Histones, the essential structural proteins of eukaryotic chromosomes, consist of five types: H1, H2A, H2B, H3, and H4. These small alkaline proteins are characterized by a high content of positively charged basic amino acids, enabling interactions with the negatively charged phosphate groups in DNA. Through various post-translational modifications (PTM), histones can modify their DNA binding, exerting influence on gene expression. Thus, histones serve as vital components in maintaining chromosome structure and act as negative regulators of gene expression. The epigenetic modifications of histones are closely linked to critical biological processes such as growth, development, and cancer.
Fig.1 Biological effects mediated by histone modifications.1,3
Fig.2 PTMs of histone amino terminus.1,3
Histone methylation is the process of adding methyl groups to lysine or arginine residues that mainly happens at the n-terminus of H3 and H4. Histone methylation is managed by various enzyme families. The protein arginine methyltransferase (PRMT) family members, like co-factor associated arginine methyltransferase (CARM1), PRMT1, and PRMT5, primarily catalyze histone arginine methylation, while the SET domain-containing methyltransferases regulate histone lysine methylation. Histone demethylases (HDMs) include proteins containing the Jumonji C domain and lysine-specific demethylase 1 (LSD1). Histone methyltransferases (HMTs) and HDMs maintain a dynamic balance of methylated histones, which may lead to various developmental disorders and diseases such as cancer when imbalanced. Specifically, the upregulation of H3K27me3 methyltransferase has been observed in conditions such as breast cancer and lymphoma.
Histone acetylation is co-regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), playing a crucial role in gene transcription. HATs like p300/CBP, p CAF, and ACTR add acetyl groups to histones, promoting an open chromatin structure that enhances transcription factor binding and gene activation. Conversely, HDACs such as HDAC1, HDAC2, and HDAC3 function to inhibit gene expression. Disruption of histone acetylation is implicated in various diseases, including tumors, metabolic disorders, and neurological conditions.
Histone phosphorylation refers to the addition of phosphate groups to the N-terminal amino acid residues of histones. Major types include phosphorylation of histone H1, H2A/H2B, H3, and H4. This modification typically takes place during DNA repair and mitosis. Different isoforms of histone phosphorylation play crucial roles in processes like gene transcription, DNA repair, apoptosis, and chromosome condensation. Histone phosphorylation plays a unique role compared to acetylation and methylation by facilitating interactions between different histone modifications. This allows for the formation of a scaffold that enables effector proteins to trigger downstream cascade reactions.
Histone ubiquitination involves attaching ubiquitin (Ub) to histone lysine residues, encompassing both mono-ubiquitination and polyubiquitination. While all histone core proteins are susceptible to ubiquitination, H2A and H2B are more commonly targeted and undergo mainly reversible mono-ubiquitination. Conversely, polyubiquitination of histones creates signals for irreversible proteasome-mediated degradation. E3 ligase facilitates the addition of Ub, and deubiquitinating enzymes (DUBs) play a role in removing Ub, maintaining a balance of ubiquitination levels in vivo. Disruption in ubiquitination regulation is implicated in various diseases, such as brain-related disorders and cancer.
Tab.1 Classification and associated markers of histone modifications.
| Modification Type | Histone Markers |
| Methylation | H1K26me1,H3K4me1/2/3,H3K9me1/2/3,H3K27me1/2/3,H3K36me1/2,H4K20me1/2 |
| Acetylation | H3K9ac,H3K14ac,H3K18ac,H4K8ac,H4K16ac |
| Phosphorylation | Gamma H2A.X,H3S10ph,H4S1ph |
| Ubiquitination | H2AK15ub,H2AK119ub,H2BK120ub1 |
ChIP is a widely used histone modification assay that helps detect the location and abundance of target proteins and their modifications in the genome. This assay is crucial for analyzing chromatin structure and gene expression. By using specific antibodies to enrich modified histones from cells or tissues, ChIP allows for further analysis of these histones through techniques like PCR, sequencing, or mass spectrometry to pinpoint the presence and localization of the modifications.
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