Abstract
In females, the long non-coding RNA Xist drives X-chromosome Inactivation (XCI) to equalize X-linked gene dosage between sexes. Unlike other somatic cells, dynamic regulation of Xist RNA and heterochromatin marks on the inactive X (Xi) in female lymphocytes results in biallelic expression of some X-linked genes, including Tlr7, Cxcr3, and Cd40l, implicated in sex-biased autoimmune diseases. We now find that while Xist RNA is dispersed across the nucleus in NK cells and dendritic cells (DCs) and partially co-localizes with H3K27me3 in bone marrow-derived macrophages, it is virtually absent in plasmacytoid DCs (p-DCs). Moreover, H3K27me3 foci are present in only 10–20% of cells and we observed biallelic expression of Tlr7 in p-DCs from wildtype mice and NZB/W F1 mice. Unlike in humans, mouse p-DCs do not exhibit sex differences with interferon alpha production, and interferon signature gene expression in p-DCs is similar between males and females. Despite the absence of Xist RNA from the Xi, female p-DCs maintain dosage compensation of six immunity-related X-linked genes. Thus, immune cells use diverse mechanisms to maintain XCI which could contribute to sex-linked autoimmune diseases.
Highlights
In the immune system, long non-coding RNAs are being increasingly recognized as important regulators of gene expression for both innate and adaptive immune responses [1]
We found that NK cells and dendritic cells (DCs) have Xist RNA transcripts dispersed across the nucleus, while bone marrow derived macrophages (BMDMs) have Xist RNA pinpoints clustered at the inactive X (Xi), and exhibit co-localization of Xist RNA and the heterochromatin mark H3K27me3
To determine if X-chromosome Inactivation (XCI) is dynamically regulated in NK cells, lymphoid-DCs (L-DCs), and myeloid DCs (m-DCs) each of these cell types were isolated from female mouse spleens (Figure 1A)
Summary
Long non-coding RNAs (lncRNAs) are being increasingly recognized as important regulators of gene expression for both innate and adaptive immune responses [1]. LncRNAs can function as regulators of immune cell differentiation, lymphocyte activation, and inflammatory responses. Similar to Morrbid, lnc-DC is upregulated during differentiation of common myeloid progenitors into dendritic cells (DCs), and regulates DC differentiation through cytoplasmic interactions with the transcription factor STAT3 [3]. Activation of DCs and macrophages through specific TLRs results in dramatic upregulation of lincRNA-Cox, which regulates over 500 genes encoding inflammatory molecules [4]. Females use XCI for dosage compensation of X-linked genes between the sexes. XCI is initiated during early female mammalian embryonic development
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