Reprogramming of DNA observed in human germ cells for first time
Some genes that escape reprogramming may contribute to human diseases in subsequent generations
A team of researchers led by the University of Cambridge has described for the first time in humans how the epigenome – the suite of molecules attached to our DNA that switch our genes on and off – is comprehensively erased in early primordial germ cells prior to the generation of egg and sperm. However, the study, published today in the journal Cell, shows some regions of our DNA – including those associated with conditions such as obesity and schizophrenia – resist complete reprogramming.
Although our genetic information – the ‘code of life’ – is written in our DNA, our genes are turned on and off by epigenetic ‘switches’. For example, small methyl molecules attach to our DNA in a process known as methylation and contribute to the regulation of gene activity, which is important for normal development. Methylation may also occur spontaneously or through our interaction with the environment – for example, periods of famine can lead to methylation of certain genes – and some methylation patterns can be potentially damaging to our health. Almost all of this epigenetic information is, however, erased in germ cells prior to transmission to the next generation.
Professor Azim Surani from the Wellcome Trust/Cancer Research UK Gurdon Institute at the University of Cambridge, explains: “Epigenetic information is important for regulating our genes, but any abnormal methylation, if passed down from generation to generation, may accumulate and be detrimental to offspring. For this reason, the information needs to be reset in every generation before further information is added to regulate development of a newly fertilised egg. It’s like erasing a computer disk before you add new data.”
When an egg cell is fertilised by a sperm, it begins to divide into a cluster of cells known as a blastocyst, the early stage of the embryo. Within the blastocyst, some cells are reset to their master state, becoming stem cells, which have the potential to develop into any type of cell within the body. A small number of these cells become primordial germ cells with the potential to become sperm or egg cells.
In a study funded primarily by the Wellcome Trust, Professor Surani and colleagues showed that a process of reprogramming the epigenetic information contained in these primordial germ cells is initiated around two weeks into the embryo’s development and continues through to around week nine. During this period, a genetic network acts to inhibit the enzymes that maintain or programme the epigenome until the DNA is almost clear of its methylation patterns.
Crucially, however, the researchers found that this process does not clear the entire epigenome: around 5% of our DNA appears resistant to reprogramming. These ‘escapee’ regions of the genome contain some genes that are particularly active in neuronal cells, which may serve important functions during development. However, data analysis of human diseases suggests that such genes are associated with conditions such as schizophrenia, metabolic disorders and obesity.
Tang WWC, Dietmann S, Irie N, Leitch HG, Floros VI, Bradshaw CR, Hackett JA, Chinnery PF, Surani MA. A unique gene regulatory network resets the human germline epigenome for development. Cell. 4 June 2015. DOI: http://dx.doi.org/10.1016/j.cell.2015.04.053