5.13 : Spreading of Chromatin Modifications

The histoneproteins in the nucleosomes are post-translationally modified (PTM) to increase or decrease access to DNA. The commonly observed PTMs are methylation, acetylation, phosphorylation, and ubiquitination of lysine amino acids in the histone H3 tail region. These histone modifications have specific meaning for the cell. Hence, they are called "histone code". The protein complex involved in histone modification is termed as "reader-writer" complex.

Writers

The writer is an enzyme that can cause specific histone modifications. The common writer enzymes are histone methyltransferases (HMT) and histone acetyltransferases (HATs). HMTs add a methyl group to histone tail, which increases the chromatin compaction, inhibits transcription, and helps to differentiate newly synthesized strands from the parental strand during DNA replication. HATs add an acetyl group to histone tail, which decreases the chromatin compaction and allows access to DNA.

Erasers

The PTMs to histones are reversible and can be removed by another group of enzymes called "erasers". Common erasers are histone deacetylase and histone demethylase. They remove the acetyl or methyl group from the histone and alter the chromatin compaction.

Barrier proteins

Reader-writer complexes mark the euchromatin and heterochromatin regions on a chromatin. Acetylation of histone tail lysine marks the euchromatin, whereas methylation marks the heterochromatin region. It is important to separate the gene-rich euchromatin from gene-poor heterochromatin, for optimal regulation of gene expression. On a long chromatin strand, series of euchromatin and heterochromatin are separated by barrier sequences. These sequences prevent the spread of histone modification by several ways. For example, barrier proteins can tether chromatin to nuclear pore and prevent the spread of heterochromatin.

The aberrant activity of writer-eraser enzymes is correlated with several human diseases, including Alzheimer's, Fragile X syndrome, and cancer. In Fragile X syndrome, gene FRM1 required for normal cognitive development is hypermethylated, which leads to transcriptional silencing of the gene.