Human linker histones: interplay between phosphorylation and O-β-GlcNAc to mediate chromatin structural modifications

Abstract

Eukaryotic chromatin is a combination of DNA and histone proteins. It is established fact that epigenetic mechanisms are associated with DNA and histones. Initial studies emphasize on core histones association with DNA, however later studies prove the importance of linker histone H1 epigenetic. There are many types of linker histone H1 found in mammals. These subtypes are cell specific and their amount in different types of cells varies as the cell functions. Many types of post-translational modifications which occur on different residues in each subtype of linker histone H1 induce conformational changes and allow the different subtypes of linker histone H1 to interact with chromatin at different stages during cell cycle which results in the regulation of transcription and gene expression. Proposed O-glycosylation of linker histone H1 promotes condensation of chromatin while phosphorylation of linker histone H1 is known to activate transcription and gene regulation by decondensation of chromatin. Interplay between phosphorylation and O-β-GlcNAc modification on Ser and Thr residues in each subtype of linker histone H1 in Homo sapiens during cell cycle may result in diverse functional regulation of proteins. This in silico study describes the potential phosphorylation, o-glycosylation and their possible interplay sites on conserved Ser/Thr residues in various subtypes of linker histone H1 in Homo sapiens.

Modulation of Epigenetic Targets for Anticancer Therapy: Clinicopathological Relevance, Structural Data and Drug Discovery Perspectives

“…First, it involves the addition of a single monosaccharide; second, it takes place in the cytoplasm and modified glycoproteins are usually nuclear and cytoplasmic, including RNA polymerase II, ER, c-Myc proto-oncogene and histones; third, it is reversible in the way that the monosaccharide can repeatedly be attached and detached. In general, the addition of O-GlcNAc is reciprocal with Ser and Thr phosphorylation, either by modification of the same residue or nearby residues [520]. This PTM modification is regulated by only two enzymes: a glycosyltransferase that catalyzes the transfer of GlcNAc to substrate proteins, also known as O-GlcNAc transferase (OGT), and a glycoside hydrolase, also known as OGlcNAcase (OGA) or O-N-acetylglucosaminidase, that catalyzes the hydrolysis of the glycosidic linkage [521].…”

“…Only recently O-GlcNAc was linked to the epigenetic code, demonstrating that the four core histones are substrates for OGlcNAc modifications and cycle genetically and physically in order to interact with other PTMs of histones [520,[522][523][524][525][526]. In addition, OGT has been described to target key members of the Polycomb and Trithorax groups [527].…”

Modulation of Epigenetic Targets for Anticancer Therapy: Clinicopathological Relevance, Structural Data and Drug Discovery Perspectives

“…First, it involves the addition of a single monosaccharide; second, it takes place in the cytoplasm and modified glycoproteins are usually nuclear and cytoplasmic, including RNA polymerase II, ER, c-Myc proto-oncogene and histones; third, it is reversible in the way that the monosaccharide can repeatedly be attached and detached. In general, the addition of O-GlcNAc is reciprocal with Ser and Thr phosphorylation, either by modification of the same residue or nearby residues [520]. This PTM modification is regulated by only two enzymes: a glycosyltransferase that catalyzes the transfer of GlcNAc to substrate proteins, also known as O-GlcNAc transferase (OGT), and a glycoside hydrolase, also known as O-GlcNAcase (OGA) or O-N-acetylglucosaminidase, that catalyzes the hydrolysis of the glycosidic linkage [521].…”

“…Only recently O-GlcNAc was linked to the epigenetic code, demonstrating that the four core histones are substrates for O-GlcNAc modifications and cycle genetically and physically in order to interact with other PTMs of histones [520,522-526]. In addition, OGT has been described to target key members of the Polycomb and Trithorax groups [527].…”

Prenatal nutrition and the risk of adult obesity: Long-term effects of nutrition on epigenetic mechanisms regulating gene expression

“…Among the proteins that were post-translationally modified by O-GlcNAcylation, the group of gene expression regulators is well represented. Several excellent reviews on the O-GlcNAcylation of transcription factors have been recently published (see[152] and references therein); here we will focus on the epigenetic mechanisms affected by O-GlcNAcylation.On the functional side, O-GlcNAcylation has been shown to regulate chromatin dynamics through two different mechanisms: i-by tagging members of the polycomb group of proteins (PcG)[153] and other epigenetic regulators, such as the Ten-Eleven Translocation (TET) family of DNA hydroxylases/demethylases[154], and ii-by directly targeting the four core histones in chromatin[155,156], although it seems that there is also some extent of crosstalk between the two mechanisms. The polycomb group proteins are transcriptional regulators that mediate the repression of numerous genes along the development to adulthood.…”