Histone modifications and traditional Chinese medicinals

Hsin-Ying Hsieh,Sun-Chong Wang,Pei-Hsun Chiu

doi:10.1186/1472-6882-13-115

Hsin-Ying Hsieh, Sun-Chong Wang + Show 1 more

Open Access

https://doi.org/10.1186/1472-6882-13-115

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Abstract

BackgroundChromatin, residing in the nuclei of eukaryotic cells, comprises DNA and histones to make up chromosomes. Chromatin condenses to compact the chromosomes and loosens to facilitate gene transcription and DNA replication/repair. Chemical modifications to the histones mediate changes in chromatin structure. Histone-modifying enzymes are potential drug targets. How herbs affect phenotypes through histone modifications is interesting.MethodsTwo public traditional Chinese medicine (TCM) databases were accessed to retrieve the chemical constituents and TCM natures of 3,294 TCM medicinals. NCBI taxonomy database was accessed to build the phylogenetic tree of the TCM medicinals. Statistical test was used to test if TCM natures of the medicinals cluster in the phylogenetic tree. A public chemical-protein interaction database was accessed to identify TCM medicinals whose constituent chemicals interact with human histone-modifying enzymes. For each histone modification, a correlation coefficient was calculated between the medicinals’ TCM natures and modification modulabilities. Information of the ingredient medicinals of 200 classical TCM formulas was accessed from a public database.ResultsIt was found that 1,170 or 36% of the 3,294 TCM medicinals interact with human histone-modifying enzymes. Among the histone-modifying medicinals, 56% of them promote chromatin condensation. The cold-hot natures of TCM medicinals were found to be phylogenetically correlated. Furthermore, cold (hot) TCM medicinals were found to be associated with heterochromatinization (euchromatinization) through mainly H3K9 methylation and H3K4 demethylation. The associations were weak yet statistically significant. On the other hand, analysis of TCM formulas, the major form of TCM prescriptions in clinical practice, found that 99% of 200 government approved TCM formulas are histone-modifying. Furthermore, in formula formation, heterochromatic medicinals were found to team up with other heterochromatic medicinals to enhance the heterochromatinization of the formula. The synergy was mainly through concurrent DNMT and HDAC inhibition, co-inhibition of histone acetylation and H3S10 phosphorylation, or co-inhibition of H3K4 demethylation and H3K36 demethylation.ConclusionsTCM prescriptions’ modulation of the human epigenome helps elucidation of phyto-pharmacology and discovery of epigenetic drugs. Furthermore, as TCM medicinals’ properties are closely tied to patient TCM syndromes, results of this materia-medica-wide, bioinformatic analysis of TCM medicinals may have implications for molecular differentiation of TCM syndromes.

Highlights

Chromatin, residing in the nuclei of eukaryotic cells, comprises DNA and histones to make up chromosomes
In an attempt to address the hypothesis, we propose to look at traditional Chinese medicine (TCM) medicinals first because of the following two observations: 1) TCM doctrine dictates that TCM syndromes should be treated by the counteracting medicinals [7]; and 2) the cold-hot annotations of most TCM medicinals are available as they have been characterized and documented ever since the first TCM materia medica 2,000 years ago [18]
When we redefined the yin-yang scores by using the TCM flavours only and repeated the correlation analysis, we found, at the significance threshold of 0.05, yin-yang scores to be negatively correlated with H3K36 methylation (r = −0.07, P = 0.020) and H3K4 methylation (H3K4) demethylation (r = −0.07, P = 0.033) and positively correlated with H3S10 phosphorylation (r = 0.07, P = 0.029)

Summary

Introduction

Chromatin, residing in the nuclei of eukaryotic cells, comprises DNA and histones to make up chromosomes. Chemical modifications to the histones mediate changes in chromatin structure. Histones are evolutionarily conserved proteins that abound in the cells of eukaryotes including plants and animals [1]. They form protein families and two copies of each of the structurally similar histones H2A, H2B, H3 and H4 assemble into histone octamers. Nucleosome-nucleosome and histone-DNA interactions take place to tighten or loosen the chromatin structure, prohibiting or permitting access of the transcriptional machinery, such as RNA polymerase II and regulatory factors, to the DNA sequence. The relaxing chromatin is associated with active gene transcription [2], so is cytosine hypomethylation, a covalent modification to the DNA that is found in association with histone acetylation [3]. A histone code, supplementary to the DNA sequence, for cellular functions was recently proposed [4]

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