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Epigenetic Aspects of Nuclear Receptor Coregulators: How Nutritional and Environmental Signals Change Gene Expression Patterns

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Handbook of Nutrition, Diet, and Epigenetics

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Abstract

Nuclear receptor coregulators are a large family of proteins that interact with nuclear receptors at promoters and enhancers to alter gene expression. Modifications induced by coregulators will either amplify or suppress the rate of transcription. Nuclear receptors themselves are transcription factors that are stimulated by hormonal, metabolic, and environmental stimuli; they are then directed to target gene promoters to initiate transcription. The nature of the nuclear receptor ligand is a large determinant of which coregulator complexes are recruited, either recruiting coactivators or corepressors. Agonists generally recruit coactivators that amplify transcription, whereas antagonists will generally recruit corepressors that will dampen transcription. Interestingly, bivalent or dual-function coregulators have recently come to light. Their effects appear to be dependent on cell-type, tissue-type, and/or developmental stage; much remains to be elucidated with regards to this class of coregulators.

Once formed, the coregulator complex exerts its effects through multiple mechanisms that are largely dependent on editing the epigenome. Enzymes are recruited into coregulator complexes that act on chromatin, DNA, and on other coregulator complex subunits. Histone acetylases, deacetylases, methyltransferases, and demethylases are some of the most important enzymes in the control of the target gene promoter context. Acetylation is generally associated with coactivator activity, while methylation acts in both activation and repression. Another mechanism implicates repositioning, eviction, or exchange of nucleosome components in an ATP-dependent manner. These and many other post-translational modifications also affect coregulators themselves, being subject to sumoylation, phosphorylation, as well as acetylation and methylation. The dynamic regulation of both coregulators and epigenomes allows rapid adaptation to the cellular and metabolic milieu.

A large number of coregulator complexes have been shown to be extremely important in nutrition and metabolism. Adipose tissue and the liver have been extensively studied and have proven to be the major tissues in which coregulators and their epigenetic functions contribute to metabolic and nutritional adaptation. Interestingly coregulators have also been demonstrated to tightly control cellular metabolism and the inflammatory response, two key processes in nutritional and metabolic disease. This chapter describes the mechanisms through which coregulators exert their functions, with a particular emphasis on the epigenome. We also describe pertinent examples from scientific literature that demonstrate the epigenetic aspects on nuclear receptor coregulators in nutrition and metabolism.

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Abbreviations

AF2:

Activator function 2

AP:

Associated protein

BAT:

Brown adipose tissue

C/EBPα:

CCAAT/enhancer-binding protein C/EBPα

CBP:

p300/CREB binding protein

CDK4:

Cyclin-dependent kinase 4

CoREST:

Repressor element-1 silencing transcription factor corepressor 1

CYP7A1:

Cholesterol hydroxylase

CYP8B1:

Sterol hydroxylase

DNA:

Deoxyribonucleic acid

DNMT:

DNA methyltransferases

EHMT:

Histone methyltransferase

ER:

Estrogen receptor (NR3A1/2)

eRNA:

Enhancer-associated RNA

GLUT:

Glucose transporter

GNAT:

Gcn5-related N-acetyltransferase

GPS2:

G-protein pathway suppressor2

HAT:

Histone acetyltransferase

HDAC:

Histone deacetylase

HIF1 α:

Hypoxia-inducible factor 1α

ISWI:

Imitation switch

LBD:

Ligand binding domain

LRH1:

Liver receptor homolog 1 (NR5A2)

LSD/KDM:

Lysine demethylases

LXR:

Liver X receptor (NR1H2/3)

MYST:

MOZ-Ybf2-Sas3-Tip60

NCOA:

Nuclear receptor coactivator

NCoR:

Nuclear receptor corepressor

NR:

Nuclear receptor

PCAF:

p300/CBP-associated factor

PGC1α:

PPARγ coactivator

PROX1:

Prospero homeobox protein 1

PTM:

Post-translational modification

RAR:

Retinoic acid receptor (NR1B1/2/3)

RIP140:

Receptor-interacting protein 140

RNA:

Ribonucleic acid

RNF4:

RING finger protein 4

SAM:

S-Adenosyl methionine

SET:

Su (var) 3-9, enhancer of zeste, trithorax

SIRT:

Sirtuin

SRA:

Steroid receptor RNA activator

SUMO:

Small ubiquitin-like modifiers

SWI/SNF:

Switch/sucrose non-fermenting

TLE3:

Transducin-like enhancer 3

TR:

Thyroid hormone receptor (NR1A1/2)

TRIM24:

Tripartite motif containing 24

UCP1:

Uncoupling protein 1

WAT:

White adipose tissue

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Authors and Affiliations

  1. Sorbonne Universités, Université Pierre et Marie-Curie, Institut National de la Santé et de la Recherche Médicale (INSERM), UMR_S 1138 Cordeliers Research, Paris, France

    Fawaz Alzaïd & Nicolas Venteclef

  2. Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden

    Tomas Jakobsson

  3. Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden

    Eckardt Treuter

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  1. Fawaz Alzaïd
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  2. Tomas Jakobsson
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  3. Eckardt Treuter
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  4. Nicolas Venteclef
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Correspondence to Fawaz Alzaïd .

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  1. School of Life Sciences, University of Westminster, London, UK

    Vinood B. Patel

  2. Diabetes and Nutritional Sciences Research Division, Faculty of Life Sciences and Medicine, King’s College London, London, UK

    Victor R. Preedy

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Alzaïd, F., Jakobsson, T., Treuter, E., Venteclef, N. (2019). Epigenetic Aspects of Nuclear Receptor Coregulators: How Nutritional and Environmental Signals Change Gene Expression Patterns. In: Patel, V., Preedy, V. (eds) Handbook of Nutrition, Diet, and Epigenetics. Springer, Cham. https://doi.org/10.1007/978-3-319-55530-0_116

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  • DOI: https://doi.org/10.1007/978-3-319-55530-0_116

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