Modeling transcriptional responsiveness in cell lines

  • Awarded: 2011
  • Award Type: Explorer
  • Award #: 217669

Mark Alter and his colleagues at the University of Pennsylvania study the relationship between brain cell maturation and the transcription of genes. Each cell type has its own transcription program, depending on which genes it uses to function. As brain cells mature, they undergo many changes in their cellular transcription programs.

These programmatic changes can be used to measure the maturity of specific cell types. For instance, in 2012 Alter and colleagues used changes in cell-type-specific transcriptional programs to show that certain brain cells that help to organize brain activity, called fast-spiking interneurons, do not mature properly in the brains of individuals with autism. Alter hypothesizes this may be the result of impaired transcriptional plasticity — the ability of cells to change their transcription patterns in response to signals such as those telling cells to mature.

Alter and his team created a cell culture system to study transcriptional plasticity by introducing a foreign gene, which can be deliberately turned on to make cells red, into a cell line. They explored whether brighter cells, which are better able to activate the inserted gene, would show greater transcriptional plasticity in general, by evaluating the response to a stimulus other than the one used to make the cells red.

To test this idea, Alter and his team stressed the cells with serum deprivation, which removes important nutrients and is known to induce a transcription program in many cell lines. The researchers found that brighter cells have a greater transcriptional response when stressed. The increased transcriptional response is accompanied by increased histone acetylation, a modification to DNA packaging proteins that is known to promote transcriptional change and cellular plasticity.

Alter’s team plans to use this system to search for additional general plasticity factors and as a screening tool for treatments that modulate cellular plasticity.

They are also working to develop a similar system in PC12 cells, which can be induced to form neuronal-like processes. This would enable scientists to assess general plasticity factors in neuron-like cells that may generate potential therapeutic targets. Such targets could modulate dysfunctional transcriptional plasticity in people with autism. Understanding and studying these general plasticity factors may be important to a wide range of mental disorders in which neuronal plasticity is impaired.

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