Year: 2023
Type: preprint
Abstract: Individual elements within a superenhancer can act in a cooperative or temporal manner, but the underlying mechanisms remain obscure. We recently identified anIrf8superenhancer, within which different elements act at distinct stages of type 1 classical dendritic cell (cDC1) development. The +41-kbIrf8enhancer is required for pre-cDC1 specification, while the +32-kbIrf8enhancer acts to support subsequent cDC1 maturation. Here, we found that compound heterozygous Δ32/Δ41 mice, lacking the +32- and +41-kb enhancers on different chromosomes, show normal pre-cDC1 specification but, surprisingly, completely lack mature cDC1 development, suggestingcisdependence of the +32-kb enhancer on the +41-kb enhancer. Transcription of the +32-kbIrf8enhancer-associated long noncoding RNA (lncRNA) Gm39266 is also dependent on the +41-kb enhancer. However, cDC1 development in mice remained intact when Gm39266 transcripts were eliminated by CRISPR/Cas9-mediated deletion of lncRNA promoters and when transcription across the +32-kb enhancer was blocked by premature polyadenylation. We showed that chromatin accessibility and BATF3 binding at the +32-kb enhancer were dependent on a functional +41-kb enhancer located incis. Thus, the +41-kbIrf8enhancer controls the subsequent activation of the +32-kbIrf8enhancer in a manner that is independent of associated lncRNA transcription.
Source: Genes & Development
Institutions: Washington University in St. Louis, Stanford University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: diamond
OpenAlex ID: W4361292770