C/EBPα regulates osteoclast lineage commitment

Chen, Wei; Zhu, Guochun; Hao, Liang; Wu, Mengrui; Ci, Hongliang; Li, Yiping

doi:10.1073/pnas.1211383110

Cited by 72 publications

(108 citation statements)

References 24 publications

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“…In this study, HDL correlated with stature in females only. C/EBPα is documented in animal studies to control lineage commitment of osteoclasts (Chen et al 2013). The inverse correlation of DNA methylation variation with stature in both males and females at Site 4…”

Section: Discussionmentioning

confidence: 99%

Patterns of DNA Methylation across the Leptin Core Promoter in Four Diverse Asian and North American Populations

Mosher¹,

Melton²,

Stapleton³

et al. 2016

Human Biology

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DNA methylation is the most widely studied of epigenetic mechanisms, with environmental effects recorded through patterned attachments of methyl groups along the DNA which are capable of modifying gene expression without altering the DNA sequencing. The degree to which these patterns of DNA methylation are heritable, the expected range of normality across populations, and the phenotypic relevance of pattern variation remain unclear. Genes regulating metabolic pathways appear to be vulnerable to ongoing nutritional programming over the life course, as dietary nutrients are significant environmental determinants of DNA methylation, supplying both the methyl groups and energy to generate the methylation process.Here we examine methylation patterns along a region of the metabolic gene leptin (LEP). LEP's putative function includes regulation of energy homeostasis, with its signals affecting energy intake and expenditure, adipogenesis and energy storage, lipid and glucose metabolism, bone metabolism and Pre-print version. Visit http://digitalcommons.wayne.edu/humbiol/ after publication to acquire the final version.reproductive endocrine function. A pattern of differential methylation across CpG sites of the LEP core promoter has been previously identified; however, any consistency of pattern or its phenotypic significance is not fully elucidated among populations. Using DNA extracted from unfractionated white blood cells of peripheral blood samples, our pilot study, divided into two parts, examines the significance of variation in DNA methylation patterns along the leptin core promoter in four populations and uses biomarkers reflecting leptin's functional process in two of those populations to investigate the relevance of the ethnic variation identified in the DNA methylation. Those two populations are the Western Buryats of Siberia and the Mennonites of Central Kansas.LEP's core promoter region contains both the C/EBPα transcription binding site (TBS) which tempers the final step in adipocyte maturity and capacity to synthesize leptin and the TATA motif controlling leptin synthesis. Previous studies report that increased methylation in this region is correlated to decreased gene expression, with others suggesting tissue-specific methylation variation at this region. We hypothesize that evidence of nutritional epigenetic programming would be identified through variation in patterns of DNA methylation and that functional relevance of that variation among populations would be identified through biomarkers which reflect leptin's metabolic signals: serum leptin levels, lipoproteins of the lipid transport system and anthropometric measures.A distinct and consistent overall pattern of differential DNA methylation across seven CpG sites of LEP core promoter is documented in all ethnicities and both sexes in our combined analyses of 313 individuals. This pattern replicates those identified in previous studies, thus suggesting a conserved core promoter region across populations. The second analyses in two of the four ...

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Section: Discussionmentioning

confidence: 99%

Patterns of DNA Methylation across the Leptin Core Promoter in Four Diverse Asian and North American Populations

Mosher¹,

Melton²,

Stapleton³

et al. 2016

Human Biology

View full text Add to dashboard Cite

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“…For example, IRF8 is expressed in pre-osteoclasts and inhibits their differentiation, whereas C/EBPa is expressed in both pre-osteoclasts and osteoclasts to promote osteoclastogenesis 41,42 . Moreover, because the DBDs are well conserved in both the IRF and C/EBP families, other IRF-C/EBP interactions may also occur.…”

Section: Discussionmentioning

confidence: 99%

IRF8 inhibits C/EBPα activity to restrain mononuclear phagocyte progenitors from differentiating into neutrophils

et al. 2014

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Myeloid progenitors lose their potential to generate neutrophils when they adopt the mononuclear phagocyte lineage. The mechanism underlying this lineage restriction remains unknown. We here report that the protein expression of IRF8, an essential transcription factor for the development of dendritic cells (DCs) and monocytes, sharply increases at the monocyte-DC progenitor (MDP) stage and remains high in common monocyte progenitors (cMoPs). Irf8 À / À MDPs and cMoPs accumulate but fail to efficiently generate their downstream populations, instead giving rise to neutrophils in vivo. IRF8 physically interacts with the transcription factor C/EBPa and prevents its binding to chromatin in MDPs and cMoPs, blocking the ability of C/EBPa to stimulate transcription and neutrophil differentiation. A partial inhibition of C/EBP activity in Irf8 À / À haematopoietic progenitors alleviates the neutrophil overproduction in vivo. Thus, IRF8 not only bestows monocyte and DC differentiation potential upon mononuclear phagocyte progenitors but also restrains these progenitors from differentiating into neutrophils.

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“…This results in NFATc1 transiently auto-amplifying its own expression (Takayanagi et al, 2002), accompanied by down-regulation of the expression of constitutively active repressors of RANK signaling (Zhao and Ivashkiv, 2011), which allows osteoclastogenesis to proceed. NFATc1 is subsequently activated by c-Fos through TRAF6/NF-κB and CCAAT/enhancer binding protein-α (Chen et al, 2013) signaling to complete OCP differentiation and subsequent OC activation. These early events in osteoclastogenesis are associated with a number of epigenetic phenomena in response to RANKL.…”

Section: Regulation Of Osteoclast Formationmentioning

confidence: 99%

Advances in the Regulation of Osteoclasts and Osteoclast Functions

2013

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Osteoclasts are derived from mononuclear hematopoietic myeloid lineage cells, which are formed in the bone marrow and are attracted to the bloodstream by factors, including sphingsine-1 phosphate. These circulating precursors are attracted to bone surfaces undergoing resorption by chemokines and other factors expressed at these sites, where they fuse to form multinucleated boneresorbing cells. All aspects of osteoclast formation and functions are regulated by macrophagecolony-stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL), cytokines essential for osteoclast formation and expressed by a variety of cell types, including osteoblast lineage cells. Since the discovery of RANKL in the mid1990s, mouse genetic and molecular studies have revealed numerous signaling pathways activated by RANKL and M-CSF. More recent studies indicate that osteoclasts and their precursors regulate immune responses and osteoblast formation and functions by means of direct cell-cell contact through ligands and receptors, such as ephrins and Ephs, and semaphorins and plexins, and through expression of clastokines. There is also growing recognition that osteoclasts are immune cells with roles in immune responses beyond mediating the bone destruction that can accompany them. This article reviews recent advances in the understanding of the molecular mechanisms regulating osteoclast formation and functions and their interactions with other cells in normal and pathologic states.

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C/EBPα regulates osteoclast lineage commitment

Cited by 72 publications

References 24 publications

Patterns of DNA Methylation across the Leptin Core Promoter in Four Diverse Asian and North American Populations

Patterns of DNA Methylation across the Leptin Core Promoter in Four Diverse Asian and North American Populations

IRF8 inhibits C/EBPα activity to restrain mononuclear phagocyte progenitors from differentiating into neutrophils

Advances in the Regulation of Osteoclasts and Osteoclast Functions

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