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Histone Modifications and Traditional Chinese Medicinals

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Histone Modifications and Traditional Chinese Medicinals

Hsin-Ying Hsieh et al. BMC Complement Altern Med.

Abstract

Background: Chromatin, 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.

Methods: Two 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.

Results: It 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.

Conclusions: TCM 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.

Figures

Figure 1
Figure 1
Phylogenetic tree of 1,208 Traditional Chinese Medicinals. Among the 3,294 TCM medicinals, 1,208 have entries in the NCBI taxonomy database. The scientific names of the medicinals, encompassing fungi, birds, snakes, …, and citrus, are replaced by numbers from 1 to 1208 counterclockwise from the right middle. Colors of the labels are linearly proportional to the cold-hot TCM natures of the medicinals so that the lighter the color the colder the medicinal. NA means the medicinal does not have a cold-hot annotation in the TCM database. Clustering of colors along the circle indicates positive phylogenetic correlation of the medicinals’ cold-hot property. Additional file 1: Figure S4 is the same figure with scientific names and in a vector format so that the image can be magnified indefinitely to read the names.
Figure 2
Figure 2
Proportion of histone-modifying TCM medicinals among the 3,294 TCM medicinals. Histone-modifying medicinals are considered chromatin unpacking if they cause more euchromatic modifications than heterochromatic modifications, etc.
Figure 3
Figure 3
Hierarchical clustering of the 1,170 histone-modifying TCM medicinals and the 18 modifications. A row represents a medicinal and a column a modification. The lighter (darker) the shade, the more potent the medicinal is to activate (inhibit) the modification. Modifications are close within clades in the upper dendrogram if they are similarly utilized among the medicinals. Refer to Table 1 for the abbreviations of the modifications.
Figure 4
Figure 4
Hierarchical clustering of the 199 histone-modifying TCM formulas and the 18 modifications. A row represents a formula and a column a modification. The lighter (darker) the shade, the more potent the formula is to activate (inhibit) the modification. Modifications are close within clades in the upper dendrogram if they are similarly utilized by the formulas. Refer to Table 1 for the abbreviations of the modifications.
Figure 5
Figure 5
Difference in the heterochromatinization between a formula and its composing medicinals. A medicinal’s heterochromatinization is from the net number of heterochromatic modifications (me for methylation, ph for phosphorylation and ac for acetylation) it makes. A formula’s heterochromatinization is from the net number of heterochromatic modifications that the chemicals in the composing medicinals make. The difference should be compared to that from the 200 simulated control formulas (in red) that are similar to the real formulas in terms of median number of composing medicinals and median number of composing medicinals that are histone-modifying, except that the medicinals are randomly selected from the pool of medicinals making up the 199 real formulas. The closer the while boxes to zero than the red boxes indicates that, when formulas are formed, changes in the heterochromatic property are less than expected.

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