Know it, to control it

Chromatin Folding Around Histones (Part II)

Originally thought to be structural proteins maintaining DNA organization, histones are now known to also have functional roles in controlling gene transcription. Modification of histones affects their charge and ability to bind and position on DNA to carry out these processes and to interact with other non-histone proteins.

Seven major post-translation modifications are known to occur on histone tails in cells, namely: 1) acetylation, 2) methylation, 3) phosphorylation, 4) adenosine diphosphate (ADP)-ribosylation, 5) glycosylation, 6) sumoylation, and 7) ubiquitylation. Each has a distinct function and regulatory mechanism, while a few other histone modifications that are also involved in the regulation of histone function and chromatin structure have been identified recently. Although histone modifications do not require energy, chromatin remodeling process uses ATP molecules to change the nucleosome structure.

Chromatin remodeling can package genomic DNA and incorporate histones into the nucleosome (chromatin folding around histones) or release DNA from the histones.

Abnormal histone modifications have been observed in cancer cells, where they interfere with gene expression and destabilize the genome. Deacetylation or methylation of histones associated with DNA containing tumor suppressor genes results in loss of their expression.

Acetylation of histones associated with oncogenes increases cell proliferation and survival. Several agents have been designed to counteract aberrant histone acetylation. Histone deacetylase inhibitors have been evaluated in clinical trials as anticancer agents as both monotherapy and in combination with radiation or other agents. In vitro, they induce differentiation, cell-cycle arrest, and apoptosis. They can also inhibit migration, invasion, and angiogenesis and show antitumor activity.

Histone modification and chromatin remodelers play crucial function in regulating chromatin status, gene activity, and genome stability in the cells. However, these two mechanisms interact with each other to regulate chromatin.

Chromatin regulators modulate various DNA-templated processes, such as DNA replication, DNA recombination, gene transcription, DNA damage repair. Dysfunction of the chromatin regulators in human cells results in various human developmental defects and diseases.

In human malignancies, genetic alterations or aberrant expression of chromatin regulators have been identified as oncogenic drivers for numerous types of cancer. DNA transactions such as DNA replication/ repair/ recombination and RNA transcription are essential for cell viability and the basis for the origin of cancers.

It is at this level of chromatin folding and DNA replication that must be inhibited, to arrest cancer since genetic alterations in chromatin remodeling components are intimately linked with the genesis of cancer. Therefore, these are now the targets of many anticancer agents currently used in cancer chemotherapy.

Overall, the complex nature of histone methylation/demethylation and shared enzyme functions and many normal functions are also dependent on the balance of modified histones. Counteracting aberrant histone modifications will require a highly specific compound, both in structure and in mechanism of action. However, these molecular mechanisms and the biology of chromatin-regulating proteins, which are critical for many cell functions, such as the cell cycle, cell differentiation, and stem cell maintenance are not clearly elucidated yet.

A clearer picture can further help in developing targeted therapies to combat specific cancers with specific mal-functioning chromatin-regulating protein.