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Molecular and Cellular Biology, July 2003, p. 4559-4572, Vol. 23, No. 13
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.13.4559-4572.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

H1 Linker Histones Are Essential for Mouse Development and Affect Nucleosome Spacing In Vivo

Yuhong Fan,1 Tatiana Nikitina,2 Elizabeth M. Morin-Kensicki,3 Jie Zhao,1 Terry R. Magnuson,3 Christopher L. Woodcock,2 and Arthur I. Skoultchi1*

Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461,1 Department of Biology, University of Massachusetts, Amherst, Massachusetts 01003,2 Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-72643

Received 12 December 2002/ Returned for modification 10 February 2003/ Accepted 10 April 2003

Most eukaryotic cells contain nearly equimolar amounts of nucleosomes and H1 linker histones. Despite their abundance and the potential functional specialization of H1 subtypes in multicellular organisms, gene inactivation studies have failed to reveal essential functions for linker histones in vivo. Moreover, in vitro studies suggest that H1 subtypes may not be absolutely required for assembly of chromosomes or nuclei. By sequentially inactivating the genes for three mouse H1 subtypes (H1c, H1d, and H1e), we showed that linker histones are essential for mammalian development. Embryos lacking the three H1 subtypes die by mid-gestation with a broad range of defects. Triple-H1-null embryos have about 50% of the normal ratio of H1 to nucleosomes. Mice null for five of these six H1 alleles are viable but are underrepresented in litters and are much smaller than their littermates. Marked reductions in H1 content were found in certain tissues of these mice and in another compound H1 mutant. These results demonstrate that the total amount of H1 is crucial for proper embryonic development. Extensive reduction of H1 in certain tissues did not lead to changes in nuclear size, but it did result in global shortening of the spacing between nucleosomes.

* Corresponding author. Mailing address: Department of Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. Phone: (718) 430-2169 or 2168. Fax: (718) 430-8574. E-mail: skoultch{at}aecom.yu.edu.

Molecular and Cellular Biology, July 2003, p. 4559-4572, Vol. 23, No. 13
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.13.4559-4572.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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