Review Molecular mechanisms of extinction: old ®ndings and new ideas Steen Massa a , Steen Junker b , Patrick Matthias a, * a Friedrich Miescher Institute, Maulbeesrtrasse 66, CH-4058 Basel, Switzerland b Department of Human Genetics, University of Aarhus, DK-8000 Aarhus C, Denmark Received 5 February 1999; accepted 29 July 1999 Abstract Fusion experiments between somatic cells have been used for a long time as a means to understand the regulation of gene expression. In hybrids between dierentiated cells such as hepatocytes or lymphocytes and undierentiated cells such as ®broblasts a phenomenon called extinction has been described. In such hybrids expression of cell- speci®c genes derived from the more dierentiated parental cell is selectively turned o (extinguished), whereas genes expressed from both cells like housekeeping genes remain active after fusion. Study of the molecular basis of extinction of the liver-speci®cally expressed tyrosine aminotransferase gene and of the B-cell-speci®cally expressed immunoglobulin genes has revealed that in hybrids the transcriptional program of the dierentiated cells is reset. This is accompanied by a loss of expression or activity of many of the regulatory molecules that were operating in the dierentiated cells. In the light of new insights in eukaryotic gene regulation we speculate that molecular mechanisms such as chromatin remodelling, recruitment to heterochromatin or subnuclear localization could underly the extinction process. # 1999 Published by Elsevier Science Ltd. All rights reserved. 1. Introduction During the development of a higher organism somatic cells dierentiate and give rise to a multi- tude of specialized cell types that will form func- tional tissues and organs. These dierentiated cells acquire their unique specialization through the selective expression of their genome. Thus, cellular identity is for the larger part the result of a unique ®nely tuned gene expression pattern. In most cases dierentiation is the result of a `cellu- lar commitment': beyond a certain dierentiation step cells lose their plasticity and, normally, can only proceed further along a de®ned pathway. Usually, dierentiation is accompanied by a decrease in the mitotic potential of the cell, and most fully dierentiated cells are postmitotic. Yet, dierentiation is not due to the irreversible loss of genetic material, as was ®rst demonstrated by Gurdon's classical nuclear transplantation ex- The International Journal of Biochemistry & Cell Biology 32 (2000) 23±40 1357-2725/99/$ - see front matter # 1999 Published by Elsevier Science Ltd. All rights reserved. PII: S1357-2725(99)00102-8 www.elsevier.com/locate/ijbcb * Corresponding author. Tel.: +41-61-697-6661; fax: +41- 61-697-3976. E-mail address: matthias@fml.ch (P. Matthias).