in at least one to two generations of offspring.
Scope of review
We limit ourselves here to paternal effects in mammals, primarily focusing on studies performed in inbred rodent models. Although hundreds of studies link paternal diets and offspring metabolism, the mechanistic basis by which epigenetic information in sperm programs nutrient handling in the next generation remains mysterious. Our goal in this review is to provide a brief overview of paternal effect paradigms and the germline epigenome. We then pivot to exploring one key mystery in this literature: how do epigenetic changes in sperm, most of which are likely to act transiently in the early embryo, ultimately direct a long-lasting physiological response in offspring?
Major conclusions
Several potential mechanisms exist by which transient epigenetic modifications, such as small RNAs or methylation states erased shortly after fertilization, could be transferred to more durable heritable information. A detailed mechanistic understanding of this process will provide deep insights into early development, and could be of great relevance for human health and disease.
- Abstract
Background
The microbiota in the human gut are an important component of normal physiology that has co-evolved from the earliest multicellular organisms. Therefore, it is unsurprising that there is intimate crosstalk between the microbial world in the gut and the host. Genome regulation through microbiota-host interactions not only affects the host's immunity, but also metabolic health and resilience against cancer. Chromatin dynamics of the host epithelium involving histone modifications and other facets of the epigenetic machinery play an important role in this process.
Scope of review
This review discusses recent findings relevant to how chromatin dynamics shape the crosstalk between the microbiota and its host, with a special focus on the role of histone modifications.
Major conclusions
Host-microbiome interactions are important evolutionary drivers and are thus expected to be hardwired into and mould the epigenetic machinery in multicellular organisms. Microbial-derived short-chain fatty acids (SCFA) are dominant determinants of microbiome–host interactions, and the inhibition of histone deacetylases (HDACs) by SCFA is a key mechanism in this process. The discovery of alternative histone acylations, such as crotonylation, in addition to the canonical histone acetylation reveals a new layer of complexity in this crosstalk.
- Abstract
Background
Metabolic diseases such as obesity are known to be driven by both environmental and genetic factors. Although genome-wide association studies of common variants and their impact on complex traits have provided some biological insight into disease etiology, identified genetic variants have been found to contribute only a small proportion to disease heritability, and to map mainly to non-coding regions of the genome. To link variants to function, association studies of cellular traits, such as epigenetic marks, in disease-relevant tissues are commonly applied.
Scope of the review
We review large-scale efforts to generate genome-wide maps of coordinated epigenetic marks and their utility in complex disease dissection with a focus on DNA methylation. We contrast DNA methylation profiling methods and discuss the advantages of using targeted methods for single-base resolution assessments of methylation levels across tissue-specific regulatory regions to deepen our understanding of contributing factors leading to complex diseases.
Major conclusions
Large-scale assessments of DNA methylation patterns in metabolic disease-linked study cohorts have provided insight into the impact of variable epigenetic variants in disease etiology. In-depth profiling of epigenetic marks at regulatory regions, particularly at tissue-specific elements, will be key to dissect the genetic and environmental components contributing to metabolic disease onset and progression.
- Abstract
Background
Many metabolites serve as important signalling molecules to adjust cellular activities and functions based on nutrient availability. Links between acetyl-CoA metabolism, histone lysine acetylation, and gene expression have been documented and studied over the past decade. In recent years, several additional acyl modifications to histone lysine residues have been identified, which depend on acyl-coenzyme A thioesters (acyl-CoAs) as acyl donors. Acyl-CoAs are intermediates of multiple distinct metabolic pathways, and substantial evidence has emerged that histone acylation is metabolically sensitive. Nevertheless, the metabolic sources of acyl-CoAs used for chromatin modification in most cases remain poorly understood. Elucidating how these diverse chemical modifications are coupled to and regulated by cellular metabolism is important in deciphering their functional significance.
Scope of review
In this article, we review the metabolic pathways that produce acyl-CoAs, as well as emerging evidence for functional roles of diverse acyl-CoAs in chromatin regulation. Because acetyl-CoA has been extensively reviewed elsewhere, we will focus on four other acyl-CoA metabolites integral to major metabolic pathways that are also known to modify histones: succinyl-CoA, propionyl-CoA, crotonoyl-CoA, and butyryl-CoA. We also briefly mention several other acyl-CoA species, which present opportunities for further research; malonyl-CoA, glutaryl-CoA, 3-hydroxybutyryl-CoA, 2-hydroxyisobutyryl-CoA, and lactyl-CoA. Each acyl-CoA species has distinct roles in metabolism, indicating the potential to report shifts in the metabolic status of the cell. For each metabolite, we consider the metabolic pathways in which it participates and the nutrient sources from which it is derived, the compartmentalisation of its metabolism, and the factors reported to influence its abundance and potential nuclear availability. We also highlight reported biological functions of these metabolically-linked acylation marks. Finally, we aim to illuminate key questions in acyl-CoA metabolism as they relate to the control of chromatin modification.
Major conclusions
A majority of acyl-CoA species are annotated to mitochondrial metabolic processes. Since acyl-CoAs are not known to be directly transported across mitochondrial membranes, they must be synthesized outside of mitochondria and potentially within the nucleus to participate in chromatin regulation. Thus, subcellular metabolic compartmentalisation likely plays a key role in the regulation of histone acylation. Metabolite tracing in combination with targeting of relevant enzymes and transporters will help to map the metabolic pathways that connect acyl-CoA metabolism to chromatin modification. The specific function of each acyl-CoA may be determined in part by biochemical properties that affect its propensity for enzymatic versus non-enzymatic protein modification, as well as the various enzymes that can add, remove and bind each modification. Further, competitive and inhibitory effects of different acyl-CoA species on these enzymes make determining the relative abundance of acyl-CoA species in specific contexts important to understand the regulation of chromatin acylation. An improved and more nuanced understanding of metabolic regulation of chromatin and its roles in physiological and disease-related processes will emerge as these questions are answered.
- Abstract
Background
Virtually all eukaryotic cells contain spatially distinct genomes, a single nuclear genome that harbours the vast majority of genes and much smaller genomes found in mitochondria present at thousands of copies per cell. To generate a coordinated gene response to various environmental cues, the genomes must communicate with each another. Much of this bi-directional crosstalk relies on epigenetic processes, including DNA, RNA, and histone modification pathways. Crucially, these pathways, in turn depend on many metabolites generated in specific pools throughout the cell, including the mitochondria. They also involve the transport of metabolites as well as the enzymes that catalyse these modifications between nuclear and mitochondrial genomes.
Scope of review
This study examines some of the molecular mechanisms by which metabolites influence the activity of epigenetic enzymes, ultimately affecting gene regulation in response to metabolic cues. We particularly focus on the subcellular localisation of metabolite pools and the crosstalk between mitochondrial and nuclear proteins and RNAs. We consider aspects of mitochondrial-nuclear communication involving histone proteins, and potentially their epigenetic marks, and discuss how nuclear-encoded enzymes regulate mitochondrial function through epitranscriptomic pathways involving various classes of RNA molecules within mitochondria.
Major conclusions
Epigenetic communication between nuclear and mitochondrial genomes occurs at multiple levels, ultimately ensuring a coordinated gene expression response between different genetic environments. Metabolic changes stimulated, for example, by environmental factors, such as diet or physical activity, alter the relative abundances of various metabolites, thereby directly affecting the epigenetic machinery. These pathways, coupled to regulated protein and RNA transport mechanisms, underpin the coordinated gene expression response. Their overall importance to the fitness of a cell is highlighted by the identification of many mutations in the pathways we discuss that have been linked to human disease including cancer.
- Abstract
Background
Poly-ADP-ribose polymerases (PARPs) are key mediators of cellular stress response. They are intimately linked to cellular metabolism through the consumption of NAD+. PARP1/ARTD1 in the nucleus is the major NAD+ consuming activity and plays a key role in maintaining genomic integrity.
Scope of review
In this review, we discuss how different organelles are linked through NAD+metabolism and how PARP1 activation in the nucleus can impact the function of distant organelles. We discuss how differentiated cells tame PARP1 function by upregulating an endogenous inhibitor, the histone variant macroH2A1.1.
Major conclusions
The presence of macroH2A1.1, particularly in differentiated cells, raises the threshold for the activation of PARP1 with consequences for DNA repair, gene transcription, and NAD+ homeostasis.
- Abstract
Background
One of the fascinating aspects of epigenetic regulation is that it provides means to rapidly adapt to environmental change. This is particularly relevant in the plant kingdom, where most species are sessile and exposed to increasing habitat fluctuations due to global warming. Although the inheritance of epigenetically controlled traits acquired through environmental impact is a matter of debate, it is well documented that environmental cues lead to epigenetic changes, including chromatin modifications, that affect cell differentiation or are associated with plant acclimation and defense priming. Still, in most cases, the mechanisms involved are poorly understood. An emerging topic that promises to reveal new insights is the interaction between epigenetics and metabolism.
Scope of review
This study reviews the links between metabolism and chromatin modification, in particular histone acetylation, histone methylation, and DNA methylation, in plants and compares them to examples from the mammalian field, where the relationship to human diseases has already generated a larger body of literature. This study particularly focuses on the role of reactive oxygen species (ROS) and nitric oxide (NO) in modulating metabolic pathways and gene activities that are involved in these chromatin modifications. As ROS and NO are hallmarks of stress responses, we predict that they are also pivotal in mediating chromatin dynamics during environmental responses.
Major conclusions
Due to conservation of chromatin-modifying mechanisms, mammals and plants share a common dependence on metabolic intermediates that serve as cofactors for chromatin modifications. In addition, plant-specific non-CG methylation pathways are particularly sensitive to changes in folate-mediated one-carbon metabolism. Finally, reactive oxygen and nitrogen species may fine-tune epigenetic processes and include similar signaling mechanisms involved in environmental stress responses in plants as well as animals.
- Abstract
Background
Organisms can be primed by metabolic exposures to continue expressing response genes even once the metabolite is no longer available, and can affect the speed and magnitude of responsive gene expression during subsequent exposures. This “metabolic transcriptional memory” can have a profound impact on the survivability of organisms in fluctuating environments.
Scope of review
Here I present several examples of metabolic transcriptional memory in the microbial world and discuss what is known so far regarding the underlying mechanisms, which mainly focus on chromatin modifications, protein inheritance, and broad changes in metabolic network. From these lessons learned in microbes, some insights into the yet understudied human metabolic memory can be gained. I thus discuss the implications of metabolic memory in disease progression in humans – i.e., the memory of high blood sugar exposure and the resulting effects on diabetic complications.
Major conclusions
Carbon source shifts from glucose to other less preferred sugars such as lactose, galactose, and maltose for energy metabolism as well as starvation of a signal transduction precursor sugar inositol are well-studied examples of metabolic transcriptional memory in Escherichia coli and Saccharomyces cerevisiae. Although the specific factors guiding metabolic transcriptional memory are not necessarily conserved from microbes to humans, the same basic mechanisms are in play, as is observed in hyperglycemic memory. Exploration of new metabolic transcriptional memory systems as well as further detailed mechanistic analyses of known memory contexts in microbes is therefore central to understanding metabolic memory in humans, and may be of relevance for the successful treatment of the ever-growing epidemic of diabetes.
- Abstract
Background
ATP-dependent chromatin remodelers are evolutionarily conserved complexes that alter nucleosome positioning to influence many DNA-templated processes, such as replication, repair, and transcription. In particular, chromatin remodeling can dynamically regulate gene expression by altering accessibility of chromatin to transcription factors.
Scope of review
This review provides an overview of the importance of chromatin remodelers in the regulation of metabolic gene expression. Particular emphasis is placed on the INO80 and SWI/SNF (BAF/PBAF) chromatin remodelers in both yeast and mammals. This review details discoveries from the initial identification of chromatin remodelers in Saccharomyces cerevisiae to recent discoveries in the metabolic requirements of developing embryonic tissues in mammals.
Major conclusions
INO80 and SWI/SNF (BAF/PBAF) chromatin remodelers regulate the expression of energy metabolism pathways in S. cerevisiae and mammals in response to diverse nutrient environments. In particular, the INO80 complex organizes the temporal expression of gene expression in the metabolically synchronized S. cerevisiae system. INO80-mediated chromatin remodeling is also needed to constrain cell division during metabolically favorable conditions. Conversely, the BAF/PBAF remodeler regulates tissue-specific glycolytic metabolism and is disrupted in cancers that are dependent on glycolysis for proliferation. The role of chromatin remodeling in metabolic gene expression is downstream of the metabolic signaling pathways, such as the TOR pathway, a critical regulator of metabolic homeostasis. Furthermore, the INO80 and BAF/PBAF chromatin remodelers have both been shown to regulate heart development, the tissues of which have unique requirements for energy metabolism during development. Collectively, these results demonstrate that chromatin remodelers communicate metabolic status to chromatin and are a central component of homeostasis pathways that optimize cell fitness, organismal development, and prevent disease.
- Abstract
Background
Virtually all eukaryotic cells contain spatially distinct genomes, a single nuclear genome that harbours the vast majority of genes and much smaller genomes found in mitochondria present at thousands of copies per cell. To generate a coordinated gene response to various environmental cues, the genomes must communicate with each another. Much of this bi-directional crosstalk relies on epigenetic processes, including DNA, RNA, and histone modification pathways. Crucially, these pathways, in turn depend on many metabolites generated in specific pools throughout the cell, including the mitochondria. They also involve the transport of metabolites as well as the enzymes that catalyse these modifications between nuclear and mitochondrial genomes.
Scope of review
This study examines some of the molecular mechanisms by which metabolites influence the activity of epigenetic enzymes, ultimately affecting gene regulation in response to metabolic cues. We particularly focus on the subcellular localisation of metabolite pools and the crosstalk between mitochondrial and nuclear proteins and RNAs. We consider aspects of mitochondrial-nuclear communication involving histone proteins, and potentially their epigenetic marks, and discuss how nuclear-encoded enzymes regulate mitochondrial function through epitranscriptomic pathways involving various classes of RNA molecules within mitochondria.
Major conclusions
Epigenetic communication between nuclear and mitochondrial genomes occurs at multiple levels, ultimately ensuring a coordinated gene expression response between different genetic environments. Metabolic changes stimulated, for example, by environmental factors, such as diet or physical activity, alter the relative abundances of various metabolites, thereby directly affecting the epigenetic machinery. These pathways, coupled to regulated protein and RNA transport mechanisms, underpin the coordinated gene expression response. Their overall importance to the fitness of a cell is highlighted by the identification of many mutations in the pathways we discuss that have been linked to human disease including cancer.