Fan Yuhong, Nikitina Tatiana, Morin-Kensicki Elizabeth M, Zhao Jie, Magnuson Terry R, Woodcock Christopher L, Skoultchi Arthur I
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Mol Cell Biol. 2003 Jul;23(13):4559-72. doi: 10.1128/MCB.23.13.4559-4572.2003.
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.
大多数真核细胞含有近乎等摩尔量的核小体和H1连接组蛋白。尽管H1亚型在多细胞生物中含量丰富且具有潜在的功能特异性，但基因失活研究未能揭示连接组蛋白在体内的基本功能。此外，体外研究表明，染色体或细胞核的组装可能并非绝对需要H1亚型。通过依次使三种小鼠H1亚型（H1c、H1d和H1e）的基因失活，我们发现连接组蛋白对哺乳动物发育至关重要。缺乏这三种H1亚型的胚胎在妊娠中期死亡，伴有广泛的缺陷。三重H1缺失胚胎的H1与核小体的正常比例约为50%。这六个H1等位基因中有五个缺失的小鼠是存活的，但在窝仔中的比例较低，且比它们的同窝仔小得多。在这些小鼠的某些组织以及另一种复合H1突变体中发现H1含量显著降低。这些结果表明，H1的总量对胚胎正常发育至关重要。某些组织中H1的大量减少并未导致核大小的变化，但确实导致核小体之间间距的整体缩短。
