Inflammation-driven cellular selection impacts X-linked mosaicism in the epidermis
- 1University of Vienna / Max Perutz Labs
Abstract
In eutherian females, the choice of which X chromosome gets embryonically inactivated is thought to be random. Somatic tissues are thus assumed to comprise cells with a 50:50 ratio of maternal:paternal X active. However, a phenomenon known as X-skewing has been observed, wherein tissue composition shifts to be dominated by cells expressing one X or the other. On a gross level, such X-skewing is phenotypically silent except in the case where one X-chromosome carries a disease mutation. Here, by leveraging a mouse model of an X-linked disease called Incontinentia Pigmenti, caused by heterozygous mutations in the NF-kB effector, Nemo, we explore how X-linked cellular dynamics shape progenitor biology in the epidermis. Lineage tracing with X-linked reporters shows that at birth, the epidermis is unexpectedly skewed toward mutant cells. Within a week, as inflammation emerges, these dynamics reverse leaving surviving animals with almost entirely wild-type epithelium. The shift is driven by loss rather than growth since mutant cells adopt an aberrant fate and die at higher rates than their wild-type neighbours; proliferation rises in both populations. Notably, wild-type proliferation scales with local tissue composition, suggesting these cells calibrate their response to the extent of the mutant burden to compensate appropriately for tissue loss. Depleting macrophages, the principal TNF- source, attenuates inflammation, mutant cell death and ultimately is expected to preserve the mutant population. Altogether, our results identify inflammation as a selective force capable of resolving deleterious mosaicism, not only in the context of an X-linked disease, but within any dynamic, clonally heterogeneous epithelium.
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BibTeX
@misc{ellis2026inflammationdriven,
title = {{Inflammation-driven cellular selection impacts X-linked mosaicism in the epidermis}},
author = {S. J. Ellis and E. Angelopoulou and K. Gandhi and M. van Wolfswinkel and L. Schmautz and I. Oyarzun and S. Nowosadtko and I. Fischer and V. Schwartz and J. J. Griss},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.08.757664},
url = {https://www.biorxiv.org/content/10.64898/2026.10.08.757664v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Inflammation-driven cellular selection impacts X-linked mosaicism in the epidermis
AU - S. J. Ellis
AU - E. Angelopoulou
AU - K. Gandhi
AU - M. van Wolfswinkel
AU - L. Schmautz
AU - I. Oyarzun
AU - S. Nowosadtko
AU - I. Fischer
AU - V. Schwartz
AU - J. J. Griss
PY - 2026
DA - 2026/10/08
PB - bioRxiv
DO - 10.64898/2026.10.08.757664
UR - https://www.biorxiv.org/content/10.64898/2026.10.08.757664v1
AB - In eutherian females, the choice of which X chromosome gets embryonically inactivated is thought to be random. Somatic tissues are thus assumed to comprise cells with a 50:50 ratio of maternal:paternal X active. However, a phenomenon known as X-skewing has been observed, wherein tissue composition shifts to be dominated by cells expressing one X or the other. On a gross level, such X-skewing is phenotypically silent except in the case where one X-chromosome carries a disease mutation. Here, by leveraging a mouse model of an X-linked disease called Incontinentia Pigmenti, caused by heterozygous mutations in the NF-kB effector, Nemo, we explore how X-linked cellular dynamics shape progenitor biology in the epidermis. Lineage tracing with X-linked reporters shows that at birth, the epidermis is unexpectedly skewed toward mutant cells. Within a week, as inflammation emerges, these dynamics reverse leaving surviving animals with almost entirely wild-type epithelium. The shift is driven by loss rather than growth since mutant cells adopt an aberrant fate and die at higher rates than their wild-type neighbours; proliferation rises in both populations. Notably, wild-type proliferation scales with local tissue composition, suggesting these cells calibrate their response to the extent of the mutant burden to compensate appropriately for tissue loss. Depleting macrophages, the principal TNF- source, attenuates inflammation, mutant cell death and ultimately is expected to preserve the mutant population. Altogether, our results identify inflammation as a selective force capable of resolving deleterious mosaicism, not only in the context of an X-linked disease, but within any dynamic, clonally heterogeneous epithelium.
ER -