Epigenetic memory in the context of nuclear reprogramming and cancer

Abstract

Epigenetic memory represents a natural mechanism whereby the identity of a cell is maintained through successive cell cycles, allowing the specification and maintenance of differentiation during development and in adult cells. Cancer is a loss or reversal of the stable differentiated state of adult cells and may be mediated in part by epigenetic changes. The identity of somatic cells can also be reversed experimentally by nuclear reprogramming. Nuclear reprogramming experiments reveal the mechanisms required to activate embryonic gene expression in adult cells and thus provide insight into the reversal of epigenetic memory. In this article, we will introduce epigenetic memory and the mechanisms by which it may operate. We limit our discussion primarily to the context of nuclear reprogramming and briefly discuss the relevance of memory and reprogramming to cancer biology.

Keywords: DNA methylation; cancer; epigenetic memory; histone modifications; nuclear reprogramming.

Figure 1:

Mechanisms that may maintain epigenetic memory through DNA replication. (A) DNA methylation (‘me’ bubbles on cytosine bases, represented by ‘C’, on DNA strands which are represented by a black lines) is maintained by a mechanism of semi-conservative replication. After replication of the DNA strands, hemi-methylated CpG sites become fully methylated by the action of DNMT1. The DNA methylation pattern in the paternal strand provides a template for methylation of the nascent strand. (Bi) Epigenetic information on nucleosomes (represented here as quartered balls, with each of the four histones as a quarter of the ball, on a DNA strand, represented by black lines) may be transmitted to each of the daughter DNA strands during DNA replication by semi-conservative distribution of half of the nucleosome to each new DNA molecule. Unmodified histones (white quarters) are then incorporated with the old histones to make up a full nucleosome with half of the octomer marked. The histone marks are then copied to the new histones within each nucleosome by the action of histone-modifying enzymes. (Bii) An alternative hypothesis to semi-conservative nucleosome replication suggests that marked nucleosomes are randomly associated with each of the new DNA strands, becoming interspersed at random with new nucleosomes without any markings. Epigenetic information will then be transmitted to new nucleosomes by the action of histone modifying enzymes using marked neighboring nucleosomes as a template.

Figure 2:

Epigenetic memory is revealed by reprogramming experiments. Memory is revealed by nuclear reprogramming experiments when the transcriptional state of a particular gene fails to change to the induced state (top box). An example of this is the failure to activate pluripotency genes, which are ‘off’ in somatic cells, following an inducing signal to activate these genes (such as the Yamanaka reprogramming factors). In contrast, genes are competent for reprogramming if they correctly change to the induced state, in which case no memory is seen (middle box). If the transcription state of a gene is the same as the induction state (‘in phase’) then no change will be observed (bottom box).