Box 1 | Histone methylation regulation is important for transcriptional control

From the following article:

Histone methylation: a dynamic mark in health, disease and inheritance

Eric L. Greer & Yang Shi

Nature Reviews Genetics 13, 343-357 (May 2012)

doi:10.1038/nrg3173

An interesting and untested hypothesis is that histone methylation could influence transcription by bringing physically separate regions of chromatin close together through chromosomal looping163 (panel a of the figure). This could include enhancer and promoter regions or, in the case of repressive interactions, it could include insulator elements164. However histone methylation might be a consequence of chromosomal looping. For instance, Polycomb group (PcG) proteins can regulate histone H3 lysine 27 (H3K27) methylation of distal sites after initial recruitment to a specific site165. Whether chromosomal looping is a cause or a consequence of transcriptional regulation remains to be determined.

Histone modifications can affect the higher-order chromatin structure directly166 or indirectly by recruiting chromatin-remodelling complexes167, 168. For example: BPTF, which is a component of the chromatin-remodelling complex NURF, contains a PHD finger that recognizes H3K4me3 (Ref. 65); zinc finger protein DPF3, a component of the BAF chromatin-remodelling complex, contains a double PHD finger that interacts with methylated histones169; and the chromodomains of chromodomain helicase (CHD) proteins also bind to methylated histones72, 170, 171. In yeast, H3K36me3 can recruit a histone deacetylase to affect transcription indirectly172.

Inaccessible chromatin domains can be 'opened' by so-called pioneering factors173, which are sequence-specific DNA-binding transcription factors (such as forkhead box protein A1 (FOXA1) and GATA4; panel b of the figure). After binding of the pioneering factors, DNA methylation and histone modifications could participate in making the chromatin more accessible for other transcription factors, the pre-initiation complex (PIC) and RNA polymerase II (RNAPII)174.

Certain histone methylation patterns (such as stretches of chromatin that are marked by a high density of H3K4 and H3K79 methylation) also appear to be necessary for binding of transcription factors (panel c of the figure), as highlighted by a study demonstrating that histone modifications affect binding of the transcription factor MYC to promoters in humans175 (presumably by providing a euchromatic environment, which facilitates sequence-specific binding). More work needs to be done to determine how widespread the role of histone modifications is in setting up local regions with specific histone modification signatures that are either conducive or antagonistic to the stable localization of DNA-binding factors, histone-modifying enzymes and effector proteins.

It is still unclear whether the recruitment of chromatin-remodelling machinery to sites of transcription176 enables more efficient transcription and/or is necessary for elongation to begin. The PHD finger of TAF3 — a component of the transcription factor II D complex (which itself is an essential component of the RNAPII PIC) — binds to H3K4me3 (Ref. 177), suggesting that the RNAPII machinery directly communicates with histone methylation to regulate transcription. The phosphorylation status of RNAPII (which determines whether RNAPII is in the initiation or elongation phase) regulates the binding of different chromatin-modifying proteins to RNAPII; these proteins methylate H3K4 or H3K36 or demethylate H3K27 potentially to facilitate transcription initiation or elongation (elongation is shown in panel d of the figure).

Despite advancements in understanding the role of histone methylation in transcriptional control, there is still a lot of uncertainty regarding the order of events; these are beginning to be deciphered176 but are still far from clear.

Histone methylation: a dynamic mark in health, disease and inheritance