Phosphorylated and dephosphorylated linker histone H1 reside in distinct chromatin domains in Tetrahymena macronuclei.

Lu, Min; Mpoke, Solomon; Dadd, Christopher A.; Allis, C. David

doi:10.1091/mbc.6.8.1077

Cited by 37 publications

(31 citation statements)

References 43 publications

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“…It has been postulated that phosphorylation of histone H1 decreases its net positive charge and repels it from negatively charged DNA. This depletion or removal of histone H1 from nucleosomes may then lead to a structural reorganization of chromatin to provide access for transcription factors involved in replication and transcription (27,34). More recent observations have provided insight into the role of histone H1 phosphorylation on chromatin structure and transcription regulation.…”

Section: Discussionmentioning

confidence: 99%

Histone H1 Phosphorylation by Cdk2 Selectively Modulates Mouse Mammary Tumor Virus Transcription through Chromatin Remodeling

Bhattacharjee¹,

Banks

Trotter

et al. 2001

Molecular and Cellular Biology

101

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Transcriptional activation of the mouse mammary tumor virus (MMTV) promoter by ligand-bound glucocorticoid receptor (GR) is transient. Previously, we demonstrated that prolonged hormone exposure results in displacement of the transcription factor nuclear factor 1 (NF1) and the basal transcription complex from the promoter, the dephosphorylation of histone H1, and the establishment of a repressive chromatin structure. We have explored the mechanistic link between histone H1 dephosphorylation and silencing of the MMTV promoter by describing the putative kinase responsible for H1 phosphorylation. Both in vitro kinase assays and in vivo protein expression studies suggest that in hormone-treated cells the ability of cdk2 to phosphorylate histone H1 is decreased and the cdk2 inhibitory p21 protein level is increased. To address the role of cdk2 and histone H1 dephosphorylation in the silencing of the MMTV promoter, we used potent cdk2 inhibitors, Roscovitine and CVT-313, to generate an MMTV promoter which is associated predominantly with the dephosphorylated form of histone H1. Both Roscovitine and CVT-313 block phosphorylation of histone H1 and, under these conditions, the GR is unable to remodel chromatin, recruit transcription factors to the promoter, or stimulate MMTV mRNA accumulation. These results suggest a model where cdk2-directed histone H1 phosphorylation is a necessary condition to permit GR-mediated chromatin remodeling and activation of the MMTV promoter in vivo.DNA in eukaryotic nuclei is highly packaged into chromatin by two molecules each of the core histone proteins H2A, H2B, H3, and H4 and one molecule of linker histone H1 (44). In addition, to the intrinsic stearic considerations of wrapping DNA around the histone octamer, the posttranslation modification of the core histones have come under increased scrutiny (22,44). Numerous studies support a strong link between transcriptional regulation and the remodeling of chromatin structure through the acetylation of core histones H3 and H4 (20, 40, 46). The acetylation of core histones in vivo is presumed to play a role in increasing the accessibility of transcription factors to the promoters of target genes (23). More recently, the Mi-2 ATPase complex, which contains chromatin remodeling activity, has been linked to both DNA methylation and histone deacetylation (39, 47).The role of histone H1 in the regulation of transcription is less clear, but there is evidence that histone H1 interacts differentially with transcriptionally active and inactive regions of chromatin (29). Indeed, studies in Xenopus and Tetrahymena thermophila have ruled out an exclusive role for histone H1 phosphorylation in chromatin condensation (31,36). However, other studies in mammals and T. thermophila have found a correlation between transcriptional activation and decreased amounts of histone H1 (9,12,14). Thus, it is plausible, given the role of histone H1 in the packaging of the nucleosome, that posttranslational modifications of this protein may also be involved in transcript...

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Section: Discussionmentioning

confidence: 99%

Histone H1 Phosphorylation by Cdk2 Selectively Modulates Mouse Mammary Tumor Virus Transcription through Chromatin Remodeling

Bhattacharjee¹,

Banks

Trotter

et al. 2001

Molecular and Cellular Biology

101

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“…H1.4 and H1.5, suggests that additional kinases, not sensitive to these compounds, are acting on the isoforms. Distribution of the H1 isoforms to distinct regions of the nucleus may also contribute to the differential functionality of the isoforms (41,42) and such trafficking may depend on post-translational modifications of the proteins in response to varied stimuli (43,44). Future experiments will need to expand on the concept of individual histone H1 isoforms acting as gene-specific regulators of transcriptional activity through the modulation of chromatin structure.…”

Section: Discussionmentioning

confidence: 99%

Hormone-mediated Dephosphorylation of Specific Histone H1 Isoforms

Banks¹,

Deterding

Tomer

et al. 2001

Journal of Biological Chemistry

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We have previously shown a connection between histone H1 phosphorylation and the transcriptional competence of the hormone inducible mouse mammary tumor virus (MMTV) promoter. Prolonged exposure of mouse cells to dexamethasone concurrently dephosphorylated histone H1 and rendered the MMTV promoter refractory to hormonal stimulation and, therefore, transcriptionally unresponsive. Using electrospray mass spectrometry, we demonstrate here that prolonged dexamethasone treatment differentially effects a subset of the six somatic H1 isoforms in mouse cells. H1 isoforms H1.0, H1.1, and H1.2 are non-responsive to hormone whereas prolonged dexamethasone treatment effectively dephosphorylated the H1.3, H1.4, and H1.5 isoforms. The protein kinase inhibitor staurosporine, shown to dephosphorylate histone H1 and down-regulate MMTV in cultured cells, appears only to completely dephosphorylate the H1.3 isoform. These results suggest that dephosphorylation of specific histone H1 isoforms may contribute to the previously observed decrease in transcriptional competence of the MMTV promoter through the modulation of chromatin structure. In a broader sense, this work advances the hypothesis that post-translational modifications of individual histone H1 isoforms directly influence the transcriptional activation/repression of specific genes.Eukaryotic DNA is efficiently organized into the highly ordered yet dynamic structure called chromatin (1, 2). The primary, repeating structural unit of chromatin is the nucleosome and is composed of 146 base pairs of DNA wrapped around an octamer of four core histone proteins: H2A, H2B, H3, and H4 (3). In addition, the linker histone or histone H1 protein binds to the linker DNA between nucleosomes and is thought to function primarily in the condensation of chromatin into higher ordered structures (4). While the core histones are highly conserved in eukaryotes, with H4 being nearly invariant, histone H1 is much more evolutionarily diverse, and in mammals, consists of six somatic H1 isoforms (H1.0 through H1.5, using the nomenclature of Doenecke and co-workers, Ref. 5) and one testis-specific isoform (H1.t). The H1 isoforms share a common protein structural fold with the N-and C-terminal "tail" regions extending from a central globular domain. The central globular domain is primarily responsible for binding to DNA, while the tail regions function to modulate protein interaction with DNA (4). It is generally accepted that histone H1 binds nucleosomes at the dyad axis and contacts duplex DNA as it enters and exits the nucleosome (6). However, in the specific case of the 5 S rRNA gene from Xenopus, there is evidence to suggest that histone H1 binds asymmetrically to the nucleosome on a position off the dyad axis and within a DNA gyre (6 -8).A growing body of evidence suggests that the linker histones function in part to modulate transcriptional activity through chromatin organization (reviewed in Ref. 9). Initially, it was thought that histone H1 would have a general role in global gene activity, as ...

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“…To test this, we did chromatin immunoprecipitation analyses of a 539-bp region upstream of CDC2 (Fig. 4A) in growing and starved cells using an antibody reported to be specific for phosphorylated Tetrahymena H1 (45). The CDC2 5Ј region was immunoprecipitated by anti-phosphorylated H1 antibody when chromatin from growing cells was used, but it was not detected in chromatin from starved cells (Fig.…”

Section: Fig 1 Northern Blot Analyses Of Poly(a)mentioning

confidence: 99%

The H1 Phosphorylation State Regulates Expression of CDC2 and Other Genes in Response to Starvation in Tetrahymena thermophila

Dou

Song

Liu

et al. 2005

Molecular and Cellular Biology

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In Tetrahymena thermophila, highly phosphorylated histone H1 of growing cells becomes partially dephosphorylated when cells are starved in preparation for conjugation. To determine the effects of H1 phosphorylation on gene expression, PCR-based subtractive hybridization was used to clone cDNAs that were differentially expressed during starvation in two otherwise-isogenic strains differing only in their H1s. H1 in A5 mutant cells lacked phosphorylation, and H1 in E5 cells mimicked constitutive H1 phosphorylation. Sequences enriched in A5 cells included genes encoding proteases. Sequences enriched in E5 cells included genes encoding cdc2 kinase and a Ser/Thr kinase. These results indicate that H1 phosphorylation plays an important role in regulating the pattern of gene expression during the starvation response and that its role in transcription regulation can be either positive or negative. Treatment of starved cells with a phosphatase inhibitor caused CDC2 gene overexpression. Expression of the E5 version of H1 in starved cells containing endogenous, wild-type H1 caused the wild-type H1 to remain highly phosphorylated. These results argue that Cdc2p is the kinase that phosphorylates Tetrahymena H1, establish a positive feedback mechanism between H1 phosphorylation and CDC2 expression, and indicate that CDC2 gene expression is regulated by an H1 phosphatase.The organization of nuclear DNA into nucleosomes by histones and the folding of nucleosomes into higher-order chromatin structures are generally believed to compact DNA and make it inaccessible to factors required for transcription (see references 30 and 34). There is now compelling evidence that chromatin structural modifications are actively involved in transcription regulation, and extensive physical and functional interactions among transcription factors, chromatin modifying activities, and nucleosomes are well documented (67). Linker histones (H1 and related proteins) have been strongly implicated in modulating chromatin structure and function at multiple levels (66). They are key components of the nucleosome, the most basic level of the hierarchy of chromatin structure in eukaryotes, where they provide extra protection to DNA wrapped around the core histone octamer, presumably by interacting with the DNA strand where it enters and exits the nucleosome core. Linker histones can affect nucleosome mobility (49) and spacing (6). They also stabilize the folding of nucleosome arrays and the association of folded arrays in vitro (10), probably by interacting with the core histone tails (11). However, in spite of intensive study, there is little agreement regarding the precise location of linker histones in nucleosomes (64) and little insight into the mechanisms by which they influence higher orders of chromatin structure.Linker histones have been implicated in the regulation of transcription and were long thought to serve as global repressors (70). However, a number of studies in a variety of organisms have found that linker histones have highly specific effects...

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Phosphorylated and dephosphorylated linker histone H1 reside in distinct chromatin domains in Tetrahymena macronuclei.

Cited by 37 publications

References 43 publications

Histone H1 Phosphorylation by Cdk2 Selectively Modulates Mouse Mammary Tumor Virus Transcription through Chromatin Remodeling

Histone H1 Phosphorylation by Cdk2 Selectively Modulates Mouse Mammary Tumor Virus Transcription through Chromatin Remodeling

Hormone-mediated Dephosphorylation of Specific Histone H1 Isoforms

The H1 Phosphorylation State Regulates Expression of CDC2 and Other Genes in Response to Starvation in Tetrahymena thermophila

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