Substantial evidence highlights divergences in immune responses between men and women. Women are more susceptible to autoimmunity, whereas men suffer from the more severe presentation of autoimmune disorders. The molecular mechanism of this sexual dimorphism remains elusive. Herein, we conducted a comprehensive analysis of sex differences in whole-blood gene expression focusing on alternative splicing (AS) events in systemic lupus erythematosus (SLE), which is a prototype sex-biased disease. This study included 79 SLE patients with active disease and 58 matched healthy controls who underwent whole-blood RNA sequencing. Sex differences in splicing events were widespread, existent in both SLE and a healthy state. However, we observed distinct gene sets and molecular pathways targeted by sex-dependent AS in SLE patients as compared to healthy subjects, as well as a notable sex dissimilarity in intron retention events. Sexually differential spliced genes specific to SLE patients were enriched for dynamic cellular processes including chromatin remodeling, stress and inflammatory responses. Remarkably, the extent of sexual differences in AS in the SLE patients and healthy individuals exceeded those in gene expression. Overall, this study reveals an unprecedent variation in sex-dependent splicing events in SLE and the healthy state, with potential implications for understanding the molecular basis of sexual dimorphism in autoimmunity.

The TA-isoform of the p63 transcription factor (TAp63) has been reported to contribute to clinical aggressiveness in chronic lymphocytic leukemia (CLL) in a hitherto elusive way. Here, we sought to further understand and define the role of TAp63 in the pathophysiology of CLL. First, we found that elevated TAp63 expression levels are linked with adverse clinical outcomes, including disease relapse and shorter time-to-first treatment and overall survival. Next, prompted by the fact that TAp63 participates in an NF-κB/TAp63/BCL2 antiapoptotic axis in activated mature, normal B cells, we explored molecular links between TAp63 and BCL2 also in CLL. We documented a strong correlation at both the protein and the messenger RNA (mRNA) levels, alluding to the potential prosurvival role of TAp63. This claim was supported by inducible downregulation of TAp63 expression in the MEC1 CLL cell line using clustered regularly interspaced short palindromic repeats (CRISPR) system, which resulted in downregulation of BCL2 expression. Next, using chromatin immunoprecipitation (ChIP) sequencing, we examined whether BCL2 might constitute a transcriptional target of TAp63 and identified a significant binding profile of TAp63 in the BCL2 gene locus, across a genomic region previously characterized as a super enhancer in CLL. Moreover, we identified high-confidence TAp63 binding regions in genes mainly implicated in immune response and DNA-damage procedures. Finally, we found that upregulated TAp63 expression levels render CLL cells less responsive to apoptosis induction with the BCL2 inhibitor venetoclax. On these grounds, TAp63 appears to act as a positive modulator of BCL2, hence contributing to the antiapoptotic phenotype that underlies clinical aggressiveness and treatment resistance in CLL.

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Nuclear architectural proteins are increasingly recognized as multifunctional regulators whose roles extend well beyond static genome organization. Here we report that SMC1A, a core subunit of the cohesin complex, undergoes a striking redistribution upon inflammatory stimulation in human monocytes, dissociating from nuclear speckles and accumulating at genomic regions enriched for stress-response genes with distinct exon-intron architectural properties. Through integrative analysis of RNA-seq, chromatin organization, and nuclear spatial data, we demonstrate that this redistribution has functional consequences at multiple levels of gene expression. SMC1A dissociation from speckles is accompanied by a reduction in intron retention events -consistent with a transition from a poised, pre-loaded transcriptional state toward active, efficient co-transcriptional processing- and by selective engagement with genes whose exon-intron architecture favors exon definition splicing, shorter nuclear mRNA residence times, and peripheral radial positioning. Genes affected by SMC1A silencing, by contrast, occupy more central nuclear positions and display fundamentally different structural properties, demonstrating that the two modes of SMC1A perturbation -stress-induced redistribution and depletion- are functionally and spatially non-equivalent. These findings suggest a genome compartmentalization in which DNA compositional preferences, gene architecture, radial positioning, and splicing mode converge to define gene sets capable of rapid, precise activation. SMC1A navigates this pre-existing landscape upon inflammatory cues, coordinating transcriptional and posttranscriptional responses simultaneously. We propose that stress-induced redistribution of architectural proteins within a largely invariant nuclear compartmental framework represents a general regulatory mechanism, one whose logic is encoded in the structural organization of the genome itself.