GEO series

Smad4-p65 interactions drive BMP-mediated protection against inflammatory cell death [ChIP-Seq]

GSE315062 Mus musculus Genome binding/occupancy profiling by high throughput sequencing 10 samples Submitted 2026/02/18 Platform GPL24247

Summary

Inflammation-induced osteoblast death undermines bone homeostasis and can aggravate bone-destructive diseases, yet how pro-survival BMP signaling intersects with inflammatory TNF–NF-κB signaling remains poorly defined. Here we show that BMP4 protects mouse osteoblasts from TNF-α–triggered apoptosis and cytotoxic death and that this cytoprotection requires both Smad4 and NF-κB p65. Integrative epigenomic profiling (ChIP-seq/ATAC-seq/RNA-seq) reveals extensive Smad4–p65 co-occupancy and identifies Samd9l as a prominent TNF-α–inducible gene that is selectively repressed by BMP4. Two Smad4/p65-bound distal elements physically contact the Samd9l promoter, exhibit TNF-responsive enhancer activity, and are required for Samd9l induction, as demonstrated by 4C-seq and CRISPR/dCas9-based chromatin closing/opening. Functionally, Samd9l depletion attenuates TNF-α–driven caspase activation and cytotoxicity in osteoblasts and enhances BMP2-driven ectopic bone formation in vivo. Cross-species mapping suggests that the two mouse regulatory elements converge into a single promoter-proximal composite element at the human SAMD9L locus, supporting a conserved inflammatory control node. Together, these findings define a BMP4–Smad4 mechanism that reshapes NF-κB enhancer outputs to limit osteoblast death and nominate the SAMD9L regulatory circuit as a therapeutic entry point for inflammatory bone loss.

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Direct links to NCBI, no account and no request form: the whole study as GSE315062_RAW.tar, processed values as the series matrix, the supplementary file directory, and per-sample supplementary files for any of the 10 samples. Raw sequencing reads are also available from ENA.

Whole study · RAW.tar ↓ Series matrix ↓ All supplementary files ↗ Raw reads on ENA ↗

Also filed as BioProject PRJNA1394945 and SRA study SRP658483. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗

Study design

5 conditions, mostly in duplicate

OB_TNFa_p65 ×2 OB_BMP4_Smad4 ×2 OB_TNFa+BMP4_p65 ×2 OB_TNFa+BMP4_Smad4 ×2 OB_input ×2

Supports a between-group comparison across 10 samples.

5 replicated groups read from 10 sample titles; they account for 10 of them. Check it against the sample list below before relying on it.

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