Each of these doubly H1-deficient mice also was fertile and exhibited no anatomic or histological abnormalities. Chromatin from the three double-knockout strains showed no significant change in the ratio of total H1 to nucleosomes. These results suggest that any individual H1 subtype is dispensable for mouse development and that loss of even two subtypes is tolerated if a normal H1-to-nucleosome stoichiometry is maintained. Multiple compound H1 knockouts will probably be needed to disrupt the compensation within this multigene family.DNA in the nuclei of all eukaryotic cells is packaged into repeating units of nucleosomes that form the basic unit of chromatin. Each nucleosome consists of an octamer core containing two molecules of each of the core histones, H2a, H2b, H3, and H4. H1 linker histones bind to the nucleosome core particle and the linker DNA between nucleosomes to facilitate further compaction of chromatin into a 30-nm fiber. Recent studies have shown that the chromatin complex, especially the nucleosome and its modifications, can have a profound influence on transcription (reviewed in references 9 and 26).Although histones are highly conserved proteins, multicellular organisms contain a variety of subtypes exhibiting significant sequence divergence. Among the histone classes, the H1 linker histones are the most divergent group. In mammals, there are at least eight H1 subtypes, including the somatic H1s, H1a to H1e, germ cell-specific H1t and H1oo, and replacement linker histone H1 0 (11, 24). These subtypes exhibit distinct patterns of expression during differentiation and development (12,24). The significance of the diversity present within the H1 family is not understood. The genes for H1a through H1e and H1t are tightly linked on mouse chromosome 13 (25). The H1 0 gene is located on mouse chromosome 15 (2). H1 0 is the smallest and most divergent member of the H1 family (27). H1 0 accumulates in quiescent cells and during terminal differentiation and terminal cell division, reaching levels as high as 30% of the total H1 in certain tissues, such as adult liver. Despite the unique properties and developmental regulation of H1 0 , previous studies in our laboratory showed that mice develop normally without H1 0 (23). Analysis of chromatin from H1 0 -null mice indicated that the level of the somatic H1s, especially H1c, H1d, and H1e, was increased so as to maintain a normal ratio of H1 to nucleosomes in H1 0 -deficient chromatin. In certain tissues, such as adult liver, H1c, H1d, and H1e accounted for 95% of the remaining H1, suggesting that these subtypes are responsible for compensating for loss of H1 0 . The present study was undertaken with the following two experimental objectives: first, to determine whether or not any one of several H1 subtypes is essential for mouse development; second, to determine whether H1c, H1d, or H1e is responsible for compensating for the loss of H1 0 in H1 0Ϫ/Ϫ mice. To achieve the first goal, we generated null mutations in each of the three somatic H1 genes by homolo...
Hi histones bind to the linker DNA between nucleosome core particles and facilitate the folding of chromatin into a 30-nm fiber. Mice contain at least seven nonal-
H1 histones bind to linker DNA and nucleosome core particles and facilitate the folding of chromatin into a more compact structure. Mammals contain seven nonallelic subtypes of H1, including testis-specific subtype H1t, which varies considerably in primary sequence from the other H1 subtypes. H1t is found only in pachytene spermatocytes and early, haploid spermatids, constituting as much as 55% of the linker histone associated with chromatin in these cell types. To investigate the role of H1t in spermatogenesis, we disrupted the H1t gene by homologous recombination in mouse embryonic stem cells. Mice homozygous for the mutation and completely lacking H1t protein in their germ cells were fertile and showed no detectable defect in spermatogenesis. Chromatin from H1t-deficient germ cells had a normal ratio of H1 to nucleosomes, indicating that other H1 subtypes are deposited in chromatin in place of H1t and presumably compensate for most or all H1t functions. The results indicate that despite the unique primary structure and regulated synthesis of H1t, it is not essential for proper development of mature, functional sperm.The histones are a family of basic proteins that are involved in organizing the DNA in the nuclei of eukaryotic cells into a compact structure called chromatin. There are five major classes of histones, the core histones H2A, H2B, H3, and H4 and the linker histone H1. Two molecules of each of the core histones constitute the protein octamer of the nucleosome core particle. H1 histones bind to DNA in the nucleosome core particle and to the linker DNA between nucleosomes. These interactions are thought to facilitate the folding of nucleosomes into the 30-nm chromatin fiber and higher-order chromatin structures (39,42). Interactions between histones and DNA would be expected to modulate gene activity, and recent evidence clearly shows that both the core histones and H1 can have a profound effect on transcription (reviewed in references 18, 43, and 44).Among the five classes of histones, the H1 histones exhibit the most diversity. For mice seven H1 subtypes have been described (24, 25), including the "somatic" subtypes H1a through H1e, the replacement subtype H1 o , and the testisspecific linker histone H1t. These seven H1 subtypes are also present in humans, and the genomic organization of the genes encoding the H1 subtypes in humans appears to be very similar to that in mice (12,40).Within the H1 family of proteins, the testis-specific H1t subtype is unique in that it is the only member exhibiting a truly tissue-specific pattern of expression. Although the other six H1 subtypes display distinct patterns of expression during differentiation and development, they are all expressed in numerous tissues (24-26). On the other hand, the H1t gene is transcribed exclusively in mid-and late-pachytene spermatocytes (10, 13, 16), and H1t protein is found only in pachytene spermatocytes and early, haploid spermatids (11,17,29), in which it constitutes up to 55% of the total H1 linker histone in chromatin (29). M...
Oocytes and embryos of many species, including mammals, contain a unique linker (H1) histone, termed H1oo in mammals. It is uncertain, however, whether other H1 histones also contribute to the linker histone complement of these cells. Using immunofluorescence and radiolabeling, we have examined whether histone H10, which frequently accumulates in the chromatin of nondividing cells, and the somatic subtypes of H1 are present in mouse oocytes and early embryos. We report that oocytes and embryos contain mRNA encoding H10. A polymerase chain reaction-based test indicated that the poly(A) tail did not lengthen during meiotic maturation, although it did so beginning at the four-cell stage. Antibodies raised against histone H10 stained the nucleus of wild-type prophase-arrested oocytes but not of mice lacking the H10 gene. Following fertilization, H10 was detected in the nuclei of two-cell embryos and less strongly at the four-cell stage. No signal was detected in H10 -/- embryos. Radiolabeling revealed that species comigrating with the somatic H1 subtypes H1a and H1c were synthesized in maturing oocytes and in one- and two-cell embryos. Beginning at the four-cell stage in both wild-type and H10 -/- embryos, species comigrating with subtypes H1b, H1d, and H1e were additionally synthesized. These results establish that histone H10 constitutes a portion of the linker histone complement in oocytes and early embryos and that changes in the pattern of somatic H1 synthesis occur during early embryonic development. Taken together with previous results, these findings suggest that multiple H1 subtypes are present on oocyte chromatin and that following fertilization changes in the histone H1 complement accompany the establishment of regulated embryonic gene expression.
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