Reprogramming the male gamete genome: a window to successful gene therapy

Hematopoiesis and spermatogenesis both initiate from a stem cell capable of renewal and differentiation. Each pathway reflects the expression of uniqu e combinations of facultative, i.e. tissue-specific and constitutive, i.e. housekeeping, genes in each cell type. In spermatogenesis, as in hematopoie sis, commitment is mediated by the mechanism of potentiation whereby specif ic chromatin domains are selectively opened along each chromosome. Within e ach open chromatin domain, a unique battery of gene(s) is availed to tissue -specific and ubiquitous transacting factors that are necessary to initiate transcription. In the absence of an open domain, trans-factor access is de nied, and the initiation of transcription cannot proceed. Cell-fate is thus ultimately defined by the unique series of open-potentiated cell-specific chromatin domains. Defining the mechanism that opens chromatin domains is f undamental in understanding how differentiation from stem cells is controll ed and whether cell-fate can be modified. A recent examination of the mamma lian spermatogenic pathway [Kramer, J.A., McCarrey, J.M. Djakiew, D., Krawe tz, S.A., 1998. Differentiation: the selective potentiation of chromatin do mains. Development 125, 4749-4755] supports the view that cell fate is medi ated by global changes in chromatin conformation. This stride underscores t he possibility of moderating differentiation through chromatin conformation . It is likely that gene therapeutics capable of selectively potentiating i ndividual genic domains in populations of differentiating and/or replicatin g cells that modify cellular phenotype will be developed in the next millen nium. (C) 1999 Elsevier Science B.V. All rights reserved.