An Upstream Control Region Required for Inducible Transcription of the Mouse H1° Histone Gene during Terminal Differentiation

Dong, Yaa Hui; Liu, Dakai; Skoultchi, A

doi:10.1128/mcb.15.4.1889

Cited by 17 publications

(10 citation statements)

References 69 publications

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“…Gene inactivation studies in mice have not revealed essential functions for any of these histone H1 subtypes, including H1c and H1(0) (15)(16)(17). Interestingly however, we reported previously that the genes encoding H1(0) and H1c exhibit differences in their regulation compared with the genes encoding the four other subtypes (40)(41)(42). These differences are attributable both to differences in transcriptional control and to the formation of H1(0) and H1c polyadenylated mRNAs, which are distinct from the cell cycledependent, nonpolyadenylated mRNAs formed by the other four genes.…”

Section: Discussionmentioning

confidence: 96%

H1 linker histone promotes epigenetic silencing by regulating both DNA methylation and histone H3 methylation

Yang

Kim

Toro

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

107

105

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Epigenetic silencing in mammals involves DNA methylation and posttranslational modifications of core histones. Here we show that the H1 linker histone plays a key role in regulating both DNA methylation and histone H3 methylation at the H19 and Gtl2 loci in mouse ES cells. Some, but not all, murine H1 subtypes interact with DNA methyltransferases DNMT1 and DNMT3B. The interactions are direct and require a portion of the H1 C-terminal domain. Expression of an H1 subtype that interacts with DNMT1 and DNMT3B in ES cells leads to their recruitment and DNA methylation of the H19 and Gtl2 imprinting control regions. H1 also interferes with binding of the SET7/9 histone methyltransferase to the imprinting control regions, inhibiting production of an activating methylation mark on histone H3 lysine 4. H1-dependent recruitment of DNMT1 and DNMT3B and interference with the binding of SET7/9 also were observed with chromatin reconstituted in vitro. The data support a model in which H1 plays an active role in helping direct two processes that lead to the formation of epigenetic silencing marks. The data also provide evidence for functional differences among the H1 subtypes expressed in somatic mammalian cells.mouse embryonic stem cell | H1 histone triple knockout T wo major types of epigenetic marks occur in mammalian genomes, DNA methylation and posttranslational modifications of histones (1, 2). The methylation of cytosines in mammalian DNA occurs primarily at CpG dinucleotides and is essential for normal mammalian development (1, 3). Perturbations of DNA methylation patterns are thought to play a role in cancer development (4). There are two classes of mammalian DNA methyltransferases (DNMTs), one that functions primarily to establish DNA methylation de novo (DNMT3A and DNMT3B) and the other to maintain it (DNMT1) (3). DNA methylation can have profound effects on gene expression and is most often associated with transcriptional silencing (1, 2). Accumulating evidence indicates the existence of crosstalk between the DNA methylation and core histone modification systems (1, 2). For example, mouse ES cells deficient for the histone H3 lysine 9 (H3K9) methyltransferases Suv39h1/h2 exhibit hypomethylation of CpGs at a subset of repetitive DNA elements (5). Additionally, several lines of evidence indicate that the presence of unmethylated lysine 4 of histone H3 (H3K4) in chromatin favors de novo methylation of DNA (6-9). Despite these advances, the factors in chromatin that coordinate DNA methylation and histone H3 methylation have not been identified.In this study, we investigated the role of the linker histone H1 in regulating DNA methylation and histone H3 methylation at the H19 and Gtl2 loci in mouse ES cells. H1 is the most distinct of the five histone proteins (H1, H2A, H2B, H3, and H4) in chromatin (10,11). Mammals contain at least eight histone H1 subtypes or variants that differ in amino acid sequences and expression during development (12-14). Functional differences among these subtypes have been difficult to identif...

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Section: Discussionmentioning

confidence: 96%

H1 linker histone promotes epigenetic silencing by regulating both DNA methylation and histone H3 methylation

Yang

Kim

Toro

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

107

105

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“…Immunoprecipitation assays were performed on 500 g of total protein extract from cells lysed by sonication by published procedures. Nuclear and cytoplasmic extracts were isolated as described (15), except that protein extract from nuclear isolates was prepared by sonication by published procedures (14). Immunoprecipitation-Kinase Assays.…”

Section: Methodsmentioning

confidence: 99%

Reprogramming leukemic cells to terminal differentiation by inhibiting specific cyclin-dependent kinases in G ₁

Matushansky

Radparvar

Skoultchi

2000

Proc. Natl. Acad. Sci. U.S.A.

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Some tumor cells can be stimulated to differentiate and undergo terminal cell division and loss of tumorigenicity. The in vitro differentiation of murine erythroleukemia (MEL) cells is a dramatic example of tumor-cell reprogramming. We found that reentry of MEL cells into terminal differentiation is accompanied by an early transient decline in the activity of cyclin-dependant kinase (CDK) 2, followed by a decline of CDK6. Later, as cells undergo terminal arrest, CDK2 and CDK4 activities decline. By analyzing stable MEL-cell transfectants containing vectors directing inducible expression of specific CDK inhibitors, we show that only inhibitors that block the combination of CDK2 and CDK6 trigger differentiation. Inhibiting CDK2 and CDK4 does not cause differentiation. Importantly, we also show that reprogramming through inhibition of CDKs is restricted to G 1 phase of the cell cycle. The results imply that abrogation of normal cell-cycle controls in tumor cells contributes to their inability to differentiate fully and that restoration of such controls in G 1 can lead to resumption of differentiation and terminal cell division. The results also indicate that CDK4 and CDK6 are functionally distinct and support our hypothesis that the two CDKs regulate cell division at different stages of erythroid maturation.

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“…To determine the kinetics of PU.1 down regulation in relation to cell commitment to terminal di erentiation, we measured PU.1 mRNA levels by a RNase protection assay (Figure 1a), PU.1 protein levels by immunoblotting ( Figure 1b Clone DS19 MEL cells were grown in Dulbecco's modi®ed Eagle medium (DME) supplemented with 10% fetal bovine serum as described previously (Cheng and Skoultchi, 1989) in the presence of 5 mM HMBA. At the times indicated, total cellular RNA was prepared by hot-phenol extraction at 608C (Soeiro and Darnell, 1969) and 20 mg of RNA were analysed by a RNase protection assay (Dong et al, 1995) for PU.1 mRNA or by Northern blot hybridization (Sambrook et al, 1989) for c-myc mRNA. A 448 nt 32 P-CTP-labeled antisense RNA probe synthesized with SP6 RNA polymerase from a SacI/PstI subclone of PU.1 cDNA in pGEM3Z was used in the RNase protection assay.…”

Section: Expression Of Pu1 Is Down Regulated As Mel Cells Commit To mentioning

confidence: 99%

Deregulated expression of the PU.1 transcription factor blocks murine erythroleukemia cell terminal differentiation

et al. 1997

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Murine erythroleukemia (MEL) cells are transformed erythroid precursors that are blocked from completing the late stages of erythroid di erentiation. A frequent event in the generation of these malignant cells is deregulation of the hematopoietic-speci®c transcription factor PU.1 (Spi-1) by retroviral insertion of the spleenfocus-forming virus component of Friend virus. During chemically induced reinitiation of MEL cell terminal di erentiation, expression of PU.1 is rapidly downregulated, suggesting that PU.1 might interfere with processes required for terminal di erentiation of erythroid precursors. To investigate the role of PU.1 in erythroid di erentiation we transfected MEL cells with a PU.1 cDNA controlled by the eucaryotic translation elongation factor EF1a promoter. Deregulated expression of PU.1 blocked chemically induced di erentiation and terminal cell division. Deregulated expression of two other protooncogenes, c-myc and c-myb, also has been shown to block MEL di erentiation. We present evidence that PU.1 inhibits terminal di erentiation at an earlier step than c-Myc and c-Myb. Thus reinitiation of MEL cell terminal di erentiation appears to be controlled by an ordered program of turning o several protooncogenes. Down-regulation of PU.1 may be a very early step in this program.

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An Upstream Control Region Required for Inducible Transcription of the Mouse H1° Histone Gene during Terminal Differentiation

Cited by 17 publications

References 69 publications

H1 linker histone promotes epigenetic silencing by regulating both DNA methylation and histone H3 methylation

H1 linker histone promotes epigenetic silencing by regulating both DNA methylation and histone H3 methylation

Reprogramming leukemic cells to terminal differentiation by inhibiting specific cyclin-dependent kinases in G ₁

Deregulated expression of the PU.1 transcription factor blocks murine erythroleukemia cell terminal differentiation

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An Upstream Control Region Required for Inducible Transcription of the Mouse H1° Histone Gene during Terminal Differentiation

Cited by 17 publications

References 69 publications

H1 linker histone promotes epigenetic silencing by regulating both DNA methylation and histone H3 methylation

H1 linker histone promotes epigenetic silencing by regulating both DNA methylation and histone H3 methylation

Reprogramming leukemic cells to terminal differentiation by inhibiting specific cyclin-dependent kinases in G 1

Deregulated expression of the PU.1 transcription factor blocks murine erythroleukemia cell terminal differentiation

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Product

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Reprogramming leukemic cells to terminal differentiation by inhibiting specific cyclin-dependent kinases in G ₁