Transcriptional Induction of the Osteocalcin Gene During Osteoblast Differentiation Involves Acetylation of Histones H3 and H4

Shen, Jincheng; Hovhannisyan, Hayk; Lian, Jane B.; Montecino, Martín; Stein, Gary S.; Wijnen, André J. van

doi:10.1210/me.2002-0122

Cited by 87 publications

(78 citation statements)

References 42 publications

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“…Acetylated histones H3 and H4 (AcH3 and AcH4) are associated with euchromatin (14), and acetylation of promoter proximal histones is associated with gene expression (15,16). Figure 1D shows that high levels of AcH3 and AcH4 are linked to elevated levels of hTR gene expression, with GM847, 5637, A2780, SKLU, C33a, and WI38 exhibiting higher levels of AcH3 and AcH4 than SUSM-1, KMST-6, and WI38-SV40.…”

Section: Resultsmentioning

confidence: 99%

Lack of Telomerase Gene Expression in Alternative Lengthening of Telomere Cells Is Associated with Chromatin Remodeling of the hTR and hTERT Gene Promoters

Atkinson

Hoare²,

Glasspool³

et al. 2005

Cancer Research

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The presence of active telomere maintenance mechanisms in immortal cells allows the bypass of senescence by maintaining telomere length. In most immortal cell lines and tumors, telomere maintenance is attributable to telomerase reactivation. However, a number of immortal cell lines and tumors can achieve telomere maintenance in the absence of detectable telomerase activity by the alternative lengthening of telomere (ALT) mechanism. Epigenetic mechanisms have been implicated in the regulation of telomerase expression. We show that specific modifications within the chromatin environment of the hTR and hTERT promoters correlate with expression of hTR and hTERT in ALT, normal and telomerasepositive tumor cell lines. Lack of expression of hTR and hTERT in ALT cell lines is associated with histone H3 and H4 hypoacetylation and methylation of Lys 9 histone H3. Conversely, hTR and hTERT expression in telomerase-positive cell lines is associated with hyperacetylation of H3 and H4 and methylation of Lys 4 H3. Methylation of Lys 20 H4 was not linked to gene expression but instead was specific to the hTR and hTERT promoters of ALT cells. This may provide an insight into the differences between ALT and telomerase-positive cells as well as a novel marker for the ALT phenotype. Treatment of normal and ALT cells with 5-azadeoxycytidine in combination with Trichostatin A caused chromatin remodeling of both promoters and reactivation of hTR and hTERT expression in ALT and normal cell lines. This data establishes a definite link between the chromatin environment of the telomerase gene promoters and transcriptional activity. (Cancer Res 2005; 65(17): 7585-90)

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Section: Resultsmentioning

confidence: 99%

Lack of Telomerase Gene Expression in Alternative Lengthening of Telomere Cells Is Associated with Chromatin Remodeling of the hTR and hTERT Gene Promoters

Atkinson

Hoare²,

Glasspool³

et al. 2005

Cancer Research

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“…C/EBP␤ has been also demonstrated to functionally interact with Runx2 (17), which in turn binds to another chromatin-remodeling complex, the HAT complex p300-P/CAF that also is recruited to the OC promoter (16). Recently, we have shown that transcriptional activation of the OC gene during normal diploid osteoblast differentiation involves increased acetylation of core histones bound to the OC promoter (37). Together these results indicate that HAT activity may also have a principal role in the chromatin-remodeling events associated with transcription of the OC gene, although in light of the results shown here, it appears as insufficient to bring the remodeling process to completion.…”

Section: Discussionmentioning

confidence: 99%

Chromatin Remodeling and Transcriptional Activity of the Bone-specific Osteocalcin Gene Require CCAAT/Enhancer-binding Protein β-dependent Recruitment of SWI/SNF Activity

Villagra

Cruzat

Carvallo

et al. 2006

Journal of Biological Chemistry

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102

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Tissue-specific activation of the osteocalcin (OC) gene is associated with changes in chromatin structure at the promoter region. Two nuclease-hypersensitive sites span the key regulatory elements that control basal tissue-specific and vitamin D 3 -enhanced OC gene transcription. To gain understanding of the molecular mechanisms involved in chromatin remodeling of the OC gene, we have examined the requirement for SWI/SNF activity. We inducibly expressed an ATPase-defective BRG1 catalytic subunit that forms inactive SWI/SNF complexes that bind to the OC promoter. This interaction results in inhibition of both basal and vitamin D 3 -enhanced OC gene transcription and a marked decrease in nuclease hypersensitivity. We find that SWI/SNF is recruited to the OC promoter via the transcription factor CCAAT/enhancer-binding protein ␤, which together with Runx2 forms a stable complex to facilitate RNA polymerase II binding and activation of OC gene transcription. Together, our results indicate that the SWI/SNF complex is a key regulator of the chromatin-remodeling events that promote tissue-specific transcription in osteoblasts.Within the eukaryotic nucleus, the packaging of DNA into nucleosomes and higher order chromatin structures have been implicated in the regulation of key cellular events, such as replication and transcription. During the last decade, a large family of protein complexes that promote transcription by altering chromatin structure have been described (1-3). Among them is the SWI/SNF complex subfamily that remodels chromatin in an ATP-dependent manner (1-3). SWI/SNF complexes are composed of several subunits, which have been implicated in a wide range of cellular events, including gene regulation, cell cycle control, development, and differentiation (1, 3). The mammalian SWI/SNF complexes contain a catalytic subunit that can be either BRG1 or BRM, which includes ATPase activity. Mutations in the ATPase domain of BRG1 or BRM that abrogate the ability of these proteins to bind ATP result in the formation of inactive SWI/SNF complexes (4 -6). Furthermore, expression of mutant BRG1 or BRM proteins in NIH3T3 cells impairs the ability of these cells to activate endogenous stress response genes in the presence of arsenite (5) and to differentiate into muscle or adipocytic cells (4, 5, 7). In addition, we have recently shown that the presence of the mutant BRG1 protein in these NIH3T3 cell lines inhibits BMP2-induced differentiation into the osteoblast lineage (8).The rat osteocalcin (OC) 3 gene encodes a 10-kDa bone-specific protein that is expressed at late stages of osteoblast differentiation, concomitant with the mineralization of the extracellular matrix (9). Osteoblast-specific transcription of the OC gene is controlled by modularly organized basal and hormoneresponsive elements located within two DNase I-hypersensitive sites (distal site Ϫ605 to Ϫ400 and proximal site Ϫ170 to Ϫ70; see Fig. 1) that are present only in osteoblastic cells expressing this gene (10). Thus, chromatin remodeling of the OC gene p...

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“…The histone acetyltransferase inhibitor TSA has been reported to favor the overall acetylation status of histones, thus increasing the accessibility of specific chromatin regions to transcription factors (53). Acetylation level of histones H3 and H4 has been shown to be functionally coupled to the chromatin remodeling events that mediate OC gene transcription during osteogenesis (35). Therefore, we were interested to see whether TSA treatment has an influence on the histone acetylation status of the BSP proximal promoter in Saos-2 cells.…”

Section: Acetylated Histone H3 Proteins Are Detectable In the Bsp Promentioning

confidence: 99%

“…HDAC3, is a class I member of the HDAC family, which are enzymes recruited by transcription factors to specific DNA regulatory sequences (32)(33)(34). Active expression of osteoblastic genes in mature osteoblasts and confluent ROS 17/2.8 osteosarcoma cells has been previously shown to involve histone H3 and H4 acetylation (35). Accordingly, HDACs inhibitors such as trichostatin A (TSA) and valproic acid promote osteoblast maturation (36,37).…”

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confidence: 99%

Runx2- and Histone Deacetylase 3-mediated Repression Is Relieved in Differentiating Human Osteoblast Cells to Allow High Bone Sialoprotein Expression

Lamour

Detry

Sanchez

et al. 2007

Journal of Biological Chemistry

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Bone sialoprotein (BSP) is a bone matrix glycoprotein whose expression coincides with terminal osteoblastic differentiation and the onset of mineralization. In this study we show that BSP expression is considerably increased in confluent Saos-2 human osteosarcoma cells and in differentiating normal human osteoblasts, concomitantly with the decrease of Runx2, a key transcription factor controlling bone formation. Therefore, we investigated the role of Runx2 in the regulation of BSP expression in Saos-2 cells. Using a mobility shift assay, we demonstrated that Runx2 binds to the BSP promoter only in preconfluent cells. Histone deacetylase 3 (HDAC3) has been recently shown to act as a Runx2 co-repressor. Chromatin immunoprecipitation assays demonstrated that both Runx2 and HDAC3 are detectable at the BSP promoter in preconfluent Saos-2 cells but not when they are confluent and overexpress BSP. Consistently, nuclear Runx2 protein level is down-regulated, whereas Saos-2 cells became increasingly confluent. Finally, the suppression of HDAC3, Runx2, or both by RNA interference induced the expression of BSP at both mRNA and protein levels in Saos-2 cells. Our data demonstrate that Runx2 and HDAC3 repress BSP gene expression and that this repression is suspended upon osteoblastic cell differentiation. Both the nuclear disappearance of Runx2 and the non-recruitment of HDAC3 represent new means to relieve Runx2-mediated suppression of BSP expression, thus allowing the acquisition of a fully differentiated and mineralization-competent phenotype by osteoblast cells.

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Transcriptional Induction of the Osteocalcin Gene During Osteoblast Differentiation Involves Acetylation of Histones H3 and H4

Cited by 87 publications

References 42 publications

Lack of Telomerase Gene Expression in Alternative Lengthening of Telomere Cells Is Associated with Chromatin Remodeling of the hTR and hTERT Gene Promoters

Lack of Telomerase Gene Expression in Alternative Lengthening of Telomere Cells Is Associated with Chromatin Remodeling of the hTR and hTERT Gene Promoters

Chromatin Remodeling and Transcriptional Activity of the Bone-specific Osteocalcin Gene Require CCAAT/Enhancer-binding Protein β-dependent Recruitment of SWI/SNF Activity

Runx2- and Histone Deacetylase 3-mediated Repression Is Relieved in Differentiating Human Osteoblast Cells to Allow High Bone Sialoprotein Expression

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