Innate immune stress pathway activation underlies heterochromatin dysfunction pathology
- 1University of Cambridge
Abstract
Heterochromatin loss disrupts nuclear architecture, gene regulation and repetitive element silencing, and is associated with diverse human diseases. However, mechanisms linking heterochromatin dysfunction to pathological phenotypes remain unclear. Using genetic interaction screening and genomic analyses in C. elegans, we identify secondary activation of the Intracellular Pathogen Response (IPR), an innate immune stress pathway, as a major contributor to heterochromatin mutant phenotypes. Constitutive IPR activation phenocopies slow growth and indirect transcriptional changes observed in these mutants. Depletion of genetic enhancers further increased, whereas suppressor RNAi attenuated IPR activation, with direct heterochromatin targets remaining substantially deregulated. Notably, many suppressors encode active chromatin components, and mild reduction of RNA polymerase II activity ameliorates growth defects in C. elegans HP1 mutants and human HP1-deficient cells. Our findings reveal secondary stress response activation as an important mechanism linking heterochromatin dysfunction to pathology and identify transcriptional dampening as a potential therapeutic strategy for mitigating these effects.
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BibTeX
@misc{pradhan2026innate,
title = {{Innate immune stress pathway activation underlies heterochromatin dysfunction pathology}},
author = {R. Pradhan and A. F. Townley and A. V. Protasio and J. M. Danac and Y. Dong and Y. Fang and A. Appert and F. N. Carelli and S. Han and H. Vaikkinen and I. Tchasovnikarova and J. Ahringer},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.23.753861},
url = {https://www.biorxiv.org/content/10.64898/2026.09.23.753861v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Innate immune stress pathway activation underlies heterochromatin dysfunction pathology
AU - R. Pradhan
AU - A. F. Townley
AU - A. V. Protasio
AU - J. M. Danac
AU - Y. Dong
AU - Y. Fang
AU - A. Appert
AU - F. N. Carelli
AU - S. Han
AU - H. Vaikkinen
AU - I. Tchasovnikarova
AU - J. Ahringer
PY - 2026
DA - 2026/09/23
PB - bioRxiv
DO - 10.64898/2026.09.23.753861
UR - https://www.biorxiv.org/content/10.64898/2026.09.23.753861v1
AB - Heterochromatin loss disrupts nuclear architecture, gene regulation and repetitive element silencing, and is associated with diverse human diseases. However, mechanisms linking heterochromatin dysfunction to pathological phenotypes remain unclear. Using genetic interaction screening and genomic analyses in C. elegans, we identify secondary activation of the Intracellular Pathogen Response (IPR), an innate immune stress pathway, as a major contributor to heterochromatin mutant phenotypes. Constitutive IPR activation phenocopies slow growth and indirect transcriptional changes observed in these mutants. Depletion of genetic enhancers further increased, whereas suppressor RNAi attenuated IPR activation, with direct heterochromatin targets remaining substantially deregulated. Notably, many suppressors encode active chromatin components, and mild reduction of RNA polymerase II activity ameliorates growth defects in C. elegans HP1 mutants and human HP1-deficient cells. Our findings reveal secondary stress response activation as an important mechanism linking heterochromatin dysfunction to pathology and identify transcriptional dampening as a potential therapeutic strategy for mitigating these effects.
ER -