Could Endometriosis Result from Aberrant Splicing Caused by Reduced Nuclear Acetylation?
Summary: Endometriosis is usually described as an inflammatory, hormonal and fibrotic disease in which endometrial-like tissue grows outside the uterus. However, a growing body of evidence suggests another layer of explanation: endometriosis may involve abnormal RNA splicing, and that abnormal splicing may in some cases arise from reduced acetylation of nuclear proteins.
This article sets out the argument for that hypothesis. The evidence does not yet prove that reduced nuclear acetylation is the root cause of endometriosis, but it does make the hypothesis biologically plausible and testable.
1. The hypothesis in simple terms
The hypothesis is that endometriosis could arise, at least in part, from a failure of cells to maintain normal nuclear acetylation. Acetylation is a chemical modification that helps regulate chromatin structure, transcription, RNA polymerase behaviour, spliceosome assembly and the activity of RNA-binding proteins.
If nuclear acetylation falls, several things may follow:
- histones may become less acetylated, changing chromatin accessibility;
- RNA polymerase II may move through genes differently;
- spliceosomal proteins and splicing regulators may change their stability, localisation or RNA-binding behaviour;
- pre-mRNA may be spliced incorrectly;
- abnormal isoforms may alter cell proliferation, survival, hormone signalling, inflammation, fibrosis and pain.
In this model, endometriosis is not simply misplaced tissue. It is a disease of cell-state regulation, in which altered metabolism, altered acetylation and altered RNA processing combine to create lesion-like behaviour.
2. Why acetylation could affect splicing
The first pillar of the argument is that acetylation is already known to influence splicing. This is not speculative biology. In yeast, Gunderson and Johnson showed that Gcn5/SAGA-mediated acetylation has a role in cotranscriptional spliceosome assembly. Their work indicated that acetylation helps recruit U2 snRNP and supports branch-point recognition during splicing.
A related study by Gunderson et al. showed that dynamic histone acetylation and deacetylation are important for cotranscriptional spliceosome assembly and spliceosomal rearrangements. This matters because splicing often occurs while a gene is still being transcribed. Chromatin state and splicing are therefore not separate processes; they are physically and temporally connected.
Human-cell data point in the same direction. Hnilicová et al. showed that histone deacetylase activity modulates alternative splicing. When HDAC activity was inhibited, alternative splicing changed across hundreds of genes. This supports the idea that the balance between acetylation and deacetylation can influence exon inclusion or exclusion.
Acetylation can also act directly on splicing factors themselves. Edmond et al. showed that Tip60 and HDAC6 regulate acetylation of the splicing factor SRSF2, with downstream effects on caspase-8 splicing. Siam et al. showed that p300 promotes exon inclusion by acetylating splicing factors including hnRNP M and Sam68. More recently, Sun et al. reported that acetylation of SmD2, a core spliceosome protein, is regulated by p300 and HDAC2 and affects cassette-exon usage.
These studies make a key point: acetylation can regulate splicing through both chromatin-dependent and non-histone mechanisms. Therefore, if nuclear acetylation is reduced in endometriosis-relevant cells, abnormal splicing would be a plausible consequence.
3. Why nuclear acetylation could be reduced
The second pillar of the argument is metabolic. Acetylation requires acetyl groups. In the nucleus, one important source of acetyl groups is acetyl-CoA generated from citrate by ATP-citrate lyase. Wellen et al. showed that ATP-citrate lyase links cellular metabolism to mammalian histone acetylation. In other words, the cell’s metabolic state can influence chromatin acetylation.
This provides a possible bridge between mitochondrial metabolism and nuclear gene regulation. If mitochondrial citrate production, citrate export, ATP-citrate lyase activity, p300/CBP activity or acetyl-CoA availability are impaired, nuclear acetylation could fall. That could then affect chromatin structure, transcriptional elongation and splicing.
This is important for endometriosis because the disease has repeatedly been associated with altered metabolism, inflammation, oxidative stress, hormone signalling and epigenetic change. A metabolic shortage of nuclear acetyl-CoA would not need to be the only cause of the disease. It could be one upstream pressure that makes lesion cells adopt abnormal transcriptional and splicing states.
4. Endometriosis lesions show altered acetylation and HDAC biology
The third pillar is that endometriosis itself shows evidence of altered acetylation. Monteiro et al. reported that endometriosis is characterised by a distinct pattern of histone H3 and H4 lysine modifications. In particular, lesions showed altered histone acetylation, including reduced H3K9ac and H4K16ac.
Other studies also implicate histone deacetylases in endometriosis. Kawano et al. investigated HDAC inhibitors as a possible therapeutic strategy for endometriosis. Colón-DÃaz et al. reported differential expression of HDAC1 and HDAC2 in endometriosis. Samartzis et al. found increased HDAC1 expression in endometriosis. More recent studies have extended the HDAC theme to specific enzymes such as HDAC2 and HDAC8.
These papers do not prove that reduced acetylation causes endometriosis through splicing. However, they show that endometriosis lesions are not acetylation-neutral. The acetylation/deacetylation machinery is disturbed, and pharmacological manipulation of that machinery can alter lesion-relevant phenotypes such as proliferation, survival, fibrosis and pain behaviour in models.
5. Endometriosis also shows abnormal splicing
The fourth pillar is that endometriosis is associated with altered RNA splicing and isoform balance. Early studies focused on individual genes. Fujino et al. examined survivin splice variants in endometriosis. Juhasz-Böss et al. studied estrogen receptor beta splice variants in endometrial tissue. Zhang et al. reported reduced alternative splicing of estrogen receptor alpha in the endometrium of women with endometriosis, with some splice-variant ratios associated with pain severity.
More recent work has moved beyond individual genes. Single-cell atlases by Tan et al. and Fonseca et al. show that endometriosis lesions contain complex multicellular niches, with altered stromal, immune, epithelial, vascular and fibrotic cell states. These atlases are not ideal for full isoform reconstruction, but they demonstrate that endometriosis is a cell-state disease rather than a simple anatomical displacement.
Splicing-specific evidence has also strengthened. Yang et al. reported regulation of RNA splicing in endometrial tissue and linked splicing regulation of GREB1 and WASHC3 to endometriosis risk. Another study by Yang et al. used integrated proteomics to implicate spliceosome dysregulation and DHX9 as a fibrosis-related hub in endometriosis.
The most direct recent support comes from Davuluri et al., who reported misregulated alternative splicing in endometriosis and functional effects of exon changes in genes including ZNF28 and GALNT7. This is important because it suggests that aberrant splice variants may not merely be markers of disease; they may contribute to endometriotic cell growth.
6. Putting the chain together
The argument can be summarised as a causal chain:
Metabolic stress or altered citrate/acetyl-CoA supply → reduced nuclear acetylation → altered histone and splicing-factor acetylation → abnormal cotranscriptional splicing → disease-promoting isoforms → proliferation, survival, fibrosis, inflammation, hormone resistance and pain.
This chain is not yet proven in endometriosis. However, each major segment has support:
- acetyl-CoA metabolism can regulate histone acetylation;
- acetylation can regulate spliceosome assembly and alternative splicing;
- endometriosis lesions show altered histone acetylation and HDAC biology;
- endometriosis tissues show altered isoforms, splice-factor signals and alternative-splicing events;
- some aberrant splice events appear functionally relevant to endometriotic cell growth.
The missing experiment is the direct demonstration of the whole sequence in endometriosis tissue or a robust endometriosis model: reduced acetylation of defined nuclear proteins causing defined splicing errors that cause defined lesion phenotypes, with rescue by restoring acetylation.
7. Why this hypothesis is attractive
The hypothesis is attractive because it could explain several features of endometriosis at once.
It links metabolism to gene regulation
Endometriosis is associated with altered inflammatory and metabolic states. A nuclear acetyl-CoA shortage would provide a way for metabolic stress to change chromatin, transcription and RNA processing.
It explains hormone-response abnormalities
Endometriosis is strongly hormone-sensitive, yet lesions often behave differently from normal endometrium. Abnormal splicing of estrogen receptor or progesterone-response pathways could contribute to distorted hormone signalling.
It explains lesion persistence
If mis-splicing affects apoptosis, cell-cycle checkpoints, adhesion, extracellular matrix remodelling or immune evasion, it could help ectopic endometrial-like cells survive and persist outside the uterus.
It explains heterogeneity
Endometriosis is not one uniform disease. Different lesions and patients may have different cell states. Acetylation-sensitive splicing could be important in some lesion subtypes without being the sole explanation for all disease.
8. What would prove or disprove the idea?
The key next step is not another broad HDAC-inhibitor experiment. HDAC inhibitors affect many pathways, so lesion shrinkage after HDAC inhibition does not prove that splicing was the crucial mechanism.
The decisive studies should combine:
- long-read RNA sequencing to identify full-length isoforms;
- nuclear acetyl-proteomics to measure acetylation of histones and splicing proteins;
- CUT&Tag or CUT&RUN for H3K9ac, H3K27ac and H4K16ac at affected genes;
- patient-derived organoids or stromal–epithelial co-cultures rather than only immortalised cell lines;
- precise perturbation of ACLY, ACSS2, p300/CBP, GCN5, HDAC1, HDAC2 and HDAC8;
- rescue experiments using acetate, acetyl-CoA support, HAT activation or acetylation-mimic mutants of splicing factors;
- functional readouts including proliferation, apoptosis, fibrosis markers, inflammatory signalling and lesion-like behaviour.
The hypothesis would gain strong support if restoring nuclear acetylation corrected disease-associated splicing errors and reduced lesion-like phenotypes. It would be weakened if acetylation changes altered transcription but did not correct splicing, or if splicing changes occurred independently of acetylation state.
9. A balanced conclusion
The evidence does not yet prove that endometriosis results from aberrant splicing caused by reduced nuclear acetylation. The stronger statement would currently overreach the data.
However, the weaker and more defensible version of the hypothesis is compelling: endometriosis may involve acetylation-sensitive splicing defects in some lesions, some cell types or some patients. This could help explain abnormal hormone signalling, lesion persistence, fibrosis, inflammation and pain.
The most useful research now would test the full causal chain directly. If reduced nuclear acetylation is shown to drive specific splice defects that promote endometriotic cell behaviour, then endometriosis would need to be understood not only as a hormonal and inflammatory disorder, but also as a disease of nuclear metabolism, chromatin state and RNA processing.
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