Most genetic information is directly encoded by the sequence of nucleotides in a chain of DNA, but further instructions may also be provided by adding chemical modifications to those nucleotides, just like inserting footnotes can alter the meaning of a text. One important modification is DNA methylation, which generally has the effect of ‘silencing’ transcriptional activity of marked genes—a secondary but essential level of regulation.
DNA methylation patterns can be transmitted from parent to child, an important process known as genomic ‘imprinting.’ Maintaining these patterns is an active process, as each cycle of DNA replication results in the production of chains that are only hemimethylated, and full methylation is subsequently restored by the enzyme DNA methyltransferase 1 (Dnmt1).
Other proteins are known to assist this process. Recent work from a group led by Haruhiko Koseki of the RIKEN Research Center for Allergy and Immunology in Yokohama, and Masaki Okano of the RIKEN Center for Developmental Biology in Kobe, has highlighted the important role of one particular protein, Np95, in directing Dnmt1 to hemimethylated DNA targets (1).
Koseki’s group initially found that Np95 associates with imprinting-related proteins, and subsequent experiments in mouse embryonic stem cells (ESCs) extended these findings, demonstrating that Np95 co-localizes with Dnmt1 and other associated proteins at hemimethylated chromosomal regions after DNA replication (Fig. 1). Eliminating the expression of Np95 altogether resulted in a marked reduction of DNA methylation in cultured ESCs, and led to full developmental arrest in mouse embryos.
Methylation does more than silence genes; it also helps stabilize DNA elements known as retrotransposons, which are otherwise capable of physically ‘jumping’ into other chromosomal regions—and potentially disrupting other genes. Koseki’s group found that Np95 helps to lock down these retrotransposons. “At the least, Np95 is essential to maintain genomic imprinting, which in turn permits normal development of embryonic and extraembryonic tissues,” he says. “But it could be possible that this process may also be important to ensure genomic stability.”
Intriguingly, Koseki’s and his colleagues also found evidence suggesting that Np95’s function may not be limited to restoring DNA methylation, but could encompass other chromosomal maintenance tasks as well—a possibility he is keen to investigate further. “Hemimethylated DNA is not simply a transient status that appears after DNA replication … it may potentially form a specific signal that could be sensed by Np95,” he says. “We presume that Np95 may form a platform that helps to organize not only DNA methylation but also other types of modifications.”
1. Sharif, J., Muto, M., Takebayashi, S., Suetake, I., Iwamatsu, A., Endo, T.A., Shinga, J., Mizutani-Koseki, Y., Toyoda, T., Okamura, K. et al. The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA. Nature 450, 908–912 (2007).
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