New CRISPR-Cas9 technology directs gene behavior without genetic modifications

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While the generation of pluripotent stem cells from non-pluripotent counterparts is possible, control of differentiation is still largely poorly understood. A recent paper is hoping to change that.

Research from Dr. Timo Otonkoski’s lab at the Meilahti medical campus of the University of Helsinki uncovered a new method of modifying a gene’s behavior without making any modifications to the genome. These modifications include directing the differentiation of stem cells with small chemicals.

The work is described in the paper titled “Conditionally Stabilized dCas9 Activator for Controlling Gene Expression in Human Cell Reprogramming and Differentiation”, and published this week in Stem Cell Reports.

The method is based on CRISPR-Cas9 technology, which we described on this blog in the past. This particular approach employs transcription activator domain VP16 which, in addition to RNA regulators targeting the OCT4 promoter, induces the cell to become receptive to external factors that regulate the cells’ differentiation.

In this case, the factors are antibiotics. The authors used the antibiotics doxycycline and trimethoprim to control differentiation of human pluripotent stem cells into endodermal lineages.

Apart from stem cells, the authors demonstrated non-genetic regulation of a variety of other cells with this method. In all cases, transcriptional activation was similar, and the cells demonstrated reproducible responsiveness to chemical regulators.

While the potential therapeutic benefits of such an approach are multi-fold, the work is still preliminary and further extrapolations about clinical efficacy are still premature.

The paper can be accessed here.

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