Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Quick notes in the genome

07.07.2020

How do stem cells stay stem cells whilst preserving information necessary to mature into specialized cell types? Jocelyn Charlton, a member of Alexander Meissner's team at the Max Planck Institute for Molecular Genetics (MPIMG), discovered a new mechanism for the control of genetic activity that might allow cells to respond rapidly to differentiation cues. The results were published in Nature Genetics.

Our genome is like a "book of life" that contains directions for each cell and the entire organism. But in order for each molecule to make its appearance at the right time, labels, notes and emphasis on top of the actual text are necessary. After all, not every single page is equally important for every cell type at all times.


Cultured human pluripotent stem cells

Jocelyn Charlton / MPI f. mol. Genet.

Taking notes chemically

Certain passages of the DNA are only relevant during embryonic development, others are only read after differentiation into muscle, skin or neural cells. When the wrong sections are accessed – or even only in the wrong order – developmental disorders or other diseases may result.

Cells enzymatically attach small chemical modifications (“methyl groups”) to the DNA – more specifically to cytosine dinucleotides – leaving the underlying genetic information untouched.

Methylated DNA is generally protected from the cellular machinery that reads information from the genome, hence the methylation of regulatory parts of the DNA is associated with their silencing.

Demethylating enzymes counteract this process by removing the methyl groups and erasing the labels, allowing for activation.

Contrary to previous assumptions, methylating and demethylating enzymes are in constant competition with each other – at least at certain genetic control sequences in human embryonic stem cells. This is what Jocelyn Charlton from Alexander Meissner's lab at the Max Planck Institute for Molecular Genetics (MPIMG) found. She presents her findings in the current issue of the scientific journal Nature Genetics.

Notes and cross-references in the genome

Charlton investigated stem cell lines that lacked different combinations of methylating and demethylating enzymes by specifically excising or “knocking out” the genes coding for the respective enzyme using CRISPR-Cas9 – silencing methylating DNMT enzymes as well TET enzymes that demethylate DNA and thereby erase the labels again. She also created the first cell line that lacks all five enzymes that are able to alter DNA methylation states.

Charlton and her colleagues cultured the genetically modified cells and sequenced their DNA to determine which sections contained methyl groups and noted remarkable differences across enhancer sequences. These DNA segments activate genes with the help of other factors. Depending on the cell type and stage of development, a wide variety of enhancers are normally active.

Competition between enzymes

“Somatic enhancers are not yet active in pluripotent stem cells, as they are only required after differentiation,” says Charlton. But while inactive, she found that thousands of somatic enhancers experienced a process where methyl groups were persistently added and removed. “There is actually quite a lot of turnover of methylation,” says Charlton.

The researchers first observed that cell lines lacking methylating DNMT enzymes quickly lost DNA methylation at tens of thousands of enhancer sites. However, when the DNMTs were knocked-out in cells first depleted of TET activity, the same regions remained highly methylated.

This confirmed that TET enzymes were responsible for the targeted demethylation. Further analysis showed that the same regions were enriched for demethylation by-products.

Charlton and her colleagues concluded that DNMT and TET enzymes are competing locally at these sites. “We found that this methylated silenced state isn't as stable and inert as we previously thought,” says Charlton. “It's actually a highly dynamic state.”

About one third of all examined enhancers are affected, the other two thirds are either in a demethylated state but kept inactive by modifications to the chromatin “packaging” of the DNA instead, or are methylated but unaffected by the process. And as soon as the stem cells mature into differentiated somatic cells, the enzymatic competition ceases.

Mechanism and function to be explored

“These findings open the door to a lot of further research,” says Charlton. “Many exciting biological questions remain, including the purpose of dynamic methylation turnover at somatic enhancers.”

The process has to cost the cell a lot of energy and the scientist and her colleagues wonder why the dynamic is important. “It could be a new epigenetically poised state, a mechanism to keep important regulatory elements inactive but readily available,” speculates Charlton. “This could allow cells to turn certain enhancers on and off very quickly when needed.”

How the enzymes find their way to their target regions is still unknown. “Neither the DNMTs nor the TETs have a specific structure or a motif with which they bind DNA, there is something else that is recruiting them there,” says Charlton. “Whether another protein or non-coding RNA bring them to the sites, we don't yet know. This is something else to follow up on.”

Despite the many unanswered questions, Charlton says the work was a huge success. “You wouldn't know there is this dynamic turnover unless you look across the different knock-outs and compare sites that switch methylation states,” says the researcher. “It’s exciting to see this completely new mode of regulation we didn’t know before.”

Wissenschaftliche Ansprechpartner:

Professor Dr. Alexander Meissner
Direktor, Leiter Abt. Genomregulation
Max-Planck-Institut für molekulare Genetik, Berlin
+49 30 8413-1880
meissner@molgen.mpg.de

Dr. Jocelyn Charlton
Max-Planck-Institut für molekulare Genetik, Berlin
+49 30 8413-1881
charlton@molgen.mpg.de

Originalpublikation:

Jocelyn Charlton, Eunmi J. Jung, Alexandra L. Mattei, Nina Bailly, Jing Liao, Eric J. Martin, Pay Giesselmann, Björn Brändl, Elena K. Stamenova, Franz-Josef Müller, Evangelos Kiskinis, Andreas Gnirke, Zachary D. Smith & Alexander Meissner (2020): TETs compete with DNMT3 activity in pluripotent cells at thousands of methylated somatic enhancers. Nature Genetics https://doi.org/10.1038/s41588-020-0639-9

Dr. Martin Ballaschk | Max-Planck-Institut für molekulare Genetik
Further information:
http://www.molgen.mpg.de

More articles from Life Sciences:

nachricht Study clarifies kinship of important plant group
05.08.2020 | Rheinische Friedrich-Wilhelms-Universität Bonn

nachricht Human cell-based test systems for toxicity studies: Ready-to-use Toxicity Assay (hiPSC)
05.08.2020 | Fraunhofer-Institut für Biomedizinische Technik IBMT

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: New Strategy Against Osteoporosis

An international research team has found a new approach that may be able to reduce bone loss in osteoporosis and maintain bone health.

Osteoporosis is the most common age-related bone disease which affects hundreds of millions of individuals worldwide. It is estimated that one in three women...

Im Focus: AI & single-cell genomics

New software predicts cell fate

Traditional single-cell sequencing methods help to reveal insights about cellular differences and functions - but they do this with static snapshots only...

Im Focus: TU Graz Researchers synthesize nanoparticles tailored for special applications

“Core-shell” clusters pave the way for new efficient nanomaterials that make catalysts, magnetic and laser sensors or measuring devices for detecting electromagnetic radiation more efficient.

Whether in innovative high-tech materials, more powerful computer chips, pharmaceuticals or in the field of renewable energies, nanoparticles – smallest...

Im Focus: Tailored light inspired by nature

An international research team with Prof. Cornelia Denz from the Institute of Applied Physics at the University of Münster develop for the first time light fields using caustics that do not change during propagation. With the new method, the physicists cleverly exploit light structures that can be seen in rainbows or when light is transmitted through drinking glasses.

Modern applications as high resolution microsopy or micro- or nanoscale material processing require customized laser beams that do not change during...

Im Focus: NYUAD astrophysicist investigates the possibility of life below the surface of Mars

  • A rover expected to explore below the surface of Mars in 2022 has the potential to provide more insights
  • The findings published in Scientific Reports, Springer Nature suggests the presence of traces of water on Mars, raising the question of the possibility of a life-supporting environment

Although no life has been detected on the Martian surface, a new study from astrophysicist and research scientist at the Center for Space Science at NYU Abu...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

“Conference on Laser Polishing – LaP 2020”: The final touches for surfaces

23.07.2020 | Event News

Conference radar for cybersecurity

21.07.2020 | Event News

Contact Tracing Apps against COVID-19: German National Academy Leopoldina hosts international virtual panel discussion

07.07.2020 | Event News

 
Latest News

Manifestation of quantum distance in flat band materials

05.08.2020 | Physics and Astronomy

Discovery shows promise for treating Huntington's Disease

05.08.2020 | Health and Medicine

Rock debris protects glaciers from climate change more than previously known

05.08.2020 | Earth Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>