NRF2-independent iron-triggered signaling via MAPK p38-ETS1 regulates LSEC Bmp6 mRNA expression
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ABSTRACT:
PROVIDER: PRJNA988111 | ENA |
REPOSITORIES: ENA
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Project description:BMP6 is an iron-sensing cytokine produced by liver sinusoidal endothelial cells (LSECs). The transcription factor NRF2 was proposed to induce Bmp6 expression in response to iron-triggered oxidative stress, and NRF2 knock-out mice were shown not capable of regulating Bmp6 in response to massive diet-imposed iron overload. However, LSEC Bmp6 expression levels in the hemochromatosis mouse model reflect hepatocytic, not endothelial iron content. Hence, it is not fully resolved how iron signals translate into alterations of Bmp6 mRNA levels. To further explore the mechanisms of Bmp6 regulation, we employed female mice aged 10-11 months that are hallmarked by hepatocytic, but not LSEC iron accumulation and decreased transferrin saturation, hinting at the absence of systemic iron overload. We found that LSECs of aged mice exhibit increased Bmp6 levels as compared to young controls, but do not show oxidative stress or a transcriptional signature characteristic of activated NFR2-mediated signaling in FACS-sorted LSECs. We further observed that primary murine LSECs derived from both wild-type and NRF2 knock-out mice induce Bmp6 in response to acute iron exposure. By analyzing RNA sequencing data of FACS-sorted LSECs from aged versus young mice, as well as upon acute injections of iron citrate in young mice, we identified ETS1 as a candidate transcription factor involved in Bmp6 regulation. By conducting siRNA-mediated knock-down and small-molecule treatments in primary LSECs, we show that Bmp6 transcription is regulated in an NRF2-independent manner via ETS1, which is activated downstream of p38 MAP kinase-mediated signaling. This knowledge expands the understanding of Bmp6 transcriptional control in both iron-triggered oxidative stress and under the conditions uncoupled to LSECs reactive oxygen species levels.
2024-01-25 | GSE235975 | GEO
Project description:BMP6 is an iron-sensing cytokine produced by liver sinusoidal endothelial cells (LSECs). The transcription factor NRF2 was proposed to induce Bmp6 expression in response to iron-triggered oxidative stress, and NRF2 knock-out mice were shown not capable of regulating Bmp6 in response to massive diet-imposed iron overload. However, LSEC Bmp6 expression levels in the hemochromatosis mouse model reflect hepatocytic, not endothelial iron content. Hence, it is not fully resolved how iron signals translate into alterations of Bmp6 mRNA levels. To further explore the mechanisms of Bmp6 regulation, we employed female mice aged 10-11 months that are hallmarked by hepatocytic, but not LSEC iron accumulation and decreased transferrin saturation, hinting at the absence of systemic iron overload. We found that LSECs of aged mice exhibit increased Bmp6 levels as compared to young controls, but do not show oxidative stress or a transcriptional signature characteristic of activated NFR2-mediated signaling in FACS-sorted LSECs. We further observed that primary murine LSECs derived from both wild-type and NRF2 knock-out mice induce Bmp6 in response to acute iron exposure. By analyzing RNA sequencing data of FACS-sorted LSECs from aged versus young mice, as well as upon acute injections of iron citrate in young mice, we identified ETS1 as a candidate transcription factor involved in Bmp6 regulation. By conducting siRNA-mediated knock-down and small-molecule treatments in primary LSECs, we show that Bmp6 transcription is regulated in an NRF2-independent manner via ETS1, which is activated downstream of p38 MAP kinase-mediated signaling. This knowledge expands the understanding of Bmp6 transcriptional control in both iron-triggered oxidative stress and under the conditions uncoupled to LSECs reactive oxygen species levels.
2024-01-25 | GSE235692 | GEO
Project description:NRF2-independent iron-triggered signaling via MAPK p38-ETS1 regulates LSEC Bmp6 mRNA expression [II]
| PRJNA988116 | ENA
Project description:NRF2-independent iron-triggered signaling via MAPK p38-ETS1 regulates LSEC Bmp6 mRNA expression [I]
| PRJNA986911 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-01-24 | GSE235976 | GEO
Project description:Homeostatic adaptation to systemic iron overload involves transcriptional induction of bone morphogenetic protein 6 (BMP6) in liver sinusoidal endothelial cells (LSECs). BMP6 is then secreted to activate signaling to the iron hormone hepcidin (Hamp) in neighboring hepatocytes. To explore the mechanism for iron sensing by LSECs, we generated TfrcTek-Cre mice with endothelial cell-specific ablation of transferrin receptor 1 (Tfr1). We also used wild type mice to characterize LSEC-specific molecular responses to iron by single cell transcriptomics. TfrcTek-Cre animals tend to have increased liver iron content compared to Tfrcfl/fl controls but do not exhibit blunted Bmp6 or Hamp mRNA expression. They respond to dietary iron challenges with Bmp6 and Hamp induction, yet sometimes to levels slightly lower relative to liver iron load. We noted that liver Bmp6 and Hamp mRNA levels significantly correlated with serum non-transferrin bound iron (NTBI) that emerged following dietary iron loading in both TfrcTek-Cre and Tfrcfl/fl mice. High dietary iron triggered more profound alterations in the LSEC transcriptome of Tfrcfl/fl mice compared to holo-transferrin injection. These culminated in robust induction of Bmp6 and other nuclear factor erythroid 2-related factor 2 (Nrf2) target genes, as well as Myc target genes involved in ribosomal biogenesis and protein synthesis. Taken together, our data suggest that during systemic iron overload, LSECs internalize NTBI, which promotes oxidative stress and thereby transcriptionally induces Bmp6 via Nrf2. The contribution of Tfr1 and transferrin-bound iron to Bmp6 induction is minimal.
2022-12-21 | GSE215324 | GEO
Project description:Environmental particle inhalation and persistent herpesvirus infection are omnipresent and associated with chronic lung diseases. Previously, we showed that pulmonary exposure to soot-like carbonaceous nanoparticles (CNP) or fibre-shaped engineered double-walled carbon nanotubes (DWCNT) induced an increase of lytic virus protein expression in latently murine gammaherpesvirus 68 (MHV-68) infected mouse lungs, with a similar pattern as acute infection suggesting virus reactivation. However, the molecular mechanisms underlying herpesvirus reactivation as well as herpesvirus reactivation associated disease exacerbation caused by particle exposure remain unclear. Here, we investigated the effects of environmental relevant repeated particle exposure and herpesvirus reactivation mechanistically, and therapeutically. In the MHV-68 mouse model, we identified elevated lung inflammation and emphysema-like injury after repetitive CNP exposure. We further uncovered that CNP reactivated latent herpesvirus mainly in CD11b+ macrophages. Mechanistically, ERK1/2, JNK and p38 MAPK were rapidly activated after CNP and DWCNT exposure in persistently MHV-68 infected bone marrow-derived macrophages, followed by upregulation of viral gene expression and increased viral titer but without generating a pro-inflammatory transcriptional signature. Pharmacological inhibition of p38 activation abrogated CNP but not DWCNT triggered virus reactivation. In vivo, p38 inhibitor pretreatment of latently infected mice also attenuated CNP exposure induced MHV-68 reactivation. Our findings suggest that particle pollution is an environmental challenge to trigger herpesvirus reactivation and related chronic lung disease by activating latent herpesvirus via p38 MAPK dependent signalling. Pharmacological p38 inhibition might serve as a protective target to alleviate particle exposure related chronic lung disease exacerbations.
2023-09-29 | GSE223818 | GEO
Project description:Mitogen-activated protein kinases (MAPKs) regulate cardiomyocyte growth and apoptosis in response to extracellular stimulation, but the downstream effectors that mediate their pathophysiological effects remain poorly understood. We determined the targets and role of p38 MAPK in the heart in vivo by using local adenovirus-mediated gene transfer of constitutively active upstream kinase mitogen-activated protein kinase kinase 3b (MKK3bE) and wild-type p38α in rats. DNA microarray analysis of animals with cardiac-specific overexpression of p38 MAPK revealed that 264 genes were upregulated more than 2-fold including multiple genes controlling cell division, cell signaling, inflammation, adhesion and transcription. Several previously unknown p38 target genes were found. Using gel mobility shift assays we identified several cardiac transcription factors that were directly activated by p38 MAPK. Finally, we determined the functional significance of the altered cardiac gene expression profile by histological analysis and echocardiographic measurements, which indicated that p38 MAPK overexpression induced gene expression results in cell proliferation, myocardial inflammation and fibrosis. In conclusion, we defined the novel target genes and transcription factors as well as the functional effects of p38 MAPK in the heart. Expression profiling of p38 MAPK overexpression identified cell cycle regulatory and inflammatory genes critical for pathological processes in the adult heart. Keywords: Gene transfer
2006-12-19 | GSE3866 | GEO
Project description:Liver sinusoidal endothelium (LSEC) is a prime example for organ-specific microvascular differentiation and functions. Disease-associated capillarization of LSEC in vivo and dedifferentiation of LSEC in vitro indicate the importance of the hepatic microenvironment. To identify the LSEC-specific molecular differentiation program in the rat, we used a two-sided gene expression profiling approach comparing LSEC freshly isolated ex vivo with both lung microvascular endothelial cells (LMEC) and with LSEC cultured for 42h. The LSEC signature consisted of 48 genes both down-regulated in LMEC and in LSEC upon culture (FC>7 in at least one comparison); qRT-PCR confirmation of these genes included numerous family members and signalling pathway-associated molecules. The LSEC differentiation program comprised distinct sets of growth (wnt2, Fzd4, 5, 9, wls, VEGFR1, 2, 3, Nrp2) and transcription factors (Gata4, Lmo3, Tcfec, Maf) as well as endocytosis-related (Stabilin-1/2, Lyve1 and Ehd3) and cytoskeleton-associated molecules (Rnd3/RhoE). Specific gene induction in cultured LSEC versus freshly isolated LSEC as well as LMEC (Esm-1, Aatf) and up-regulation of gene expression to LMEC levels (CXCR4, Apelin) confirmed true transdifferentiation of LSEC in vitro. In addition, our analysis identified a novel 26 kDa single-pass transmembrane protein, liver endothelial differentiation-associated protein (Leda)-1, that was selectively expressed in all liver endothelial cells and preferentially localized to the abluminal cell surface. Upon forced over-expression in MDCK cells, Leda-1 was sorted baso-laterally to E-cadherin-positive adherens junctions suggesting functional involvement in cell adhesion and polarity. Conclusion: Comparative microvascular analysis in rat identified a hepatic microenvironment-dependent LSEC-specific differentiation program including the novel junctional molecule Leda-1. Highly pure liver sinusoidal endothelial cells (LSEC) and lung microvascular endothelial cells (LMEC) were isolated by enzymatic digestion, density gradient centrifugation and MACS sorting and subjected to RNA extraction and affymetrix hybridization without any culturing step (LSEC_0h, LMEC_0h). LSEC were also plated on collagen coated dishes and RNA extraction and Affymetrix hybridization was carried out after 2h and 42h in culture (LSEC_2h, LSEC_42h).
2010-05-05 | E-GEOD-20375 | biostudies-arrayexpress
Project description:Molecular function of BMPs in metastatic melanoma progression is undefined. The goal of this study is to identify BMP6-activated gene signaturs associated with metastatic progresses in human cutaneous melanoma. Transcriptome profiles (RNA-seq) of three melanoma cell lines (WM1341D, WM983B, and 1205Lu) stably expressing BMP6 and coressponding control cells were generated by deep sequencing using illumona HiSeq and mapped more than 30 million sequencing reads per sample to the human genome (build Hg19). Gene signatures down-regulated by BMP6 are mostly associated with extracellular matrix organization and growth factor binding, suggesting a metastasis-suppressive role of BMP6 in melanoma.
2021-01-10 | GSE164495 | GEO