Scientists reveal how epigenetic changes in DNA are interpreted

May 4, 2017, Karolinska Institutet

A new study in Science from Karolinska Institutet maps out how different DNA-binding proteins in human cells react to certain biochemical modifications of the DNA molecule. The scientists report that some 'master' regulatory proteins can activate regions of the genome that are normally inactive due to epigenetic changes. Their findings contribute to a better understanding of gene regulation, embryonic development and the processes leading to diseases such as cancer.

The DNA molecule carries information in the form of a sequence of four nucleotide bases, adenine (A), cytosine (C), guanine (G) and thymine (T), which can be thought of as the letters of the genomic language. Short sequences of the letters form 'DNA words' that determine when and where proteins are made in the body.

Almost all of the in the human body contain the letters in precisely the same order. Different are however active (expressed) in different cell types, allowing the cells to function in their specialised roles, for example as a brain cell or a muscle cell. The key to this lies in specialised DNA-binding proteins— factors—that bind to the sequences and activate or repress gene activity.

The DNA letter C exists in two forms, cytosine and methylcytosine, which can be thought of as the same letter with and without an accent (C and Ç). Methylation of DNA bases is a type of epigenetic modification, a biochemical change in the genome that does not alter the DNA sequence. The two variants of C have no effect on the kind of proteins that can be made, but they can have a major influence on when and where the proteins are produced. Previous research has shown that genomic regions where C is methylated are commonly inactive, and that many transcription factors are unable to bind to sequences that contain the methylated Ç.

By analysing hundreds of different human transcription factors, researchers at Karolinska Institutet in Sweden have now found that certain transcription factors actually prefer the methylated Ç. These include transcription factors that are important in , and for the development of prostate and colorectal cancers.

"The results suggest that such 'master' regulatory factors could activate regions of the genome that are normally inactive, leading to the formation of organs during development, or the initiation of pathological changes in cells that lead to diseases such as cancer", says Professor Jussi Taipale at Karolinska Institutet's Department of Medical Biochemistry and Biophysics who led the research.

The results pave the way for cracking the genetic code that controls the expression of genes, and will have broad implications for the understanding of development and disease. The availability of genomic information relevant to disease is expanding at an exponentially increasing rate.

"This study identifies how the modification of the DNA structure affects the binding of , and this increases our understanding of how genes are regulated in cells and further aids us in deciphering the grammar written into DNA", says Professor Taipale.

Explore further: Complex grammar of the genomic language

More information: Yimeng Yin, Ekaterina Morgunova, Arttu Jolma, Eevi Kaasinen, Biswajyoti Sahu, Syed Khund-Sayeed, Pratyush K. Das, Teemu Kivioja, Kashyap Dave, Fan Zhong, Kazuhiro R. Nitta, Minna Taipale, Alexander Popov, Paul A. Ginno, Silvia Domcke, Jian Yan, Dirk Schübeler, Charles Vinson, and Jussi Taipale. 'Impact of cytosine methylation on DNA binding specificities of human transcription factors'. Science, 5 May 2017. science.sciencemag.org/cgi/doi … 1126/science.aaj2239

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HannesAlfven
1 / 5 (5) May 05, 2017
Epigenetics has been mired in unwarranted controversy for a long time now. It seems most likely at this point that we should have known about this much earlier ...

The Rejection of Epigenetics
https://plus.goog...eZRc6xyp
Da Schneib
5 / 5 (4) May 05, 2017
The fight over epigenetics is finally ending. But not by denouncements from the pulpit- by hard data, which is how science really works.
gerardschmitt
5 / 5 (1) May 06, 2017
A very interesting book about epigenetics (published in 2011 already!)
The Epigenetics Revolution: How Modern Biology is Rewriting our Understanding of Genetics, Disease and Inheritance from Nessa Carey

Dingbone
May 06, 2017
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MadScientist72
5 / 5 (4) May 06, 2017
IMO the epigenetic has lotta to do with so-called dark matter of genetics, i.e. with so-called "junk" DNA, which doesn't code any useful protein.

Actually, the main function of epigenetics is to control the expression of genes & to ensure that the right proteins are produced at the right time in the right cells. The genome contains the recipe for making _all_ the proteins for _every_ cell in the body and some proteins that are essential for (for example) muscle cells could be extremely harmful if expressed in brain cells.
Epigenetics is also used to pass down _temporary_ adaptations (typically lasting no more than 3-4 generations) to transient environmental conditions like famine (https://www.scien...5240.htm ).
Da Schneib
5 / 5 (1) May 06, 2017
I have to admit I lost a lot of respect for genetic biologists when I observed their extremely negative reaction to the rather obvious (to anyone who knows any systematics) ideas of epigenetics. We already know, for example, that expression of enzymes for converting lactose is controlled by the presence of lactose, and that this happens directly on the DNA. It seems rather silly to argue against experimental evidence to me.
Da Schneib
5 / 5 (1) May 06, 2017
I think what I found most disheartening was that science professionals deployed the same sorts of arguments that evolution deniers used in denying epigenetics. It was unseemly to say the least. Now that data are flowing in, I hope they have a sense of embarrassment regarding this. It is this type of argument that marks the cranks, and apparently there were some very experienced and senior molecular biologists arguing against epigenetics who didn't think about the implications of the arguments they used. Since this has happened on this site I consider it cowardice that they have nothing to say on the matter.
Dingbone
May 06, 2017
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Da Schneib
5 / 5 (1) May 06, 2017
@Dungbone, you have nothing to say in this argument that is pertinent. Evolution is an established fact, and your denial is proof of your ignorance.
Dingbone
May 06, 2017
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Da Schneib
3 / 5 (2) May 06, 2017
@dungbone,
the epigenetics was most loudly dismissed just by evolution purists
Evolution.
Dingbone
May 06, 2017
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