Chromatin insulators: regulatory mechanisms and epigenetic inheritance

Abstract

Enhancer-blocking insulators are DNA elements that disrupt the communication between a regulatory sequence, such as an enhancer or a silencer, and a promoter. Insulators participate in both transcriptional regulation and global nuclear organization, two features of chromatin that are thought to be maintained from one generation to the next through epigenetic mechanisms. Furthermore, there are many regulatory mechanisms in place that enhance or hinder insulator activity. These modes of regulation could be used to establish cell-type-specific insulator activity that is epigenetically inherited along a cell and/or organismal lineage. This review will discuss the evidence for epigenetic inheritance and regulation of insulator function.

Figure 1

The role of insulators in epigenetic memory. (A) Insulator protein binding could be an epigenetic mark that is maintained through cell division. Locus A and Locus B represent two different genomic loci that contain insulator elements. Locus A is bound by an insulator protein that prevents transcription, whereas locus B is unbound and therefore able to produce a gene product (pentagon). If insulator protein binding acts as an epigenetic mark, binding or lack of binding is remembered after cell division. (B) An insulator could participate in an epigenetic signal through regulating a gene that establishes an epigenetic mark. In this situation, loss of insulator protein binding leads to production of a gene product (pentagon) that establishes an epigenetic mark, here in Locus B. The epigenetic mark is maintained through cell division regardless of the state of the insulator. Therefore, the insulator participates in the establishment of the epigenetic mark, but is not the mark itself. Squares – enhancer binding proteins; Circles – insulator proteins; Pentagons – gene products whose expression is regulated by insulators; Ovals – epigenetic marks.

Figure 2

Regulation of insulator activity. (A) Insulator function could be regulated on the level of DNA-binding activity. Regulation could be positive or negative and could occur by various molecular mechanisms, including DNA modification, protein modification, protein-protein interaction, and effects of nearby chromatin. (B) Insulator function could be regulated on the level of protein-protein interaction. Again, regulation could be positive or negative. Molecular mechanisms could include protein modification, protein-protein interaction, effects of nearby chromatin, and interaction with small RNAs.