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X-Chromosome Inactivation and Epigenetic Mechanisms

Arthur D. Riggs, Thomas N. Porter


In each female mammalian cell, one of the two X chromosomes is genetically silent and heterochromatin-like, as a result of a process called X-chromosome inactivation (XCI). Transcriptional silencing by XCI is efficient, stable, and somatically heritable, yet genes on the inactive X chromosome (the Xi) retain the ability to function in the next generation. In mammals, XCI was the first recognized epigenetic phenomenon that, by definition, does not involve irreversible alteration of base sequence. Instead of sequence changes, epigenetic phenomena such as XCI are usually assumed to depend on heritable chromatin structure for the mitotic or meiotic transfer of information from parent to progeny. Ohno et al. (1959) first correctly deduced that the Barr body, a dark-staining, condensed object seen in interphase nuclei, was a single X chromosome. Soon thereafter, Lyon (1961) cogently explained some unusual mouse coat-color genetics as the result of epigenetic inactivation of one X chromosome. We now know that mammals are cellular mosaics, with approximately half of somatic cells expressing only paternally derived X-linked genes and half expressing only maternally derived X-linked genes. XCI thus causes monoallelic expression of X-linked genes in diploid cells, a feature shared with imprinted autosomal genes (see chapters on genomic imprinting by Ainscough and Surani; Walter et al.; both this volume). In this review we focus on the question, How is this accomplished at the molecular level? Although this question cannot yet be fully answered, we review more than 30 years of research on XCI that has led to a considerable...

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