Distinct chromatin modifications at the <i>Il33</i> locus in mast cells contribute to sex dimorphic susceptibility to EAE, an autoimmune CNS demyelinating disease
Bibliographic record
Abstract
Abstract Many autoimmune diseases, including multiple sclerosis (MS) exhibit a striking female bias, but the underlying mechanisms remain poorly understood. Using the SJL mouse model of MS, experimental autoimmune encephalomyelitis (EAE), which recapitulates this sex dimorphism, we previously demonstrated that preferential IL-33 expression contributes to male protection. IL-33 expression by mast cells in PLP139–151-immunized males activates type 2 innate lymphoid cells, which in turn drives a non-pathogenic Th2 response to myelin peptide. Testosterone directly activates Il33 in male but not female mast cells, but this male-specific response is also maintained with other modes of activation, including FcɛR1-crosslinking, suggesting there are constraints on the chromatin landscape that limit Il33 expression in females. Here we use ChIP and ATAC-seq to show that the dynamics of chromatin modifications at the Il33 locus is sex-dimorphic. At steady state, ChIP assays reveal activating H3K4me3 and H3K9ac histone modifications at the promoter and conserved non-coding sequences within the Il33 gene are most prevalent in male-derived cells, while H3K27me3 repressive marks dominate in females. This pattern is similar in IgE-DNP-activated mast cells. Increased basal Il33 chromatin accessibility assessed by ATAC-seq is evident in males. Together, these results indicate that while testosterone can directly stimulate IL-33 production, it also exerts effects on Il33 during development conferring a higher potential for expression in males.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".