Monday, 6 June 2016

Editing and Interpreting Chromatin Modifications

Molecular tagging of chromatin marks structural and functional genome regions, enhancing transcriptional responses to distinct signaling cues.

A useful conceptual model for epigenetics is that of writers, erasers, and readers of chemical modifications on histones and DNA.

Specific enzymes modify discrete residues on chromatin, generating marks that designate certain regions for transcriptional regulation.

Another class of enzymes, the so-called erasers, can remove these histone and DNA modifications.

Finally, a third group of proteins—readers—recognises and associates with chromatin marks, facilitating or inhibiting assembly of the transcriptional machinery and subsequently regulating gene expression. 

The best characterised chromatin modification is the classically epigenetic methylation of cytosine (methyl-cytosine) nucleotides immediately adjacent to guanine nucleotides (CpG) in the DNA sequence.

DNA methylation is commonly associated with gene suppression when enriched at or near gene regulatory regions by modulating transcription factor binding to directly interfere with gene activation, or by interacting with specific regulatory proteins such as MeCP2 (methyl-CpG binding protein 2).

Recent characterization of the family of ten-eleven-translocation (TET) proteins, which can generate hydroxymethylcytosine, formylcytosine, and carboxylcytosine from existing methylcytosine has inspired strong interest in demethylating pathways. 

Similarly, the myriad post-translational modifications are written to and erased from predominantly arginine and lysine amino acid residues on the protruding N-terminal tails of chromatinised histones by specialised enzymes and modifying complexes.

Methyl groups also feature heavily on histone tails and are associated with both active and silent genes depending on the specific location and degree of modification. The histone methylating functions of enzymes such as Set7 are opposed by the demethylating activities of enzymes such as LSD1.

Contrasting this dual role of histone methylation, histone lysine acetylation, regulated by opposing roles of acetyltransferases (HATs) and deacetylases (HDACs), is exclusively associated with transcriptional competency.

The influence of histone post-translational modifications on higher order chromatin structure and transcriptional regulation is largely attributed to (1) charge disruption of histone tails in the case of acetylation/deacetylation which alters affinity for adjacent histones and DNA, and (2) the establishment of high-affinity binding sites for recruitment of complexes that actively remodel the chromatin.

In conjunction with transcription factor networks and remodelling complexes, these covalent and post-translational modifications collaboratively drive the functional exchange between repressed and active states of chromatin to contextualise gene activity.

Our review, published in Circulation Research (May 2016), discusses recent key findings in a rapidly burgeoning arena of research into chromatin-dependent mechanisms defining cardiometabolic health and dysfunction. Read the full article here.