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| Status |
Public on Jan 25, 2024 |
| Title |
NRF2-independent iron-triggered signaling via MAPK p38-ETS1 regulates LSEC Bmp6 mRNA expression [I] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
We analyzed in total 5 versus 5 RNA samples derived from FAC-sorted LSECs obtained from young female Balb/c mouse mice, intravenously injected with citrate buffer or iron-citrate solution (150 ug), respectively.
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| Contributor(s) |
Zurawska G, Jończy A, Sas Z, Rumieńczyk I, Kulecka M, Piwocka K, Rygiel T, Mikula M, Mleczko-Sanecka K |
| Citation(s) |
38293789 |
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| Submission date |
Jun 23, 2023 |
| Last update date |
Apr 25, 2024 |
| Contact name |
Michał Mikula |
| E-mail(s) |
mikula.michal@gmail.com
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| Phone |
+48225462655
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| Organization name |
Maria Skłodowska-Curie National Research Institute of Oncology
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| Department |
Genetics
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| Street address |
Roentgena 5
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| City |
Warsaw |
| ZIP/Postal code |
02781 |
| Country |
Poland |
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| Platforms (1) |
| GPL18635 |
Ion Torrent Proton (Mus musculus) |
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| Samples (8)
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| GSM7507976 |
LSECs; citrate buffer-injected mouse, rep. 1 |
| GSM7507977 |
LSECs; citrate buffer-injected mouse, rep. 2 |
| GSM7507978 |
LSECs; citrate buffer-injected mouse, rep. 3 |
| GSM7507979 |
LSECs; citrate buffer-injected mouse, rep. 4 |
| GSM7507980 |
LSECs; iron citrate-injected mouse, rep. 1 |
| GSM7507981 |
LSECs; iron citrate-injected mouse, rep. 2 |
| GSM7507982 |
LSECs; iron citrate-injected mouse, rep. 3 |
| GSM7507983 |
LSECs; iron citrate-injected mouse, rep. 4 |
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| This SubSeries is part of SuperSeries: |
| GSE235976 |
NRF2-independent iron-triggered signaling via MAPK p38-ETS1 regulates LSEC Bmp6 mRNA expression |
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| Relations |
| BioProject |
PRJNA986911 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE235692_RAW.tar |
810.0 Kb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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