PT  - JOURNAL ARTICLE
AU  - Chandwani, Rohit
AU  - Fang, Terry C.
AU  - Dewell, Scott
AU  - Tarakhovsky, Alexander
TI  - Control of enhancer activation in the type I interferon response by the histone demethylase Kdm4d / JMJD2d
AID  - 10.1101/2023.01.14.524033
DP  - 2023 Jan 01
TA  - bioRxiv
PG  - 2023.01.14.524033
4099  - http://biorxiv.org/content/early/2023/01/15/2023.01.14.524033.short
4100  - http://biorxiv.org/content/early/2023/01/15/2023.01.14.524033.full
AB  - Transcriptional activation depends on the interplay of chromatin modifiers to establish a permissive epigenetic landscape. While histone 3 lysine 9 (H3K9) methylation has long been associated with gene repression, there is limited evidence to support a role for H3K9 demethylases in gene activation. Here we describe the H3K9 demethylase Kdm4d/JMJD2d as a positive regulator of type I interferon responses. In mouse embryonic fibroblasts (MEFs), depletion of JMJD2d attenuates the transcriptional response, conferring increased viral susceptibility, while overexpression of the demethylase results in more robust IFN activation. We find that the underlying mechanism of JMJD2d in type I interferon responses consists of an effect both on the transcription of enhancer RNAs (eRNAs) and on dynamic H3K9me2 at associated promoters. In support of these findings, we establish that JMJD2d is associated with enhancer regions throughout the genome prior to stimulation but is redistributed to inducible promoters in conjunction with transcriptional activation. Taken together, our data reveal JMJD2d as a chromatin modifier that connects enhancer transcription with promoter demethylation to modulate transcriptional responses.Competing Interest StatementThe authors have declared no competing interest.