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Transcriptional deregulation during osteoclastic differentiation due to diuron exposure affects preferentially super-enhancers regulated genes

ABSTRACT: Transcriptional deregulation during osteoclastic differentiation due to diuron exposure affects preferentially super-enhancers regulated genes

PROVIDER: PRJNA737649 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14813500_1.fastq.gz	Fastqsanger.gz
	SRR14813500_2.fastq.gz	Fastqsanger.gz
	SRR14813501_1.fastq.gz	Fastqsanger.gz
	SRR14813501_2.fastq.gz	Fastqsanger.gz
	SRR14813502.fastq.gz	Fastqsanger.gz

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Transcriptional deregulation during osteoclastic differentiation due to diuron exposure affects preferentially super-enhancers regulated genes

Project description:Osteoclasts are major actors in the maintenance of bone homeostasis. The full functional maturation of osteoclasts from monocyte lineage cells is essential for the degradation of old/damaged bone matrix. To better characterize the differentiation and maturation of CD14+ monocytes into functionally mature osteoclasts, we performed Chromatin Immunoprecipitation against H3K27ac followed by Sequencing (ChIP-Seq) and RNA-Sequencing at different stages of an in vitro differentiation model. The combinatorial study of the epigenetic and transcriptional dynamics taking place during the course of differentiation has allowed us to reveal a very dynamic epigenetic profile that supports the expression of genes vital for osteoclasts differentiation and function. In total, we identified 122 genes induced by dynamic super-enhancers at late days. Since diuron, a commonly detected herbicide in our environment, is suspected to affect bone development, we then sought to evaluate the potential impact of diuron exposure on bone homeostasis. We performed RNA-Seq and functional test during in vitro osteoblastic and osteoclastic differentiation. First of all, our data suggest that high-dose of diuron (50 µM) affects viability of mesenchymal stem cells and thus inhibits bone mineralization. We observed at lower dose (1 µM) an inhibitory effect of this herbicide on number of osteoclasts derived from CD14+ monocytes without affecting cell viability. RNA-Seq data analysis revealed that diuron is specifically affecting the transcriptional network dedicated to osteoclasts differentiation and activity. Among the diuron affected genes, our analysis suggests a significant enrichment of genes targeted by gained super-enhancers along the differentiation process, with an odds ratio of 5.12 (ρ = 2.59 x 10-5). Taken together our results suggest that diuron exposure disrupts osteoclasts maturation by impairing the expression of cell-identity determining genes.

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Project description:Estrogen clearly prevents osteoporotic bone loss by attenuating bone resorption. The molecular basis of how this is accomplished, however, remains elusive. Here we report a critical role of osteoclastic ERa in mediating estrogen action on bone in females. We selectively ablated ERa in differentiated osteoclasts (ERa dOc/dOc). ERa dOc/dOc females, but not males, exhibited clear trabecular bone loss, similar to the osteoporotic bone phenotype in post-menopausal women. Recovery of bone loss by estrogen treatment of the ovariectomized ERa dOc/dOc females was ineffective in the trabecular areas of the long bones and lumbar vertebral bodies. Osteoclastic apoptosis, induced by estrogen, occurred simultaneously with up-regulation of Fas ligand (FasL) expression in intact trabecular bones of ERa +/+mice, but not in ERa dOc/dOc mice. ERa was also required for similar effects of estrogen and tamoxifen in cultured osteoclasts. These findings suggest that the osteoprotective actions of estrogen and SERMS are mediated at least in part through osteoclastic ERa in trabecular bone; and the life span of mature osteoclasts is regulated through activation of the Fas/FasL system. Keywords: Study about estrogen response of osteoclast-specific estrogen receptor alpha mice

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