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Sex-specific lymphoid lineage differentiation is modulated by CIZ1

Guglielmi, E.; Monge-Lozano, R.; Pearson, J. F.; Pais, F. S.; James, S. R.; Hewitson, J. P.; Kent, D. G.; Coverley, D.; Ainscough, J. F. X.

2026-08-27 cell biology
10.64898/2026.08.26.747233 bioRxiv
Show abstract

The epigenetic stability factor CIZ1 helps maintain X-chromosome inactivation, and its absence results in murine female-specific splenomegaly. By exploring the aetiology of this pathology, we reveal unexpected evidence for dosage compensation via modification of X-linked gene expression in males. Genes known to escape repression on the inactive X-chromosome in females, including the B-cell maturation factor DDX3X, require CIZ1 in males to maintain parity between the sexes. Furthermore, absence of this single regulator triggers stark sex-specific changes to large autosomal domains in B cells, causing naive female B cells to shift prematurely towards germinal centre transcriptional signatures, including immunoglobulin and pro-proliferation genes even without immune challenge. Conversely, males acquire natural killer-like gene expression through elevation of Killer cell Lectin-like Receptors. Together, the data indicate that CIZ1 limits sexually dimorphic gene expression on autosomes, and promotes dosage compensation by modulation of the male X-chromosome, introducing a new paradigm for sex biased disorders of the immune system.

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