5.13

Spreading of Chromatin Modifications

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Reader enzymes act in collaboration with writer or eraser enzymes to create chromatin modifications and spread the chromatin changes for a substantial distance along a chromosome.

The process, which functions similarly with writer and eraser enzymes, is described here using the reader and writer combination as an example.

The process begins when a transcriptional regulatory protein binds to a specific DNA sequence. After binding, the regulatory protein recruits a writer enzyme to that specific site on a chromosome.

The writer enzyme then starts to add marks to the core histones.

Once marks have been added to one or more neighboring nucleosomes, a multiprotein complex containing a ‘reader’ enzyme that recognizes these marks, binds tightly to the newly modified nucleosome.

The binding activates the ‘writer’ enzyme of the multiprotein complex and positions it near an adjacent nucleosome, enabling it to add a new mark.

Working in concert, the reader and writer enzymes of the complex catalyze a series of many ‘read and write’ cycles. These cycles spread a chromatin modification, such as chromatin condensation, along a chromosome.

The boundary between adjacent chromatin domains like euchromatin and heterochromatin, which have different structures and functions, is marked by specific DNA sequences called ‘barrier sequences.’

These barrier sequences act as the binding sites for various barrier proteins, which block the propagation of heterochromatin into euchromatin by mediating different barrier actions.

For example, some barrier proteins recruit histone-modifying enzymes which erase the histone marks that are required for the spreading of the heterochromatin.

Some barrier proteins tightly bind to the group of nucleosomes, covering them up and thereby making the covered euchromatin resistant to heterochromatin spreading.

Yet another barrier protein tethers a region of chromatin to large fixed sites, such as nuclear pores, and forms a barrier that stops the spread of heterochromatin.

Overview

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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.

Transcript

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$$\rightleftharpoonup{xx}$$ $$\longleftharp{xx}$$, $$\longrightharp{xx}$$,

Reader enzymes act in collaboration with writer or eraser enzymes to create chromatin modifications and spread the chromatin changes for a substantial distance along a chromosome.

The process, which functions similarly with writer and eraser enzymes, is described here using the reader and writer combination as an example.

The process begins when a transcriptional regulatory protein binds to a specific DNA sequence. After binding, the regulatory protein recruits a writer enzyme to that specific site on a chromosome.

The writer enzyme then starts to add marks to the core histones.

Once marks have been added to one or more neighboring nucleosomes, a multiprotein complex containing a ‘reader’ enzyme that recognizes these marks, binds tightly to the newly modified nucleosome.

The binding activates the ‘writer’ enzyme of the multiprotein complex and positions it near an adjacent nucleosome, enabling it to add a new mark.

Working in concert, the reader and writer enzymes of the complex catalyze a series of many ‘read and write’ cycles. These cycles spread a chromatin modification, such as chromatin condensation, along a chromosome.

The boundary between adjacent chromatin domains like euchromatin and heterochromatin, which have different structures and functions, is marked by specific DNA sequences called ‘barrier sequences.’

These barrier sequences act as the binding sites for various barrier proteins, which block the propagation of heterochromatin into euchromatin by mediating different barrier actions.

For example, some barrier proteins recruit histone-modifying enzymes which erase the histone marks that are required for the spreading of the heterochromatin.

Some barrier proteins tightly bind to the group of nucleosomes, covering them up and thereby making the covered euchromatin resistant to heterochromatin spreading.

Yet another barrier protein tethers a region of chromatin to large fixed sites, such as nuclear pores, and forms a barrier that stops the spread of heterochromatin.

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Chromatin Modifications

Histone Modifications

Reader Writer Complex

Histone Methylation

Histone Acetylation

Chromatin Compaction

Barrier Proteins

Euchromatin Heterochromatin

Transcriptional Regulation