Chromatin Insulators and Epigenetic Inheritance in Health and Disease

The genome of eukaryotic organisms is compacted in the nucleus in a manner that allows transmission of the genetic material between generations and access of the replication and transcription machinery to the DNA. Expression or repression of specific genes is accompanied by alterations in the local chromatin carried out by DNA methyl transferases, histone modifying enzymes, ATP-dependent chromatin remodeling complexes, and histone chaperones that replace canonical histone for specific variants. Some of these changes in chromatin structure can be transmitted from mother to daughter cells or from one organismal generation to the next. As a consequence, alterations in the structure of the 10 nm chromatin fiber can carry epigenetic information encoding a memory of specific transcriptional states. Less understood is whether this chromatin fiber is arranged into higher-order levels of organization and, if so, whether they contribute to the establishment of patterns of gene expression that can be epigenetically inherited. Results obtained in the last few years suggest an affirmative answer to these two questions. Chromatin insulators are DNA-bound protein complexes that can mediate intra- and inter-chromosome interactions. In doing so, they can bring close together regulatory sequences located at large distances from each other. The effect on the expression of adjacent genes depends on the nature of the sequences brought into proximity, resulting in activation or repression of single genes or large chromosomal domains. In the process, insulators can then alter the status of the chromatin in these genes or domains and, as a consequence, modify patterns of epigenetic inheritance. It is now becoming apparent that insulator-mediated interactions contribute to the establishment of a three-dimensional organization of the DNA in the nucleus. Since this structure is directly related to gene expression, it follows that the organization of the genome within the nucleus is in part a determinant and in part a consequence of the transcriptional status of a