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Pathophysiology/Etiology
- Post-translational modifications (PTMs) of histone proteins (H2A, H2B, H3, H4) that regulate chromatin structure and gene expression. Histones are proteins that package DNA into nucleosomes.
- These modifications alter the electrostatic interactions between histones and DNA, and serve as docking sites for regulatory proteins.
- The “histone code” refers to the idea that specific combinations of modifications dictate downstream cellular events like transcription, DNA repair, and replication.
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Key Modifications & Their Function
- Acetylation:
- Mechanism: Addition of an acetyl group to lysine residues by Histone Acetyltransferases (HATs). This neutralizes the positive charge of lysine.
- Effect: Relaxes chromatin structure (euchromatin), making DNA more accessible for transcription. Generally associated with gene activation.
- Reversal: Removed by Histone Deacetylases (HDACs), leading to chromatin condensation and gene repression.
- Methylation:
- Mechanism: Addition of a methyl group to lysine or arginine residues by Histone Methyltransferases (HMTs).
- Effect: Can be either activating or repressing, depending on the specific amino acid residue methylated and the number of methyl groups added (mono-, di-, or tri-methylation).
- Activation Example: H3K4me3 (trimethylation of lysine 4 on histone H3) is associated with active gene promoters.
- Repression Example: H3K27me3 (trimethylation of lysine 27 on histone H3) is a repressive mark, often silencing developmental genes.
- Reversal: Removed by Histone Demethylases (HDMs).
- Phosphorylation:
- Mechanism: Addition of a phosphate group to serine, threonine, or tyrosine residues by kinases.
- Effect: Often involved in signaling pathways, particularly in DNA damage repair and chromosome condensation during mitosis.
- Ubiquitination:
- Mechanism: Addition of a ubiquitin protein to lysine residues.
- Effect: Can have varied effects; H2A ubiquitination is often repressive, while H2B ubiquitination can be activating or repressive. It also plays a role in the DNA damage response.
- Acetylation:
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Enzymes (Writers, Erasers, Readers)
- Writers: Enzymes that add modifications (e.g., HATs, HMTs, kinases).
- Erasers: Enzymes that remove modifications (e.g., HDACs, HDMs).
- Readers: Proteins that recognize and bind to specific histone modifications, recruiting other proteins to enact downstream effects.
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Clinical Correlations & Key Associations
- Cancer: Dysregulation of histone-modifying enzymes is a hallmark of many cancers.
- Oncogenes can be activated by aberrant acetylation.
- Tumor suppressor genes can be silenced by repressive methylation marks (e.g., increased H3K27me3 by overactive EZH2 methyltransferase in prostate and breast cancer).
- HDAC inhibitors (e.g., Vorinostat) are a class of anti-cancer drugs that promote histone acetylation, leading to the re-expression of silenced tumor suppressor genes.
- Neurological Disorders:
- Alzheimer’s Disease: Reduced histone acetylation has been observed, leading to the repression of genes involved in memory and learning.
- Fragile X Syndrome & Rett Syndrome: Associated with abnormal histone methylation patterns affecting genes crucial for brain development.
- Inflammatory Diseases: Histone modifications play a role in regulating inflammatory responses in conditions like rheumatoid arthritis and inflammatory bowel disease.
- Hematologic Malignancies: Altered patterns of histone methylation and acetylation are common in leukemias and lymphomas.
- Cancer: Dysregulation of histone-modifying enzymes is a hallmark of many cancers.
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Buzzwords
- Euchromatin: “Loose” chromatin, transcriptionally active. Associated with histone acetylation.
- Heterochromatin: “Condensed” chromatin, transcriptionally inactive. Associated with histone deacetylation and certain repressive methylation marks (e.g., H3K9me3).
- Epigenetics: Heritable changes in gene expression that do not involve alterations to the underlying DNA sequence. Histone modification is a key epigenetic mechanism.