Histone Modifications: The “Regulatory Switch” for Gene Expression
Notation of histone modifications: histone structure + amino acid name + amino acid position + type of modification. For example, H3K4ac indicates acetylation at lysine 4 on histone H3, and H2AK119ub1 represents monoubiquitination at lysine 119 on histone H2A.
01 Methylation Histone methylation is a crucial epigenetic modification regulating gene expression by adding methyl groups to specific amino acid residues (mainly lysine and arginine) on histones. Methylation is closely related to chromatin structure and function, promoting or repressing gene expression through various mechanisms.
Common methylation sites: H3K4: Associated with transcriptional activation. H3K9: Associated with transcriptional repression and heterochromatin formation. H3K27: Associated with gene silencing. H3K36: Associated with active transcription elongation. H3K79: Involved in DNA damage repair and transcription regulation. H4R3: Associated with transcription activation or repression, depending on methylation status.
Modifying enzymes: Histone methyltransferases (HMTs) and histone demethylases (HDMs).
Functional significance:
Regulating gene expression.
Controlling chromatin states.
Influencing cell differentiation and development.
Associated with diseases such as cancer, autoimmune disorders, and neurological diseases.
02 Acetylation Histone acetylation regulates chromatin structure and gene expression by adding acetyl groups (-COCH₃) to lysine residues on histones. This dynamic process is reversible and enzyme-regulated.
Common acetylation sites: H3K9ac: Generally linked to gene activation. H3K27ac: Associated with enhancer activity. H3K14ac: Linked to active transcription. H4K16ac: Associated with chromatin openness and gene activation.
Modifying enzymes: Histone acetyltransferases (HATs) and histone deacetylases (HDACs).
Functional significance:
Modulating chromatin openness.
Facilitating transcriptional activation.
Influencing cellular differentiation, DNA repair, and stress responses.
Linked to diseases such as cancer, neurodegeneration, and metabolic disorders.
03 Phosphorylation Histone phosphorylation regulates chromatin structure and gene expression by adding phosphate groups to specific amino acid residues (serine, threonine, tyrosine). This modification is linked to cellular signaling pathways, DNA damage repair, cell cycle regulation, and chromatin remodeling.
Common phosphorylation sites: H3S10:Associated with chromatin decondensation and gene activation. H3S28: Linked to gene activation. H2AXS139 (γ-H2AX): Marker for DNA damage repair. H2BS14: Associated with apoptosis.
Modifying enzymes: Protein kinases (addition) and phosphatases (removal).
Functional significance:
Altering chromatin structure.
Promoting gene activation.
Facilitating DNA damage repair.
Regulating the cell cycle and apoptosis.
04 Ubiquitination Histone ubiquitination involves covalent attachment of ubiquitin to specific histone sites, modulating chromatin structure, gene expression, and DNA repair.
Common ubiquitination sites: H2AK119ub1: Associated with gene silencing. H2BK120ub1: Associated with transcriptional activation.
05 Lactylation Histone lactylation, a newly discovered epigenetic modification (first reported in 2019), adds lactyl groups to histone lysine residues. It connects metabolism to epigenetic regulation.
Common lactylation sites: H3K18la: Linked to transcriptional activation.
Functional significance:
Regulating gene expression in response to metabolic changes.
Linking cellular metabolism to epigenetic regulation, especially during hypoxia, inflammation, and immune responses.
Potentially interacting with other histone modifications.
Histone Code These histone modifications work combinatorially to form a "histone code," recognized by specialized reader proteins determining chromatin states. Readers: Recognize and bind specific modifications (e.g., BRD4 binds acetylation). Writers: Enzymes catalyzing the addition of modifications (e.g., HATs, HMTs). Erasers: Enzymes removing modifications (e.g., HDACs, HDMs).
These proteins collectively regulate the dynamic nature and functional outcomes of histone modifications, forming intricate epigenetic regulatory networks.
