4 research outputs found
The chromatin reader ZMYND8 regulates Igh enhancers to promote immunoglobulin class switch recombination
Class switch recombination (CSR) is a DNA recombination reaction that diversifies the effector component of antibody responses. CSR is initiated by activation-induced cytidine deaminase (AID), which targets transcriptionally active immunoglobulin heavy chain (Igh) switch donor and acceptor DNA. The 3' Igh super-enhancer, 3' regulatory region (3'RR), is essential for acceptor region transcription, but how this function is regulated is unknown. Here, we identify the chromatin reader ZMYND8 as an essential regulator of the 3'RR. In B cells, ZMYND8 binds promoters and super-enhancers, including the Igh enhancers. ZMYND8 controls the 3'RR activity by modulating the enhancer transcriptional status. In its absence, there is increased 3'RR polymerase loading and decreased acceptor region transcription and CSR. In addition to CSR, ZMYND8 deficiency impairs somatic hypermutation (SHM) of Igh, which is also dependent on the 3'RR. Thus, ZMYND8 controls Igh diversification in mature B lymphocytes by regulating the activity of the 3' Igh super-enhancer
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The Magnitude of IFN-Îł Responses Is Fine-Tuned by DNA Architecture and the Non-coding Transcript of Ifng-as1
Interferon gamma (IFN-Îł), critical for host defense and tumor surveillance, requires tight control of its expression. Multiple cis-regulatory elements exist around Ifng along with a non-coding transcript, Ifng-as1 (also termed NeST). Here, we describe two genetic models generated to dissect the molecular functions of this locus and its RNA product. DNA deletion within the Ifng-as1 locus disrupted chromatin organization of the extended Ifng locus, impaired Ifng response, and compromised host defense. Insertion of a polyA signal ablated the Ifng-as1 full-length transcript and impaired host defense, while allowing proper chromatin structure. Transient knockdown of Ifng-as1 also reduced IFN-Îł production. In humans, discordant expression of IFNG and IFNG-AS1 was evident in memory TÂ cells, with high expression of this long non-coding RNA (lncRNA) and low expression of the cytokine. These results establish Ifng-as1 as an important regulator of Ifng expression, as a DNA element and transcribed RNA, involved in dynamic and cell state-specific responses to infection.
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•Ifng-as1 regulates Ifng expression locally, in cis without affecting other genes•Ifng-as1 gene locus, but not its non-coding transcript, impacts chromatin organization•Ifng and Ifng-as1 transcripts can be discordantly regulated in long-lasting memory cells
Petermann et al. report that the long non-coding RNA locus Ifng-as1 is an important regulator of Ifng. It does so through its role as a modifier of DNA structure, but also through transcription of the lncRNA itself, which is involved in dynamic and cell state-specific regulation of IFN-γ-mediated host defense