Nutrient regulation of gene expression by O-GlcNAcylation of chromatin

https://doi.org/10.1016/j.cbpa.2016.06.005Get rights and content

Highlights

  • Nearly all transcription proteins are dynamically O-GlcNAcylated.

  • Histone O-GlcNAcylation interplays with other histone marks.

  • Epigenetic writers/erasers are regulated by the sugar.

  • OGT and OGA are required for the transcription cycle.

O-GlcNAcylation is a dynamic post-translational modification that is responsive to nutrient availably via the hexosamine biosynthetic pathway and its endproduct UDP-GlcNAc. O-GlcNAcylation serves as a nutrient sensor to regulate the activities of many proteins involved in nearly all biological processes. Within the last decade, OGT, OGA and O-GlcNAcylation have been shown to be at the nexus of epigenetic marks controlling gene expression during embryonic development, cell differentiation, in the maintenance of epigenetic states and in the etiology of epigenetic related diseases. OGT O-GlcNAcylates histones and epigenetic writers/erasers, and regulates gene activation, as well as gene repression. Here, we highlight recent work documenting the important roles O-GlcNAcylation and its cycling enzymes play in the nutrient regulation of epigenetic partners controlling gene expression.

Introduction

Can what we eat change our genetics? Beside toxic compounds that have the ability to induce mutations, our eating habits do not change the nucleotide sequence of our genes. However, organisms with a predefined set of genes have to maintain proper homeostasis and adapt to their environment, especially to adapt to nutrient availability. Phenotype adaptation is a long-term adjustment to the environment and can be done by heritable encoded information on DNA without changes in the gene sequence [1]. This second layer of information is called epigenetics and includes DNA methylation, post-translational modifications (PTMs) of histones and chromatin remodeling. Epigenetics is also an important feature of embryogenesis and cell fate, controlling and defining transcriptional pattern crucial for cellular lineage.

The first evidence that link O-GlcNAcylation to chromatin and transcription was found in Drosophila [2]. O-GlcNAcylation is a versatile PTM controlled by two non-redundant enzymes: the O-GlcNAc transferase (OGT) transfers the GlcNAc moiety from UDP-GlcNAc to a serine or a threonine residue, while the O-GlcNAcase (OGA) removes the modification. UDP-GlcNAc is a main cellular nutrient sensor since its synthesis through the hexosamine biosynthetic pathway (HBP) depends on flux through every major metabolic pathway (graphical abstract). Since OGT's enzymatic activity and substrate specificity varies according UDP-GlcNAc concentration, variation in metabolism that feed the HBP have profound effects on protein O-GlcNAcylation [3]. Within the last decade, studies have defined O-GlcNAcylation as an epigenetic mark and linked its cycle to the regulation of chromatin modifications.

Section snippets

Multiple roles of histone O-GlcNAcylation

The histone code is written by molecular complexes that add or remove part of the code in response to various cellular stimuli or metabolism. Although a recent paper called into question histone O-GlcNAcylation [4], the presence of the sugar on each subunit of the nucleosome has been reported independently by many laboratories and some sites have been mapped (reviewed in [2]). Some of the site-specific functions have been documented (Figure 1).

The O-GlcNAc/phosphorylation interplay on histone

OGA, a histone acetyltranferase?

The histone acetyltransferase (HAT) activity of OGA has been controversial. Its putative HAT domain is located in the C-terminal domain, while the O-GlcNAcase activity resides in the N-terminal domain of the molecule. Although our lab was not able to observe this activity in vitro [15], others have reported it in different publications. Toleman et al. have shown that mouse OGA acetylates histones in vitro and mutations within the C-terminal domain lead to substantial loss of its HAT activity [16

OGT and O-GlcNAcylation regulate epigenetic marks

Much evidence strongly suggest that nutrients impact epigenetic modifications of chromatin [21] and recent publications have highlighted the important role of the nutrient sensors OGT and O-GlcNAcylation modulating chromatin marks.

Conclusions and future outlook

It is clear that O-GlcNAcylation and its cycling enzymes are important regulators of epigenetics. The sugar itself is a chromatin mark and its interplay with other PTMs to histones establishes a specific pattern recognized by protein complexes to activate or repress gene expression. Deregulation of O-GlcNAcylation, observed in diabetes, cancer and neurodegenerative diseases [41], could, by altering chromatin marks and gene expression, underlie the etiology of these diseases.

As a nutrient

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The authors are supported by R01DK61671 and P01HL107153. G.W.H. receives a share of royalties received by Johns Hopkins University on sales of the CTD110.6 antibody, which is managed by JHU.

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