Error Report: Incorrect Annotation of Gene Sets FOSTER_TOLERANT_MACROPHAGE_DN and FOSTER_TOLERANT_MACROPHAGE_UP in GSEA

[钟恺]

Dear GSEA Administrator,I am writing to report an annotation error in the GSEA/MSigDB database for the human gene sets "FOSTER_TOLERANT_MACROPHAGE_DN" and "FOSTER_TOLERANT_MACROPHAGE_UP". These gene sets are derived from the literature: Foster et al., 2007, "Gene-specific control of inflammation by TLR-induced chromatin modifications" (Nature, DOI: 10.1038/nature05836).Issue Description:​The current "Brief description" for these gene sets in GSEA is inconsistent with the original article. Specifically:

• The gene set "FOSTER_TOLERANT_MACROPHAGE_DN"​ is incorrectly described as corresponding to Class NT (non-tolerizable) genes.
• According to the article, Class NT genes are defined as genes induced during the first LPS stimulation and expressed at equal or higher levels in tolerant macrophages (i.e., (N+L)/(T+L) ≤ 1). These genes should be associated with an "UP" suffix, indicating up-regulation.
• However, the gene set "FOSTER_TOLERANT_MACROPHAGE_DN"​ (with "DN" suffix) should correctly correspond to Class T (tolerizable) genes, which are defined as genes induced during the first LPS stimulation and downregulated more than 3-fold in tolerant macrophages (i.e., (N+L)/(T+L) > 3). This is explicitly stated in the article's Methods section.

Evidence from Literature:​The article defines:

• Class T genes: "genes induced in naive macrophages stimulated with LPS and downregulated more than 3-fold in tolerant macrophages stimulated with LPS (that is, (N+L)/(T+L) > 3)."
• Class NT genes: "genes induced in naive macrophages stimulated with LPS and expressed at equal or higher levels in tolerant macrophages stimulated with LPS (that is, (N+L)/(T+L) ≤ 1)."This is supported by experimental results in Fig. 1e of the article, which shows qPCR validation of gene expression differences.

Suggested Corrections:​To align with the original literature, I recommend updating the "Brief description" in GSEA as follows:

• For "FOSTER_TOLERANT_MACROPHAGE_DN":Correct the description to: "Class T (tolerizable) genes: induced during the first LPS stimulation and not re-induced or induced to a much lesser degree in tolerant macrophages (as defined by (N+L)/(T+L) > 3)."
• For "FOSTER_TOLERANT_MACROPHAGE_UP":Correct the description to: "Class NT (non-tolerizable) genes: induced during the first LPS stimulation and induced at equal or greater degree in tolerant macrophages (as defined by (N+L)/(T+L) ≤ 1)."

This correction will ensure the database accurately reflects the scientific findings and improves reliability for users. I have attached relevant screenshots from the article and GSEA for your reference.Thank you for your attention to this matter. I am available to provide additional details if needed.
Best regards,​Kai Zhong 

[Anthony Castanza]

Hello,

Thank you for reaching out to us about this issue. My apologies in the delay getting back to you.
After investigating your report I think the issue might actually be a deeper inversion in the set labeling than you've indicated.

The gene members of FOSTER_TOLERANT_MACROPHAGE_DN do appear to originate from the "a) Class T genes" column of Supplementary table 1 of the publication as indicated in the Exact Source field of the gene set details, and likewise  FOSTER_TOLERANT_MACROPHAGE_UP originates from the "b) Class NT genes" portion of the data.

This says to me that not only do the descriptions need to be corrected as you've indicated, the set names will also need to be corrected to fix this inversion.

In the next release, based on this information, I'll plan to rename  FOSTER_TOLERANT_MACROPHAGE_DN to  FOSTER_TOLERANT_MACROPHAGE_UP, with the description:  "Class T (tolerizable) genes: induced during the first LPS stimulation and not re-induced or induced to a much lesser degree in tolerant macrophages (as defined by (N+L)/(T+L) > 3).", and associating it with the gene list from the current _DN set which originates from the "Class T Genes" data.

And likewise, the current  FOSTER_TOLERANT_MACROPHAGE_UP set will be renamed  FOSTER_TOLERANT_MACROPHAGE_DN with the description  "Class NT (non-tolerizable) genes: induced during the first LPS stimulation and induced at equal or greater degree in tolerant macrophages (as defined by (N+L)/(T+L) ≤ 1).", and associating it with the gene list from the current _DN set which originates from the "Class NT Genes" data.

Do these changes meet the expectations you would have had if you were to have encountered these sets in your results?  

-Anthony

Anthony S. Castanza, PhD
Curator, Molecular Signatures Database
Mesirov Lab, Department of Medicine
University of California, San Diego