Nav: Home

The silence of the genes

November 24, 2015

Research led by Dr. Keiji Tanimoto from the University of Tsukuba, Japan, has brought us closer to understanding the mechanisms underlying the phenomenon of genomic imprinting. In this intriguing event, one copy of a gene is 'turned off', or silenced, depending on whether it was derived from the mother or the father. The research team has identified a segment of DNA that is essential in the imprinting process for the closely linked Igf2/H19 genes, two of the first imprinted genes to be discovered. If these genes are incorrectly imprinted, it can lead to the overgrowth (Beckwith-Wiedemann) or dwarfism (Silver Russell) syndromes, and also has a role in some kidney and liver cancers.

We each inherit two copies of every gene - one from our mother and one from our father. For most genes, both copies are active and working. In a small number of genes, however, one copy is turned off depending on its parental origin. These genes are termed imprinted because the one copy was tagged or imprinted via modifications to the DNA in either the egg or the sperm. The mechanisms for imprinting are not fully understood, but they involve modifications to the DNA that are removed and then reset 'de novo' during the creation of eggs and sperm. These modifications are termed epigenetic modifications, as the DNA sequence itself is not altered.

Normally we only have one copy of a silenced gene. If an error occurs in the imprinting process, we might end up with two active copies of the gene or two inactive or silenced copies. This can lead to abnormal development, behavioral disorders, cancer and various disease syndromes, such as the behavioral and neurodevelopmental disorders Prader-Willi and Angelman syndromes. Imprinting disorders have also been linked to diabetes, for example.

As reported in the latest volume of the prestigious journal Development, the team of scientists from the University of Tsukuba, the Nagahama Institute of Bio-Science and Technology, Osaka University and the National Research Institute for Child Health and Development, investigated when and how the imprinted Igf2/H19 genes in mouse are modified during early development in order to further understand the mechanisms underlying the imprinting process. The Igf2/H19 genes in mouse are two of the best characterized imprinted genes and the same imprinting pattern has been found in their human equivalents, making them ideal candidates for further research.

Imprinted genes are controlled by nearby DNA sequences, so-called imprinting control regions (ICRs), which have parental-specific modifications, including DNA methylation. Methylation is a chemical reaction that attaches small molecules called methyl groups to certain segments of DNA. In genes that undergo genomic imprinting, methylation is one way that a gene's parent of origin is marked during the formation of egg and sperm cells. ICRs are methylated by proteins called DNA methyltransferases (DMTs) during egg and sperm development. This methylation is faithfully maintained at the imprinted gene throughout development, even in early embryos where genomes undergo extensive reprogramming, including removal of methylation from the DNA. The H19 ICR in the mouse is DNA-methylated by two DMTs, Dnmt3a and Dnmt3L, during sperm formation. This methylation is maintained on the paternally-derived copy of the Igf2/H19 genes following fertilization, rendering these genes 'imprinted'. The research team were interested to discover when and how this methylation is so faithfully maintained.

Using an elegant genetic strategy involving the cross-breeding of several strains of transgenic mice, the team found that paternal-specific methylation of the H19 ICR commences soon after fertilization and that the maternally-supplied DNA methyltransferases Dnmt3a and Dnmt3L are required for this process. This is the first example demonstrating a role for Dnmt3L during early embryogenesis.

Even when the methylation of the mouse H19 ICR was partially obstructed in the sperm, the paternal H19 ICR also exhibited postfertilization methylation. It therefore seems likely that the H19 ICR acquired an unknown epigenetic mark or tag, other than DNA methylation, during sperm formation, and after fertilization the de novo DNA methylation machinery recognized this mark. Possible candidates for the epigenetic marks acquired during sperm formation are modifications or variants in histones, the proteins around which DNA is wrapped.

The team were then able to narrow down the sequence within the ICR responsible for this postfertilization acquisition of methylation to a sequence located right at the beginning of the ICR, the so-called 5'-region. Deletion of this 5'-region from the mouse H19 ICR results in a partial loss of methylation on the paternal copy of the gene, abnormal expression of H19 and its neighboring imprinted gene, Igf2 and growth retardation. This is the first example of a regulatory DNA sequence that is able to regulate the methylation of the paternal H19 ICR, as all other regulatory sequences to date function to maintain the unmethylated state of the maternal H19 ICR, postimplantation.

Dr Tanimoto concludes that 'these results demonstrate that this segment of the H19 ICR is essential for its de novo post-fertilization DNA methylation, and that this activity contributes to the maintenance of imprinted methylation at the H19 ICR during early embryogenesis'.

One of the next steps is to find the primary mark that instructs imprinted DNA methylation in early embryos in the genes responsible for imprinting disorders in humans. This knowledge may have therapeutic benefits in future, by allowing us, for example, to induce the re-expression of the silent parental gene copies in patients in order to improve their symptoms.
-end-


University of Tsukuba

Related Dna Articles:

Zigzag DNA
How the cell organizes DNA into tightly packed chromosomes. Nature publication by Delft University of Technology and EMBL Heidelberg.
Scientists now know what DNA's chaperone looks like
Researchers have discovered the structure of the FACT protein -- a mysterious protein central to the functioning of DNA.
DNA is like everything else: it's not what you have, but how you use it
A new paradigm for reading out genetic information in DNA is described by Dr.
A new spin on DNA
For decades, researchers have chased ways to study biological machines.
From face to DNA: New method aims to improve match between DNA sample and face database
Predicting what someone's face looks like based on a DNA sample remains a hard nut to crack for science.
Self-healing DNA nanostructures
DNA assembled into nanostructures such as tubes and origami-inspired shapes could someday find applications ranging from DNA computers to nanomedicine.
DNA design that anyone can do
Researchers at MIT and Arizona State University have designed a computer program that allows users to translate any free-form drawing into a two-dimensional, nanoscale structure made of DNA.
DNA find
A Queensland University of Technology-led collaboration with University of Adelaide reveals that Australia's pint-sized banded hare-wallaby is the closest living relative of the giant short-faced kangaroos which roamed the continent for millions of years, but died out about 40,000 years ago.
DNA structure impacts rate and accuracy of DNA synthesis
DNA sequences with the potential to form unusual conformations, which are frequently associated with cancer and neurological diseases, can in fact slow down or speed up the DNA synthesis process and cause more or fewer sequencing errors.
Changes in mitochondrial DNA control how nuclear DNA mutations are expressed in cardiomyopathy
Differences in the DNA within the mitochondria, the energy-producing structures within cells, can determine the severity and progression of heart disease caused by a nuclear DNA mutation.
More DNA News and DNA Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Listen Again: Meditations on Loneliness
Original broadcast date: April 24, 2020. We're a social species now living in isolation. But loneliness was a problem well before this era of social distancing. This hour, TED speakers explore how we can live and make peace with loneliness. Guests on the show include author and illustrator Jonny Sun, psychologist Susan Pinker, architect Grace Kim, and writer Suleika Jaouad.
Now Playing: Science for the People

#565 The Great Wide Indoors
We're all spending a bit more time indoors this summer than we probably figured. But did you ever stop to think about why the places we live and work as designed the way they are? And how they could be designed better? We're talking with Emily Anthes about her new book "The Great Indoors: The Surprising Science of how Buildings Shape our Behavior, Health and Happiness".
Now Playing: Radiolab

The Third. A TED Talk.
Jad gives a TED talk about his life as a journalist and how Radiolab has evolved over the years. Here's how TED described it:How do you end a story? Host of Radiolab Jad Abumrad tells how his search for an answer led him home to the mountains of Tennessee, where he met an unexpected teacher: Dolly Parton.Jad Nicholas Abumrad is a Lebanese-American radio host, composer and producer. He is the founder of the syndicated public radio program Radiolab, which is broadcast on over 600 radio stations nationwide and is downloaded more than 120 million times a year as a podcast. He also created More Perfect, a podcast that tells the stories behind the Supreme Court's most famous decisions. And most recently, Dolly Parton's America, a nine-episode podcast exploring the life and times of the iconic country music star. Abumrad has received three Peabody Awards and was named a MacArthur Fellow in 2011.