Isolation and characterization of two replication-dependent mouse H1 histone genes

Dong, Yaa Hui; Sirotkin, Allen; Yang, Yih Sheng; Brown, David T.; Sittman, Donald B.; Skoultchi, Arthur I.

doi:10.1093/nar/22.8.1421

Cited by 29 publications

(25 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To investigate the effect of disruption of linker-to-core histone stoichiometry, we sought to combine H1 histone-null mutations in a single strain. We chose first to combine mutations in the genes for H1c and H1e because, of the five somatic H1 subtypes, these two have very closely related amino acid sequences and their expression is often coordinately regulated (12,13,26,51). We previously described mice null for either H1c or H1e (17).…”

Section: Resultsmentioning

confidence: 99%

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

Fan

Nikitina

Morin‐Kensicki

et al. 2003

Molecular and Cellular Biology

Self Cite

287

355

View full text Add to dashboard Cite

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 midgestation 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.DNA in the eukaryotic nucleus is organized into a highly compact nucleoprotein complex referred to as chromatin (48,53). The histones constitute a family of proteins that are intimately involved in organizing chromatin structure. The nucleosome core particle, the highly conserved unit of chromatin organization in all eukaryotes, consists of an octamer of four core histones (H2A, H2B, H3, and H4) around which about 145 bp of DNA is wrapped. The chromatin fiber also contains a fifth histone, the linker histone (usually referred to as H1), which can bind to core particles and protect an additional ϳ20 bp of DNA (linker DNA) from nuclease digestion. The precise location and stoichiometry of H1 within the chromatin fiber are uncertain (45,46,49), but in higher eukaryotes, there is, on average, nearly one H1 molecule for each core particle (48). Most of our knowledge about the role of H1 in chromatin structure is based on in vitro experiments. These studies indicate that two principal functions of linker histones are to organize and stabilize the DNA as it enters and exits the core particle and to facilitate the folding of nucleosome arrays into more compact structures (19,38). Despite the presumed fundamental role of linker histones in chromatin structure, elimination of H1 in Tetrahymena, Saccharomyces cerevisiae, and Aspergillus nidulans and silencing of H1 in Ascobolus immersus showed that H1 is not essential in these unicellular eukaryotes (3,34,39,41,47).In higher organisms, additional levels of control on chromatin organization and function are available because of the existence of multiple nonallelic linker histone variants or subtypes (6, 33). In mice, there are at least eight H1 subtypes, including the widely expressed subtypes H1a through H1e, the testis-specific subtype H1...

show abstract

Section: Resultsmentioning

confidence: 99%

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

Fan

Nikitina

Morin‐Kensicki

et al. 2003

Molecular and Cellular Biology

Self Cite

287

355

View full text Add to dashboard Cite

show abstract

“…All of the genomic DNA clones used in construction of targeting vectors were isolated by screening a strain 129J/sv mouse genomic DNA library with gene-specific probes described previously (4,25). Twenty-five and 50 g of Acc65I-linearized H1c targeting vector (Fig.…”

Section: Methodsmentioning

confidence: 99%

Individual Somatic H1 Subtypes Are Dispensable for Mouse Development Even in Mice Lacking the H1⁰Replacement Subtype

Fan

Sirotkin

Russell

et al. 2001

Molecular and Cellular Biology

Self Cite

174

166

View full text Add to dashboard Cite

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...

show abstract

“…Mice-The genomic DNA clones used in construction of the H1a targeting vector were isolated by screening a 129X1/SvJ (briefly, 129X1) genomic library as described previously (15). To generate an H1a targeting vector (Fig.…”

Section: Disruption Of the H1a Gene In Es Cells And Generation Of Chimentioning

confidence: 99%

Reductions in Linker Histone Levels Are Tolerated in Developing Spermatocytes but Cause Changes in Specific Gene Expression

Lin

Inselman

Han

et al. 2004

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

H1 linker histones are involved in packaging chromatin into 30-nm fibers and higher order structures. Most eukaryotic cells contain nearly one H1 molecule for each nucleosome core particle. Male germ cells in mammals contain large amounts of a germ cell-specific linker histone, HIST1HT, herein denoted H1t, which is particularly abundant in pachytene spermatocytes. Despite its abundance in male germ cells and significant divergence in primary sequence from other H1 subtypes, inactivation of the H1t gene in mice showed that it is not required for spermatogenesis. Analysis of germ cell chromatin from H1t null mice showed that other H1 subtypes, especially the testis-enriched HIST1H1A, herein denoted as the H1a subtype, were able to compensate for the absence of H1t to maintain a normal total H1 to nucleosome core ratio. To disrupt the compensation, we generated H1t and H1a double null mice by two sequential gene-targeting steps in embryonic stem cells. Elimination of both H1t and H1a led to a 25% decrease in the ratio of H1 to nucleosome cores in double null germ cells. Surprisingly, the reduction in H1 did not perturb spermatogenesis or produce detectable defects in meiotic processes. Microarray analysis of gene expression showed that the reduced linker histone levels did not affect global gene expression, but it did cause changes in expression of specific genes. Our results indicate that a partial reduction in linker histone-nucleosome core particle stoichiometry is tolerated in developing male germ cells.

show abstract

Isolation and characterization of two replication-dependent mouse H1 histone genes

Cited by 29 publications

References 38 publications

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

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

Individual Somatic H1 Subtypes Are Dispensable for Mouse Development Even in Mice Lacking the H1⁰Replacement Subtype

Reductions in Linker Histone Levels Are Tolerated in Developing Spermatocytes but Cause Changes in Specific Gene Expression

Contact Info

Product

Resources

About

Isolation and characterization of two replication-dependent mouse H1 histone genes

Cited by 29 publications

References 38 publications

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

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

Individual Somatic H1 Subtypes Are Dispensable for Mouse Development Even in Mice Lacking the H10Replacement Subtype

Reductions in Linker Histone Levels Are Tolerated in Developing Spermatocytes but Cause Changes in Specific Gene Expression

Contact Info

Product

Resources

About

Individual Somatic H1 Subtypes Are Dispensable for Mouse Development Even in Mice Lacking the H1⁰Replacement Subtype