Epigenetics could explain puzzle of diabetes inheritance

A mother's diet in pregnancy can permanently affect her child — and could be strongly influenced by genetic variation in an unexpected part of the genome — her ribosomal DNA.

According to research led by Queen Mary University of London (QMUL), a mother's diet during pregnancy can permanently affect her offspring, as measured by how her diet affects her ribosomal DNA (rDNA). This discovery could be why many human gene studies cannot fully explain how certain diseases, such as type 2 diabetes and obesity, are inherited.

This research is published in Science and co-authored by University of Cambridge and King's College London.

Genetic variation in ribosomal DNA (rDNA) could be driving how the womb environment determines an offspring's attributes. rDNA is the genetic material that forms ribosomes — protein building machines within each cell.

The ribosome is a complex machine within all living cells. It reads messenger RNA (mRNA) then links proteins to the amino acids specified. Ribosomes have two major components: (1) a small ribosomal unit to read RNA, and (2) a large unit that joins mRNA to amino acids — thereby making polypeptide chains. Together the two units are known as a translational apparatus.

Lead researcher Vardhman Rakyan PhD, Professor of Epigenetics from QMUL: "The fact that genetic variation of ribosomal DNA seems to play such a major role suggests that many human genetics studies could be missing a key part of the puzzle. These studies only looked at a single copy of part of an individuals' genomes — never at ribosomal DNA.

"This could be the reason why we've only so far been able to explain a small fraction of the heritability of many health conditions; which makes a lot of sense in the context of metabolic diseases, such as type 2 diabetes."

Within the in-utero environment, environmental factors act alongside genetic factors to determine a person's attributes. When offspring are in the womb, they experience their mothers environmental influences (like diet, stress, and smoking). These influences continue to affect offspring even when they are adults. 'Developmental programming' is a large contributor to our obesity epidemic.

A major contributor in this process is 'epigenetics' — modifications to genes that control when or if, certain genes function. One modification involves tagging DNA with compounds called methyl groups.

Methyl groups mark which genes are turned on and functioning (expressed) or not (un-expressed).

Liver cells and kidney cells are genetically identical
except for their epigenetic marks.

It has been observed that an offspring's
epigenetic profile changes in response
to a poor in-utero environment.

The team compared offspring of pregnant mice fed a low protein diet - 8 per cent protein - to a normal diet of 20 per cent protein. After being weaned, all mouse pups were fed the same normal diet with 20 per cent protein. The team then looked at the difference in DNA methylation in pups born to mothers exposed to low protein and normal protein diets.

Histones (dark blue balls ) wind DNA chomatine tightly - and make it inaccesible for transcription into protein — or loosely alowing DNA to be more easily transcribed (readable). Methyl groups TAG histone tails marking chromosome areas for change. Image Credit: Epigenetics for Beginners

"Initially, we found nothing, so that was a big surprise, but then we looked at the ribosomal DNA (rDNA) data and found huge epigenetic differences.

"When cells are stressed — for example when nutrient levels are low — they alter protein production as a survival strategy. In our low protein mice mothers, we saw that their offspring had methylated ribosomal DNA (rDNA).

"This slowed the expression [turning on] of their rDNA, which could influence the function of ribosomes, and result in smaller offspring — as much as 25 per cent lighter."

Vardhman Rakyan PhD, Professor of Epigenetics, Centre for Genomics and Child Health, Queen Mary University of London.

These epigenetic effects occur in a critical developmental window, while the offspring is in-utero, to create a permanent effect remaining throughout adulthood. A pregnant mother's low protein diet is therefore likely to have more severe consequence on her offspring's epigenetic state and weight, than an offspring's own diet after weaned from its mother.

In any given genome, there are many copies of rDNA, and Professor Rakyan and colleagues found that not all copies of rDNA responded epigenetically. In offspring from mothers fed low protein diets, only one form of rDNA — the 'A-variant' — appeared to undergo methylation affecting weight.

This means an epigenetic response in any given mouse is determined by their own genetic variation of rDNA. Those mice with more A-variant rDNA end up being smaller.

"Even though all mice in the study were bred to be genetically identical, we found that rDNA in individual mice is not genetically identical. That even within an individual mouse, different copies of rDNA were genetically distinct.

"So there is huge variation in rDNA also playing a big role in determining the attributes given offspring."

Vardhman Rakyan PhD

Heritability of type 2 diabetes — the risk of disease explained by genetic factors — is estimated to be between 25 and 80 per cent in different studies. However, only about 20 per cent of heritability of type 2 diabetes is explained in people with the disease. Genetic variation in rDNA could explain some missing heritability.

These findings also complement other studies where mice put on high fat diets have pups with increased rDNA methylation — suggesting methylation is a general stress response. This may explain our rise in obesity happening around the world.

Abstract Reference
Research paper: 'Early life nutrition modulates the epigenetic state of specific rDNA genetic variants in mice'. Michelle L. Holland, Robert Lowe, Paul W. Caton, Carolina Gemma, Guillermo Carbajosa, Amy F. Danson, Asha A. M. Carpenter, Elena Loche, Susan E. Ozanne, Vardhman K. Rakyan. Science 2016; 7 July 2016; DOI: 10.1126/science.aaf7040

The study was funded by the Biotechnology and Biological Sciences Research Council (BBSRC), Research Councils UK, EU-FP7, British Heart Foundation and Medical Research Council (MRC).

About Queen Mary University of London
Queen Mary University of London (QMUL) is one of the UK's leading universities, and one of the largest institutions in the University of London, with 20,260 students from more than 150 countries.
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Within a cell, the (5) rough endoplasmic reticulum is studded with protein
manufacturing ribosomes (dark blue dots), giving it a "rough" appearance .
Image Credit: Wikipedia.org