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Histone H1 depletion triggers an interferon response in cancer cells

Researchers of the IBMB have shown that simultaneous depletion of particular histone H1 variants in human breast cancer cells triggers the cellular interferon response, originally designed to fight against invading pathogen-associated nucleic acids such as DNA or RNA viruses. They have shown that this is due to the derepression of heterochromatic non-coding RNAs such as satellites and endogenous retroviruses, which may be naturally repressed with the participation of particular histone H1 subtypes such as H1.2 and H1.4.
Histone H1 depletion triggers an interferon response in cancer cells

Figure: Model of H1 involvement in the repression of the interferon response.

Histone H1 has seven variants in human somatic cells and contributes to chromatin compaction and transcriptional regulation. Knock-down (KD) of each H1 variant in breast cancer cells results in altered gene expression and proliferation differently in a variant specific manner with H1.2 and H1.4 KDs being most deleterious. Here we show combined depletion of H1.2 and H1.4 has a strong deleterious effect resulting in a strong interferon (IFN) response, as evidenced by an up-regulation of many IFN-stimulated genes (ISGs) not seen in individual nor in other combinations of H1 variant KDs. Although H1 participates to repress ISG promoters, IFN activation upon H1.2 and H1.4  KD is mainly generated through the activation of the IFN response by cytosolic nucleic acid receptors and IFN synthesis, and without changes in histone modifications at induced ISG promoters. H1.2 and H1.4 co-KD also promotes the appearance of accessibility sites genome wide and, particularly, at satellites and other repeats. The IFN response may be triggered by the expression of noncoding RNA generated from heterochromatic repeats or endogenous retroviruses upon H1 KD. In conclusion, redundant H1-mediated silencing of heterochromatin is important to maintain cell homeostasis and to avoid an unspecific IFN response.

 

This research has been performed by the ‘Chromatin regulation of human and viral gene expression’ group (Dr. Albert Jordan) of the IBMB, in collaboration with researchers from CNAG, VHIO and IDIBELL, and has been published in Nucleic Acids Research.

 

Izquierdo-Bouldstridge A*, Bustillos A*, Bonet-Costa C, Aribau P, Garcia D, Dabad M, Esteve-Codina A, Pascual L, Peiro S, Esteller M, Murtha M, Millán-Ariño Ll, Jordan A (2017) Histone H1 depletion triggers an interferon response in cancer cells via activation of heterochromatic repeats. Nucleic Acids Research doi.org/10.1093/nar/gkx746.

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