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Developmental Biology - CRISPR

Controlling Cell Identity

Using CRISPR to guide brain stem cell development...

Researchers from Ludwig-Maximilians-University (LMU), Munich, Germany used CRISPR technology to probe mechanisms for guiding development of brain stem cells. Their results show how cell switches are doubly protected against unintended activation, yet can be manipulated.

Higher eukaryotic organisms, like ourselves, are made up of a wide variety of specialized cells. The precise identity and function of each is established by molecular interactions controlling gene expression. Proteins known as master transcription factors play a vital role by initiating genetic programs determining cell identity.
Genes that code for these master transcription factor proteins must be tightly controlled. Any improper activation could endanger the integrity of the entire organism and effectively override any previously established cell state.

Led by Dr. Stefan Stricker of the Munich Center for Neurosciences in LMU's Biomedical Center and the Helmholtz Zentrum München, researchers have now shown progenitors of nerve cells use a double-lock mechanism to avoid untimely production of master transcription factors. The study appears in the online journal Nature Communications.

The project actually set out to address a different question.

"We initially wanted to investigate how genes can be turned on and off with the help of the CRISPR-Cas9 technique," Stricker explains. He and his colleagues chose the mouse Sox1 gene as their target, to test technical aspects directly relevant to differentiation in cell types. The Sox1 gene codes for a master transcription factor known to be active in neural stem cells (NSCs).
In all other classes of neural cells, including the somewhat more mature neuronal progenitor cells (NPCs), Sox1 is repressed or turned off. In the absence of Sox1, neural stem cells progressively lose capacity to differentiate into neurons that transmit electrical signals.

Using the CRISPR/Cas9 approach, researchers guided a trans-activating protein to the Sox1 gene in NPCs where the gene is normally inactive. Many other genes have already been shown to be activated by this method — but Sox1 responded very poorly.

This finding suggests re-activation of Sox1 in NPCs might be prevented by some special mechanism. To test this hypothesis, the LMU team focused on methylation patterns around the Sox1 gene in NPCs. Methylation means adding methyl (CH3) groups to certain nucleotide bases in genomic DNA. It can play a significant role inactivating epigenetic genes.
"To explore the role of methylation, we again made use of CRISPR-Cas9, this time to remove methyl groups from the DNA around the Sox1 gene. Indeed, the combination of targeted demethylation and transactivation allowed us to reactivate Sox1. This is essentially equivalent to rejuvenating those cells, as they recovered their stem-cell properties and were able to differentiate into neurons."

Stefan H. Stricker PhD, MCN Junior Research Group, Munich Center for Neurosciences, Ludwig-Maximilian-Universitaet, BioMedical Center, Planegg-Martinsried, Germany

The ability to reactivate repressed genes might make it possible to cause neuronal progenitor cells to revert into a stem-cell state. Such rejuvenated stem cells would have great therapeutic potential. "But the route from our basic research to the application of reactivated stem cells is a very long one," Stricker cautions.
The authors believe in addition to inhibiting expression, cells impose a specific repressive chromatin layer on genes that control cell identity, protecting them from inadvertent activation. Together, both measures act as a double lock to prevent re-activation of such genes after they have done their job.

Master transcription factors have the ability to direct and reverse cellular identities, and consequently their genes must be subject to particular transcriptional control. However, it is unclear which molecular processes are responsible for impeding their activation and safeguarding cellular identities. Here we show that the targeting of dCas9-VP64 to the promoter of the master transcription factor Sox1 results in strong transcript and protein up-regulation in neural progenitor cells (NPCs). This gene activation restores lost neuronal differentiation potential, which substantiates the role of Sox1 as a master transcription factor. However, despite efficient transactivator binding, major proportions of progenitor cells are unresponsive to the transactivating stimulus. By combining the transactivation domain with epigenome editing we find that among a series of euchromatic processes, the removal of DNA methylation (by dCas9-Tet1) has the highest potential to increase the proportion of cells activating foreign master transcription factors and thus breaking down cell identity barriers.

Valentin Baumann, Maximilian Wiesbeck, Christopher T. Breunig, Julia M. Braun, Anna Köferle, Jovica Ninkovic, Magdalena Götz and Stefan H. Stricker.

The authors acknowledge the Core Facility Flow Cytometry at the Biomedical Center, Ludwig-Maximilians-Universitaet München and the Sequencing Core facility of the Helmholtz Institute Munich for providing equipment, services and expertise.

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Jun 4 2019   Fetal Timeline   Maternal Timeline   News  

Assays reveal changes in potency of Sox1-positive neural progenitor cells: CONTROL (no gRNA transduction or foreign DNA introduced) and ACTIVATED (STAgR 1-9) cells with GREEN response.
CREDIT Stricker laboratory, LMU, Munich, Germany.

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