Nutritional Regulation of Gene Expression and Nutritional Genomics1



Nutritional Regulation of Gene Expression and Nutritional Genomics1


Robert J. Cousins

Louis A. Lichten





1Abbreviations: ATP, adenosine triphosphate; ChIP, chromatin immunoprecipitation; CoA, coenzyme A; ES, embryonic stem; FAS, fatty acid synthase; HIF, hypoxia-inducible factor; miRNA, micro RNA; PCR, polymerase chain reaction; siRNA, small interfering RNA; TF, transcription factor; USF1, upstream transcription factor-1.


Gene expression is a term that has different interpretations. These interpretations are dictated by the context in which the term is used. For example, phenotypes of health or disease are manifestations of gene expression. Similarly, the mechanics and control factors for gene transcription and mRNA translation that influence which proteins are produced also constitute gene expression. From the standpoint of nutritional influences on gene expression, processes are envisioned in which dietary conditions, either through direct interaction of specific nutrients with transcription factors (TFs) or mRNA-binding proteins or, more commonly, through indirect or exocrine means, produce changes that define phenotypic expression. The technical approaches described in this tutorial chapter are central to all research in contemporary biologic science and are actively applied in the nutritional sciences.


HISTORICAL PERSPECTIVE

Although the classic experiments of Nobel laureates François Jacob and Jacques Monod in 1961 were conducted in bacteria, they demonstrated that genes, under nutrient control through an operon, influence synthesis of enzymes involved in the metabolism of that nutrient (1). Experiments with mammalian systems with specific nutrients followed after the operon model was proposed. Classic experiments of particular note were those demonstrating that polyribosome formation depended on the presence of essential amino acids in the diet, and the interaction of metabolites of vitamin A and vitamin D with nuclear receptors to produce physiologic effects.


GENE REGULATION BY NUTRIENTS

Nutrient regulation of gene expression is a well-recognized research emphasis in contemporary nutritional science. It is difficult to separate direct effects of individual nutrients on gene expression from those produced indirectly through physiologically controlled mediators and modulating molecules that are responsive to the diet. Consequently, experiments at the level of individual cells are essential to identify effects of nutrients that are clearly direct. However, interpretation of cell-level findings must be kept within an integrative context of the multicellular organ system to appreciate fully how dietary components and patterns influence the expression of genes in various tissues. The way in which the diet—in concert with hormones, cytokines, and growth factors—interacts to influence the differential expression of specific genes has reached a level of awareness that a new term, nutritional genomics (or nutrigenomics/nutrigenetics), has evolved to describe such relationships (2). Nutritional genomics includes all genetic factors, including epigenetic events, as they modulate individual genes and gene networks. It is one of a growing number of terms in general use in the nutritional sciences literature (Table 39.1), and it tends to replace the former term nutrient-gene interactions. The latter is a narrow term that implies a direct interaction of a nutrient with a gene. The closest examples of a nutrientgene interaction may include nutrient binding to a TF for subsequent interaction with a response element of a gene, the methylation of specific genes, nutrient influenced acylation of TFs, or nutrient inhibition and activation of pathways that influence gene activation.

A generalized cell showing different modes of gene regulation by nutrients is illustrated in Figure 39.1. A “direct” effect of some nutrients (active metabolites of vitamins A and D; zinc; n-3 fatty acids and sterols) on gene transcription is shown in which, subsequent to ligand binding to

a specific TF, cytoplasmic to nuclear translocation of the complex occurs, and interaction through a specific domain of the factor with a response element sequence (specific nucleotide sequence) of the regulatory region produces a change in transcription rate of the gene. In most situations involve a complex of multiple TFs and modifying proteins. Amino acid deprivation at the cellular level may activate transcription from specific defense genes through cis-acting nutrient-sensing response elements (see also Chapter 47: Mechanisms of Nutrient Sensing). The control of translation of specific mRNAs by iron is another example of a “direct” nutrient effect on gene expression, in this case at the level of mRNA stability and translation efficiency, to increase the abundance of a protein. Repression of mRNA by micro RNA leading to mRNA degradation is also shown in Figure 39.1.








TABLE 39.1 TERMS FREQUENTLY USED IN STUDIES ON NUTRITIONAL REGULATION OF GENE EXPRESSION



















































































Acetylome

Reversible acetylation at the whole proteome level

Nuclear receptor

A transcription factor protein that requires a ligand (e.g., calcitriol for nuclear translocation and DNA binding)


Chromatin immunoprecipitation (ChIP)

Transcription factor antibodies precipitate DNA fragments to identify genes regulated by a specific transcription factor

Nutritional genomics

Genomic studies that relate nutritional factors in regulation of genes that influence cellular processes genome wide


cis-Acting

DNA elements on the same strand as a structural gene, to which transcription factors bind to and initiate transcription

Ortholog

A gene with similar function to a gene in evolutionarily related to species; ortholog comparisons help predict gene function


DNA array

Immobilized sequences of single-stranded DNA (probe) on a matrix that allows hybridization of mRNAs for quantitation of transcript abundance (also called gene chips or DNA chips)

PAGE

Polyacrylamide gel electrophoresis


Epigenetic

Nonmutational modification of a gene (e.g., by methylation and histone changes that influence expression of a specific gene)

PCR

Polymerase chain reaction


Exon-intron junction

A junction between a block of coding sequence (exon) and an adjacent block of noncoding sequence (intron) present in DNA and in precursor messenger RNA (pre-mRNA)

Polygenic

Disease or phenotypic characteristic caused by more than one gene


Functional genomics

Relationship of genes, proteins, and regulatory networks with physiologic function

Protein array

Antibodies or other proteins immobilized to a matrix allowing abundance of specific proteins to be qualitatively detected or interacting proteins to be identified


Genomics

Study of the singular or collective roles that genes play in cellular processes as influenced by external factors; prefixes such as chemo-, epi-, pharmaco-, or toxico- can define specialization in genomics

Proteomics

Proteome-wide analysis of protein structure, posttranslational modification, interactions, and function


Haplotype

A set of DNA variations, or polymorphisms, usually inherited together; haplotype can refer to a combination of alleles or to a set of single nucleotide polymorphisms found on the same chromosome

qPCR

Quantitative PCR in which the relative abundance of a sequence (mRNA derived cDNA) is compared to a normalizing sequence


Homolog

Gene that has the same evolutionary origin and function in two or more species

Response element

Portion of a gene sequence that must be present for that gene to respond to a stimulus; response elements are binding sites for transcription factors


In silico

In or by means of computer simulation of complex biologic systems; term frequently used in microarray research in which extensive computational algorithms or comparisons are executed

RNA interference (RNAi or siRNA)

Use of short RNA molecules, frequently derived from double-stranded RNA, that, on introduction into cells and complementary hybridization to specific mRNA, decrease gene expression


Metabolomics

Global analysis of all metabolites in a complex system

Single nucleotide polymorphism (SNP)

Single base substitution in coding sequence of a gene; frequently determines phenotypic differences in a population (human genome has ˜10 million SNPs)


Micro RNA (miRNA)

Short regulatory form of RNA that binds to a target RNA molecule and generally suppresses its translation

Systems biology

Study of complex interactions of organ systems down to molecules


Monogenic

Disease or phenotypic characteristic pro-duced by a single gene

trans-Acting factors

DNA-binding proteins (transcription factor) are trans because they are products of genes from other chromosomes that bind to regulatory elements; transcription factors that bind some nutrients are trans-acting factors


Noncoding RNAs

Segments of RNA that are not translated into amino acid sequences but may be involved in the regulation of gene expression

Transcription factor (TF)

Proteins that bind regulatory regions of a gene and influence the transcription rate of the gene. Some bind to nutrients vitamins and minerals for activity


Transcriptome

All transcribed mRNAs within a cell or tissue at a particular time


Frequently, gene regulation by nutrients is complex. Multiple and interconnected factors, including nutrient effects on signal transduction pathways, epigenetic effects on specific genes, gene polymorphisms, alternative mRNA splicing and translation, and posttranslational modifications, converge to define indirect effects on expression of a specific gene. Studies have shown that nutritionally responsive TFs (e.g., sterol regulatory element-binding protein [SREBP]) are able to influence activity of numerous promoters through TF isoforms and coregulatory nuclear proteins that regulate lipid metabolic genes (3). Hypoxia-inducible factor (HIF) induced by iron deficiency similarly regulates multiple genes of iron metabolism (4). Metal-response element binding transcription factor-1 (MTF1)-activated nuclear translocation and DNA binding by interacting with zinc induces multiple zinc-regulatory and zinc-transporter proteins (5). Moving further clockwise around the nuclear envelope, Figure 39.1 shows the influence of TF phosphorylation, which can be either activating or deactivating. Zinc-repressing phosphatase activity, with sustained TF activation, is given as an example (6). Citrate, a product of intermediary metabolism, can diffuse into the nucleus, and adenosine triphosphate (ATP)-citrate lyase activity produces acetyl-coenzyme A (CoA). Nuclear acetyl-CoA leads to histone acetylation and activation of hexokinase 2 and other glucose-metabolizing enzymes and possibly to global changes in acetylation and gene expression (7). An example of the complexity in nutrient gene regulation is the fatty acid synthase (FAS) gene (8). During fasting, FAS is held in check by upstream transcription factors-1 and 2 (USF1 and USF2), TFs that are deacetylated by histone deacetylases (HDACs), thus leading to FAS promoter inactivation. On feeding, USF1 is phosphorylated; this process generates interactions with numerous other interacting TFs (>7) to produce increased USF1 acetylation and FAS promoter activation.

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Jul 27, 2016 | Posted by in PUBLIC HEALTH AND EPIDEMIOLOGY | Comments Off on Nutritional Regulation of Gene Expression and Nutritional Genomics1

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