Transcriptional Regulation and Epigenetics

Epigenetics

Somatic cells have tags (such as DNA methylation or histone alterations) on most genes, which prevent them being expressed and only allow the subset of genes needed in that tissue to be active (see more on our teaching pages here). These tags prevent adult skin cells from turning into, say, nerve cells, by blocking the genes needed for nerve function. To generate Dolly the sheep, scientists fused adult skin cells with an egg: the egg removed the blocks on gene transcription and reverted the specialised skin cell to a stem cell. This could then go on to form nerve cells and all the other tissues found in an adult animal. Reprogramming is still, however, enormously inefficient. We have been studying how cells undergo reprogramming, especially how they remove blocks on transcription of certain genes and when they add new blocks. We are studying how and when this process occurs and what proteins are involved in controlling it. We have found a number of candidates, which are likely to be involved by a variety of techniques such as RT-PCR, RACE cloning and the use of microarray screening.

DNA methylation is the tag which we know most about and for which evidence is strogest that it plays a vital role in determining which genes are actvie and inactive. Methylation plays a key role in regulating the imprinted genes, such as H19 and Snrpn and can be found in regulatory regions called

DMR (Figure 1).

Figure 1

Figure 1. Schematic showing the position of the Differentially Methylated Regions (DMR) which control the expression of the H19 (top) and Snrpn (bottom) genes. Failure to establish menthylation correctly can contribute to overgrowth disorders in humans such as Beckwith-Weidemann and Prader-Willi Syndromes.

Imprinted genes have methyl tags on one chromosome (we have two copies of each chromosome except the sex chromosomes) which prevent that copy from being active. Thus, we inherit an active H19 from the mother, but a silent, methylated H19 from the father (Figure 2).

Figure 2

Figure 2. Methylation status of four imprinted genes in mouse. In oocytes, no methylation is present on Gtl2, Rasgrf1 and H19, but Snrpn is heavily methylated (filled circles). The opposite is true of the copies present in sperm (second row). In other, somatic tissues 50% of the copies of the genes are methylated, representing the father’s (H19) or mother’s (Snrpn) chromosomes respectively.

Problems with methylation establishment can lead to infertility, a failure to establish imprints and subsequent problems with embryogenesis or childhood disease. See also the page on fertility.