Histone macroH2A1 is concentrated in the inactive X chromosome of female mammals


In female mammals one of the X chromosomes is rendered almost completely transcriptionally inactive1,2 to equalize expression of X-linked genes in males and females. The inactive X chromosome is distinguished from its active counterpart by its condensed appearance in interphase nuclei3, late replication4, altered DNA methylation2, hypoacetylation of histone H4 (ref. 5), and by transcription of a large cis-acting nuclear RNA called Xist6,7,8,9,10. Although it is believed that the inactivation process involves the association of specific protein(s) with the chromatin of the inactive X, no such proteins have been identified11. We discovered a new gene family encoding a core histone which we called macroH2A (mH2A)12,13. The amino-terminal third of mH2A proteins is similar to a full-length histone H2A, but the remaining two-thirds is unrelated to any known histones. Here we show that an mH2A1 subtype is preferentially concentrated in the inactive X chromosome of female mammals. Our results link X inactivation with a major alteration of the nucleosome, the primary structural unit of chromatin.

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Figure 1: Specificity of mH2A antibodies.
Figure 2: Sex-specific distribution of mH2A1 protein.
Figure 3: Colocalization of MCBs to X chromosomes.
Figure 4: Correlation of MCBs with inactive X chromosomes.


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We thank E. M. Eicher for the XXsxr mice; M. Monestier for the anti-fibrillarin antibody; M. L. Atchison, E. L. F. Holzbaur, O. Jacenko, L. D. Peachey and J. D. Tucker for making their resources available; G. Gray-Board, E. A. Holleran, X. Lowe, M. Radic and J. D. Tucker for technical advice; and M. L. Atchison, N. G. Avadhani, J. Burch, L. H. Cohen and E. A. Holleran for comments on this manuscript. This work was supported by the NIH. Part of this work was done in the Biomedical Image Analysis Facility at the University of Pennsylvania, supported by the NIH. The dog material was supplied by A. Polesky and J. H. Wolfe, supported by the NIDDK.

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Correspondence to John R. Pehrson.

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Costanzi, C., Pehrson, J. Histone macroH2A1 is concentrated in the inactive X chromosome of female mammals. Nature 393, 599–601 (1998). https://doi.org/10.1038/31275

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