Correlation Between Histone Lysine Methylation and Developmental Changes at the Chicken β-Globin Locus

Litt, Michael D.; Simpson, Melanie A.; Gaszner, Miklos; Allis, D. David; Felsenfeld, Gary

doi:10.1126/science.1064413

Cited by 551 publications

(465 citation statements)

References 19 publications

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“…18 One can also attribute the cell type selectivity to the physiological role of insulators, that is, the regulation of stage-specific gene expression by regulating higher chromatin structure. 16,17 Recently, double-stranded DNA-binding protein, SATB1, was reported to play a key role in forming thymocytespecific nuclear architecture. 34 SATB1 is proposed to be involved in the chromatin loop formation and regulation of histone modifications.…”

Section: Discussionmentioning

confidence: 99%

“…40 In addition, insulators have been shown to exert their activity through the regulation of the chromatin structure. 3,16,17 Therefore, we focused on the epigenetic changes of the integrated vector sequence to unravel the mechanism of action of ArsI. We analyzed the acetylation status of histone H3 in the provirus, which reflects the open state of chromatin fiber as well as DNA methylation.…”

Section: Sea Urchin Insulator In Lentiviral Vectormentioning

confidence: 99%

“…2,10,[15][16][17][18][19] Previous reports have shown that HS4 insulator protects transgenes from position effect variegation when introduced into MoMLV-based retroviral vectors. 20,21 Since the HS4 fragment is active in restricted cell types, 21 a quest for alternative insulators is necessary to propagate the use of the insulator in various cell types and tissues.…”

Section: Introductionmentioning

confidence: 99%

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Sea urchin insulator protects lentiviral vector from silencing by maintaining active chromatin structure

et al. 2004

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Suppressed expression of transgenes in vivo is the major obstacle in the gene therapy. For the long-term expression, we utilized a chromatin insulator from sea urchin arylsulfatase (Ars) gene locus (Ars insulator, ArsI), which has been shown to epigenetically regulate gene expression across species. ArsI was able to prevent silencing of the transgene in a myeloid cell line, HL-60, and a murine embryonic stem cell line, CCE, in an orientation-dependent manner, but not in Huh-7, K562 and MCF-7 cells, indicating that the effect of ArsI on gene silencing was cell type dependent. Although anti-silencing effect of ArsI was almost equivalent to that of chicken b-globin insulator, incorporation of ArsI into lentiviral vector had little effect on the virus titer compared with chicken b-globin insulator. Clonal analysis of transduced HL-60 cells revealed that ArsI protects the lentiviral vector from position effects regardless of its orientation. Furthermore, chromatin immunoprecipitation assays revealed that a high acetylation level was observed in the promoter of the insulated vector, whereas that of ArsI was independent of its anti-silencing capacity. In addition to it having little deteriorative effect on the virus titer, the identified anti-silencing effect of ArsI suggested its possibility for application in gene therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Sea Urchin Insulator In Lentiviral Vectormentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Sea urchin insulator protects lentiviral vector from silencing by maintaining active chromatin structure

et al. 2004

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“…Hyperacetylation of histone H3 and H4 lysine residues is generally associated with active chromatin, whereas deacetylation has been correlated with inactive genes (35). Another histone modification that has been associated with transcriptionally active chromatin is methylation at Lys 4 of histone H3 (36,37). In cancer cells, histone modifications work in concert with DNA methylation to silence tumor suppressor genes (13,28,38).…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Regulation of Tumor Endothelial Cell Anergy: Silencing of Intercellular Adhesion Molecule-1 by Histone Modifications

Hellebrekers

Castermans

Viré³

et al. 2006

Cancer Research

143

107

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Tumors can escape from immunity by repressing leukocyte adhesion molecule expression on tumor endothelial cells and by rendering endothelial cells unresponsive to inflammatory activation. This endothelial cell anergy is induced by angiogenic growth factors and results in reduced leukocytevessel wall interactions, thereby attenuating infiltration of leukocytes into the tumor. This report describes a novel mechanism of endothelial cell anergy regulation. We recently reported that DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors have angiostatic activity. Here, we studied whether epigenetic mechanisms regulate this angiogenesis-mediated escape from immunity. We found that DNMT inhibitors 5-aza-2 ¶-deoxycytidine and zebularine, as well as HDAC inhibitor trichostatin A, reexpressed intercellular adhesion molecule-1 (ICAM-1) on tumor-conditioned endothelial cells in vitro , resulting in restored leukocyte-endothelial cell adhesion. In addition, treatment with DNMT or HDAC inhibitors in vivo also restored ICAM-1 expression on tumor endothelial cells from two different mouse tumor models. Furthermore, leukocyte-vessel wall interactions in mouse tumors were increased by these compounds, as measured by intravital microscopy, resulting in enhanced leukocyte infiltration. We show that ICAM-1 down-regulation in tumor endothelial cells is associated with ICAM-1 promoter histone H3 deacetylation and loss of histone H3 Lys 4 methylation but not with DNA hypermethylation. In conclusion, our data show that ICAM-1 is epigenetically silenced in tumor endothelial cells by promoter histone modifications, which can be overcome by DNMT and HDAC inhibitors, suggesting a new molecular mechanism based on which novel therapeutic approaches for cancer can be

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“…Rb appears to circumscribe heterochromatin in the photoreceptors 14 , whereas it appears in a diffuse nuclear pattern in neurons and progenitor cells. It has been suggested that the genome is divided into transcriptional domains and that this organization is regulated by a higher order chromatin structure that is organized by histones [29][30][31][32] . Rb is recruited to specific promoters through protein-protein interactions with E2F/DP heterodimers bound to their cognate binding sites 33 .…”

Section: Thus Rb Family Members May Not Be Completely Interchangeablmentioning

confidence: 99%

Rb regulates proliferation and rod photoreceptor development in the mouse retina

et al. 2004

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In the mouse, the seven main classes of retinal cell types (rod, cone, bipolar, horizontal, amacrine, ganglion and Müller glial cells) are produced from multipotent progenitor cells over a 17-d interval starting at embryonic day (E) 11.5 and continuing through postnatal day (P) 9. The overall size of the retina and the proportion of each cell type contained therein is essential for proper visual processing; therefore, during retinal development, cell cycle exit and cell fate specification are coordinated to ensure that the adult retina forms appropriately 1,2 . When cell proliferation and cell fate specification become uncoupled, as in retinoblastoma 3 , microphthalmia 4,5 and some forms of retinal dysplasia 6,7 and degeneration 8 , vision is severely compromised. By studying individual proteins that integrate the decision to exit the cell cycle and to specify cell fate, we may begin to gain insights into the synchronization of these two important processes during neural development.Rb lies at the heart of the regulatory network that executes cell cycle exit during the G1 phase through interactions with the E2F transcription factor family. There is also evidence that Rb has a role in cell fate specification [9][10][11] . In support of this notion, Rb can bind more than 110 different proteins, several of which are tissue-restricted transcription factors 12 . It is conceivable that Rb binds to E2F and regulates cell cycle exit through its canonical pathway and then contributes to cell fate specification, differentiation or both through interactions with tissuerestricted transcription factors.To overcome the embryonic lethality of Rb1 -/-embryos, which die in utero around E13.5, we used an explant culture procedure to study the development of isolated whole retinas beyond E13.5. To complement and extend the explant culture studies in vivo, we inactivated the gene Rb1 in the retina by using a new tissue-specific Cre transgenic line (Chx10-cre) crossed to Rb1 lox mice. Finally, we injected a Cre-expressing replication-incompetent retrovirus into the eyes of newborn Rb1 lox mice to generate clones of cells lacking Rb. These experiments showed that Rb is required in a cell-autonomous manner for appropriate cell cycle exit and rod development in the mouse retina. This is the first example of a cell-autonomous role for an Rb family member in these two interrelated processes in the developing retina. RESULTS Rb expression during developmentTo identify the cells expressing Rb in the developing mouse retina, we immunolabeled retinal cryosections at six postnatal stages of development (P0, P3, P6, P9, P12 and P21). At P0, when approximately 35% of cells are still dividing and 65% are postmitotic 1,13 (R. Martins and M.A.D., unpublished results), Rb was expressed in the nuclei of dividing retinal progenitor cells in the outer neuroblastic layer and postmitotic differentiating neurons in the developing inner nuclear layer (Fig. 1a-d). To verify that the cells expressing Rb in the outer neuroblastic layer were actively dividin...

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Correlation Between Histone Lysine Methylation and Developmental Changes at the Chicken β-Globin Locus

Cited by 551 publications

References 19 publications

Sea urchin insulator protects lentiviral vector from silencing by maintaining active chromatin structure

Sea urchin insulator protects lentiviral vector from silencing by maintaining active chromatin structure

Epigenetic Regulation of Tumor Endothelial Cell Anergy: Silencing of Intercellular Adhesion Molecule-1 by Histone Modifications

Rb regulates proliferation and rod photoreceptor development in the mouse retina

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