Organization of transcriptional regulatory machinery in osteoclast nuclei: Compartmentalization of Runx1

Saltman, Laura H.; Javed, Amjad; Ribadeneyra, John; Hussain, Sadiq; Young, Daniel W.; Osdoby, Philip; Amcheslavsky, Alla; Wijnen, André J. van; Stein, Janet L.; Lian, Jane B.; Bar‐Shavit, Zvi

doi:10.1002/jcp.20329

Cited by 25 publications

(15 citation statements)

References 54 publications

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“…Runx factors recruit coregulatory proteins important for signal transduction mediation [32]. Real-time PCR has identified Runx1 as the predominant member of the Runx family in mouse osteoclast and osteoclast-precursor cells [33]. Interestingly, Runx1 mRNA expression decreases with the addition of NF-kB ligand (RANKL), the major stimulator of osteoclast differentiation and activity, in these mouse models [33].…”

Section: Discussionmentioning

confidence: 99%

“…Real-time PCR has identified Runx1 as the predominant member of the Runx family in mouse osteoclast and osteoclast-precursor cells [33]. Interestingly, Runx1 mRNA expression decreases with the addition of NF-kB ligand (RANKL), the major stimulator of osteoclast differentiation and activity, in these mouse models [33]. By binding to the FDPS promoter site made by the rs2297480 A allele, Runx1 may decrease osteoclast activity by inhibiting FDPS transcription.…”

Section: Discussionmentioning

confidence: 99%

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Farnesyl diphosphate synthase: A novel genotype association with bone mineral density in elderly women

et al. 2007

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Mini-Abstract-Farnesyl diphosphate synthase (FDPS) is the molecular target of nitrogencontaining bisphosphonates. We analyzed the association between a SNP in the FDPS gene with bone mineral density (BMD) in post-menopausal Caucasian women. The SNP was associated with decreased BMD after adjusting for age and BMI. Genetic variation in FDPS may contribute to BMD in this population.Objective-We evaluated the association between a single nucleotide polymorphism in the farnesyl diphosphate synthase gene (FDPS), BMD and bone turnover markers.Methods-283 community-dwelling Caucasian women aged 65 or older were screened from the greater Boston area. A validated FDPS SNP (rs2297480, A/C) was genotyped and evaluated for effect on bone mineral density (spine, hip, forearm) and bone turnover markers (urine N-telopeptide crosslinked collagen type 1, osteocalcin and bone-specific alkaline phosphatase).Results-BMD was lower at all sites measured in women with the C/C or C/A genotypes. Statistically significant differences (p<0.05) were found at the PA spine, trochanter, distal radius, and proximal ulna after adjustment for age and BMI. No significant differences were found in bone turnover markers.Conclusion-These findings suggest that a single nucleotide polymorphism in the FDPS gene (rs2297480) may be a genetic marker for lower BMD in postmenopausal Caucasian women.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Farnesyl diphosphate synthase: A novel genotype association with bone mineral density in elderly women

et al. 2007

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“…MOs stimulated with RANKL and M-CSF generate functional OCs [27], which degrade bone and express OC markers [28]. As indicated, the involvement of transcription factors in this model has been well studied, however very few reports have analyzed the role of epigenetic changes during osteoclastogenesis, and these focus mainly on histone modifications [29,30]. Given the relationship between transcription factors and DNA methylation, we hypothesized that examining DNA methylation changes would provide clues about the involvement of specific factors in the dynamics and hierarchy of these changes in terminal differentiation.…”

Section: Introductionmentioning

confidence: 99%

PU.1 target genes undergo Tet2-coupled demethylation and DNMT3b-mediated methylation in monocyte-to-osteoclast differentiation

et al. 2013

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BackgroundDNA methylation is a key epigenetic mechanism for driving and stabilizing cell-fate decisions. Local deposition and removal of DNA methylation are tightly coupled with transcription factor binding, although the relationship varies with the specific differentiation process. Conversion of monocytes to osteoclasts is a unique terminal differentiation process within the hematopoietic system. This differentiation model is relevant to autoimmune disease and cancer, and there is abundant knowledge on the sets of transcription factors involved.ResultsHere we focused on DNA methylation changes during osteoclastogenesis. Hypermethylation and hypomethylation changes took place in several thousand genes, including all relevant osteoclast differentiation and function categories. Hypomethylation occurred in association with changes in 5-hydroxymethylcytosine, a proposed intermediate toward demethylation. Transcription factor binding motif analysis revealed an over-representation of PU.1, NF-κB, and AP-1 (Jun/Fos) binding motifs in genes undergoing DNA methylation changes. Among these, only PU.1 motifs were significantly enriched in both hypermethylated and hypomethylated genes; ChIP-seq data analysis confirmed its association to both gene sets. Moreover, PU.1 interacts with both DNMT3b and TET2, suggesting its participation in driving hypermethylation and hydroxymethylation-mediated hypomethylation. Consistent with this, siRNA-mediated PU.1 knockdown in primary monocytes impaired the acquisition of DNA methylation and expression changes, and reduced the association of TET2 and DNMT3b at PU.1 targets during osteoclast differentiation.ConclusionsThe work described here identifies key changes in DNA methylation during monocyte-to-osteoclast differentiation and reveals novel roles for PU.1 in this process.

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“…Runx1 and Runx2 are scaffolding proteins that assemble regulatory complexes at specific intranuclear sites to mediate activation or repression of target genes (Stein et al, 2004b; Stein et al, 2005; Lian et al, 2006; Harrington et al, 2002; Saltman et al, 2005; Zeng et al, 1998). During interphase these proteins are associated with the nuclear matrix through a 31–35 amino acid nuclear matrix targeting signal (NMTS) in the carboxy terminus (Zeng et al, 1997; Zaidi et al, 2001; Tang et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Subnuclear targeting of the Runx3 tumor suppressor and its epigenetic association with mitotic chromosomes

Pande

Ali

Dowdy

et al. 2008

Journal Cellular Physiology

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Runx proteins are tissue-specific transcriptional scaffolds that organize and assemble regulatory complexes at strategic sites of target gene promoters and at intranuclear foci to govern activation or repression. During interphase, fidelity of intranuclear targeting supports the biological activity of Runx1 and Runx2 proteins. Both factors regulate genes involved in cell cycle control and cell growth (e.g., rRNA genes), as well as lineage commitment. Here, we have examined the subcellular regulatory properties of the third Runx member, the tumor suppressor protein Runx3, during interphase and mitosis. Using in situ cellular and biochemical approaches we delineated a subnuclear targeting signal that directs Runx3 to discrete transcriptional foci that are nuclear matrix associated. Chromatin immunoprecipitation results show that Runx3 occupies rRNA promoters during interphase. We also find that Runx3 remains associated with chromosomes during mitosis and localizes with nucleolar organizing regions (NORs), reflecting an interaction with epigenetic potential. Taken together, our study establishes that common mechanisms control the subnuclear distribution and activities of Runx1, Runx2 and Runx3 proteins to support RNA polymerase I and II mediated gene expression during interphase and mitosis.

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Organization of transcriptional regulatory machinery in osteoclast nuclei: Compartmentalization of Runx1

Cited by 25 publications

References 54 publications

Farnesyl diphosphate synthase: A novel genotype association with bone mineral density in elderly women

Farnesyl diphosphate synthase: A novel genotype association with bone mineral density in elderly women

PU.1 target genes undergo Tet2-coupled demethylation and DNMT3b-mediated methylation in monocyte-to-osteoclast differentiation

Subnuclear targeting of the Runx3 tumor suppressor and its epigenetic association with mitotic chromosomes

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