Sex-specific lymphoid lineage differentiation is modulated by CIZ1
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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.
Highlights
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CIZ1 forms protein assemblies at the inactive X-chromosome in females, that disaggregate in naive B cells and reform on antigen stimulation in vitro and challenge in vivo .
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X-linked escape gene expression in females is normally compensated in males, but polarises in the absence of CIZ1 via suppression in males.
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Autosomal gene clusters respond to absence of CIZ1 in a sex-specific manner leading to divergent B cell differentiation even before immune challenge.
Summary
This study shows that CIZ1 promotes dosage compensation of X-linked escape genes via modulation of male gene expression, and also dampens divergent expression of autosomal loci in B cells, protecting against sex-biased gene expression, and lymphocyte hyperplasia in females.
