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Nuclear reprogramming in heterokaryons is rapid, extensive, and bidirectional

Adam Palermo^*,, Regis Doyonnas^*, Nidhi Bhutani^*, Jason Pomerantz^*,, Ozan Alkan^*, and Helen M. Blau^*,1

^* Department of Microbiology and Immunology and Stem Cell Institute, Stanford University School of Medicine, Stanford, California, USA;

Genzyme Corporation, Framingham, Massachusetts, USA;

Division of Reconstructive and Plastic Surgery, Department of Surgery, University of California at San Francisco, San Francisco, California, USA; and

Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA

¹ Correspondence: Stanford University School of Medicine, 269 Campus Dr., Stanford, CA 94305-5175, USA. E-mail: hblau{at}stanford.edu

An understanding of nuclear reprogramming is fundamental to the use of cells in regenerative medicine. Due to technological obstacles, the time course and extent of reprogramming of cells following fusion has not been assessed to date. Here, we show that hundreds of genes are activated or repressed within hours of fusion of human keratinocytes and mouse muscle cells in heterokaryons, and extensive changes are observed within 4 days. This study was made possible by the development of a broadly applicable approach, species-specific transcriptome amplification (SSTA), which enables global resolution of transcripts derived from the nuclei of two species, even when the proportions of species-specific transcripts are highly skewed. Remarkably, either phenotype can be dominant; an excess of primary keratinocytes leads to activation of the keratinocyte program in muscle cells and the converse is true when muscle cells are in excess. We conclude that nuclear reprogramming in heterokaryons is rapid, extensive, bidirectional, and dictated by the balance of regulators contributed by the cell types.—Adam Palermo, Regis Doyonnas, Nidhi Bhutani, Jason Pomerantz, Ozan Alkan, Helen M. Blau. Nuclear reprogramming in heterokaryons is rapid, extensive, and bidirectional.

Key Words: gene expression • time course • microarrays • somatic fate change • balance of regulators