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Epigenetic memory

September 1, 2013, San Diego, Calif.—Each of us possesses our own unique genetic code, a fact that presents a monumental conundrum: How does that one singular sequence of DNA dictate the creation and function of our multitudinous and varied cells. Your skin cells, muscle cells and fat cells all share the same genetic information, but perform wildly different roles. What defines and determines those functions?

The answer, in a word, is the epigenome, a Greek-derived word that literally means “above the genome.” The epigenome consists of all of the chemical compounds that modify or mark the genome in a way that tells DNA what to do, where to do it and when.

The study of the epigenome is a relatively young endeavor, and much is not known. One of the tools of the epigenome is DNA methylation, a process in which a methyl group is added to cytosine DNA nucleotides, marking genes for repression, silencing repetitive elements and making genomic imprinting possible.

In normal mammalian development, DNA methylation dramatically changes as new cell lineages emerge. “This complex remodeling is evidently essential for development, as loss of the machinery that established DNA methylation results in embryonic lethality,” said Gary C. Hon, a Ludwig scientist based at UC San Diego.

In a new paper published online Sunday in Nature Genetics, first author Hon, senior author Bing Ren, PhD, Ludwig scientist at UC San Diego, and colleagues probe deeper into the mysteries of epigenetics, reporting on how DNA methylation changes in different kinds of tissue.

“We created very high resolution maps of DNA methylation for 17 diverse tissues in an individual mouse,” said Hon. “Interestingly, we found that if you look at DNA methylation with a wide angle lens, you’ll find that it is generally constant between different tissues. But if you zoom in, there are a large number of short regions that show very tissue-specific DNA methylation, and the vast majority of these regions happened at the many regulatory elements encoded in the genome that control the genes specifically to a tissue.”

The epigenome reveals the current state of a cell and, in embryonic cells, portions of it can reflect the cell’s potential future developmental paths – what it will be when it grows up. Ren, Hon and colleagues discovered, to their surprise, that in adult tissues, some of these regions of tissue-specific DNA methylation involved regulatory elements that were no longer active, but had been during development.

“In this way, the epigenome of each adult tissue is imprinted with the regulatory memory of its past,” said Hon.

The findings are fundamental science. They “do not have immediate clinical relevance. They simply help understanding of development,” said Hon. But they may also auger greater import in the future, bolstering the recognized importance of DNA methylation and providing “an epigenetic signature that can be used to find regulatory elements active in development, but which are no longer active in adult tissues.”

Such a signature might be helpful to understanding the origins of diseases that occur early in developing life, a necessary step before science can take action to prevent them.

Bing Ren is a Ludwig member and head of the laboratory of gene regulation at Ludwig San Diego.

Adapted with permission of the UC San Diego School of Medicine.


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