Interferon Regulatory Factor 8 (IRF8) Deficiency Promotes Osteoclast Transcriptional Program
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ABSTRACT:
PROVIDER: PRJNA475210 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7280160.fastq.gz | Fastqsanger.gz | |||
| SRR7280170.fastq.gz | Fastqsanger.gz | |||
| SRR7280180.fastq.gz | Fastqsanger.gz | |||
| SRR7280190.fastq.gz | Fastqsanger.gz | |||
| SRR7280200.fastq.gz | Fastqsanger.gz |
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Project description:Stimulator of Interferon Genes (STING) is a key mediator of type-I interferon (IFN-I) signaling in response to a variety of stimuli, but the contribution of STING to homeostatic processes is not fully characterized. Previous studies showed ligand activation of STING limits osteoclast differentiation in vitro through the induction of IFN and IFN-I Interferon Stimulated Genes (ISGs). In a disease model (SAVI) driven by the V154M gain-of-function mutation in STING, fewer osteoclasts form from SAVI precursors in response to RANKL in an IFN-I-dependent manner. Due to the described role of STING-mediated regulation of osteoclastogenesis in activation settings, we sought to determine whether basal STING signaling contributes to bone homeostasis, an unexplored area. Using whole-body and myeloid-specific deficiency, we show that STING signaling prevents trabecular bone loss in mice over time and that myeloid-restricted STING activity is sufficient for this effect. STING-deficient osteoclast precursors differentiate with greater efficiency than wildtypes. RNA sequencing of wildtype and STING-deficient osteoclast precursor cells and differentiating osteoclasts reveals novel clusters of ISGs including a previously undescribed ISG set expressed in RANKL naïve precursors (tonic expression) and downregulated during differentiation. We identify a 50 gene tonic ISG signature that is STING-dependent and shapes osteoclast differentiation. From this list, we identify Interferon Stimulated Gene 15 (ISG15) as a tonic STING-regulated ISG that limits osteoclast formation. Thus, STING is an important upstream regulator of tonic IFN-I signatures shaping the commitment to osteoclast fates, providing evidence for a nuanced and novel role for this pathway in bone homeostasis.
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Project description:Interferon regulatory factor 8 (IRF8), also known as interferon consensus sequence-binding protein, is an essential lineage-specific transcriptional regulator in the IRF family, controls diverse cellular processes and is has been implicated in innate immunity, immune cell differentiation. IRF8 has been shown to have both oncogenic and tumor suppressor activities, in myeloid cells and nonhematopoietic cells. As a transcription factor, other functions which may contribute to its oncogenic and anti tumor potential are not clear. So it is meaningful to study the role of IRF8 in different diseases. The roles and the underlying mechanisms of intrahepatic IRF8 in Hepatocellular carcinoma have not been reported up to date.
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Project description:The transcription factor (TF) interferon regulatory factor 8 (IRF8) controls both developmental and inflammatory stimulus-inducible genes in macrophages, but the mechanisms underlying these two different functions are largely unknown. One possibility is that these different roles are linked to the ability of IRF8 to bind alternative DNA sequences. We found that IRF8 is recruited to distinct sets of DNA consensus sequences before and after lipopolysaccharide (LPS) stimulation. In resting cells, IRF8 was mainly bound to composite sites together with the master regulator of myeloid development PU.1. Basal IRF8M-bM-^@M-^SPU.1 binding maintained the expression of a broad panel of genes essential for macrophage functions (such as microbial recognition and response to purines) and contributed to basal expression of many LPS-inducible genes. After LPS stimulation, increased expression of IRF8, other IRFs, and AP-1 family TFs enabled IRF8 binding to thousands of additional regions containing low-affinity multimerized IRF sites and composite IRFM-bM-^@M-^SAP-1 sites, which were not premarked by PU.1 and did not contribute to the basal IRF8 cistrome. While constitutively expressed IRF8-dependent genes contained only sites mediating basal IRF8/PU.1 recruitment, inducible IRF8-dependent genes contained variable combinations of constitutive and inducible sites. Overall, these data show at the genome scale how the same TF can be linked to constitutive and inducible gene regulation via distinct combinations of alternative DNA-binding sites. Chromatin immuno-precipitations of transcription factors IRF8, IRF1, PU.1, STAT1, STAT2 and of H3 lysine 27 acetylated followed by multiparallel sequencing, performed in bone marrow-derived macrophages from wild type (WT) and BXH2/TyJ mice. Cells were treated with lipopolysaccharide (LPS) for 2 or 4 hours, or interferon b (IFNb) for 30 or 60 minutes, 2 or 4 hours, or left unstimulated.
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