Re-Analysis of Public Transcriptomes Identifies a Candidate Histone-Cluster Signal in Eutopic Endometrium: A
Xinyue Cui1, Jiaxuan Liu2, Shengwu Wang2
1Department of Obstetrics and Gynecology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, People's Republic of China.
Background:
Endometriosis is a leading cause of chronic pelvic pain (CPP), but the public transcriptomic datasets analysed here contain no pain phenotype, links to CPP are therefore hypothesis-generating.
Methods:
We re-analysed GSE153739 (four endometriosis, three controls) and tested replication in GSE51981 (77 cases, 34 disease-free controls). Non-reproducible differential-expression results from the original submission were removed. Both cohorts were rebuilt from source processed matrices. Histone-cluster scores were modelled with menstrual-cycle and proliferation covariates, and ranked enrichment was tested before and after histone-gene depletion. A separate ion-channel analysis was pre-specified before execution.
Results:
Histone scores were higher in endometriosis in GSE153739 (β = 1.108, P = 0.047) and GSE51981 (β = 0.321, P = 0.0025; phase-adjusted β = 0.394, P = 0.00021). In GSE51981 the effect was concentrated in proliferative-phase endometrium (β = 0.665, P = 0.00083), with a disease-by-phase interaction (P = 0.020). S-phase or proliferation-PC1 adjustment attenuated the effect below nominal significance. In phase-adjusted analyses, SLE enrichment had q = 0.038, whereas NET formation was not enriched (q =0.73); removing clustered histones abolished enrichment in GSE51981 and reversed NET enrichment to negative. The pre-specified ion-channel endpoint was positive (phase-adjusted β = 0.240, P = 8 × 10-6; voltage-gated potassium NES = 1.550, q = 0.013), but the histone and ion-channel scores both covaried with proliferation measures and the same array-level technical axis.
Conclusion:
A reproducible, proliferative-phase-concentrated histone-cluster signal is present in eutopic endometrium, but its biological and technical components cannot be separated in these data. Histone-rich KEGG annotations should not be interpreted as independent pathways. The data do not establish extracellular histone release, NETosis, or a causal mechanism for pelvic pain.
