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The long non-coding RNA Morrbid regulates Bim and short-lived myeloid cell lifespan
Abstract
Neutrophils, eosinophils and ‘classical’ monocytes collectively account for about 70% of human blood leukocytes and are among the shortest-lived cells in the body. Precise regulation of the lifespan of these myeloid cells is critical to maintain protective immune responses and minimize the deleterious consequences of prolonged inflammation. However, how the lifespan of these cells is strictly controlled remains largely unknown. Here we identify a long non-coding RNA that we termed Morrbid, which tightly controls the survival of neutrophils, eosinophils and classical monocytes in response to pro-survival cytokines in mice. To control the lifespan of these cells, Morrbid regulates the transcription of the neighbouring pro-apoptotic gene, Bcl2l11 (also known as Bim), by promoting the enrichment of the PRC2 complex at the Bcl2l11 promoter to maintain this gene in a poised state. Notably, Morrbid regulates this process in cis, enabling allele-specific control of Bcl2l11 transcription. Thus, in these highly inflammatory cells, changes in Morrbid levels provide a locus-specific regulatory mechanism that allows rapid control of apoptosis in response to extracellular pro-survival signals. As MORRBID is present in humans and dysregulated in individuals with hypereosinophilic syndrome, this long non-coding RNA may represent a potential therapeutic target for inflammatory disorders characterized by aberrant short-lived myeloid cell lifespan.
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In the citing paper
“Morrbid+/− or Morrbid−/− mice manifest decreased myeloid cells in peripheral blood (Kotzin et al., 2016).”
From Inhibition of Inflammatory Signaling in Tet2 Mutant Preleukemic Cells Mitigates Stress-Induced Abnormalities and Clonal Hematopoiesis (2018) · cites this paper as Kotzin et al., 2016
In the citing paper
“Morrbid negatively regulates Bcl2l12 (encoding Bim) expression”
From Inhibition of Inflammatory Signaling in Tet2 Mutant Preleukemic Cells Mitigates Stress-Induced Abnormalities and Clonal Hematopoiesis (2018) · cites this paper as Kotzin et al., 2016
In the citing paper
“We inhibited the expression of Morrbid by knocking-down its expression using a lentivirus in Tet2-KO cells (Figure S7A), or by breeding Morrbid+/− mice to Tet2+/− mice, given that both heterozygous mutants closely mimic the phenotype observed in complete knockout for these genes (Figure 7A) (Kotzin et al., 2016; Quivoron et al., 2011).”
From Inhibition of Inflammatory Signaling in Tet2 Mutant Preleukemic Cells Mitigates Stress-Induced Abnormalities and Clonal Hematopoiesis (2018) · cites this paper as Kotzin et al., 2016
In the citing paper
“Morrbid is a recently identified long non-coding RNA (lncRNA) involved in regulating the expression of Bim and in the survival of myeloid cells including neutrophils; however, the role of Morrbid in the survival of pre-leukemic HSPCs is not known (Kotzin et al., 2016).”
From Inhibition of Inflammatory Signaling in Tet2 Mutant Preleukemic Cells Mitigates Stress-Induced Abnormalities and Clonal Hematopoiesis (2018) · cites this paper as Kotzin et al., 2016
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Cites
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Self-citationFate Mapping Reveals Origins and Dynamics of Monocytes and Tissue Macrophages under Homeostasis
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Cai, Z., Kotzin, J. J., Ramdas, B., Chen, S., Nelanuthala, S., Palam, L. R., Pandey, R., Mali, R. S., Liu, Y., Kelley, M. R., et al. (2018) · Cell Stem Cell · doi:10.1016/j.stem.2018.10.013 · Cited by 394
Self-citationThe translation of non-canonical open reading frames controls mucosal immunity
Jackson, R., Kroehling, L., Khitun, A., Bailis, W., Jarret, A., York, A. G., Khan, O. M., Brewer, J. R., Skadow, M. H., Duizer, C., et al. (2018) · Nature · doi:10.1038/s41586-018-0794-7 · Cited by 242
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Metadata
- Authors
- Kotzin, J. J., Spencer, S. P., McCright, S. J., Kumar, D. B. U., Collet, M. A., Mowel, W. K., Elliott, E. N., Uyar, A., Makiya, M. A., Dunagin, M. C., Harman, C. C. D., Virtue, A. T., Zhu, S., Bailis, W., Stein, J., Hughes, C., Raj, A., Wherry, E. J., Goff, L. A., Klion, A. D., Rinn, J. L., Williams, A., Flavell, R. A., & Henao-Mejia, J.
- Venue
- Nature
- Published
- 2016-08-15
- Volume
- 537
- Issue
- 7619
- Pages
- 239-243
- ISSN
- 0028-0836
- 1476-4687
- PMC
- PMC5161578
- Cited by
- 288
- References
- 26
- Language
- en
- Licence
- www.springer.com/tdm (tdm)
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- Kotzin, J. J., Spencer, S. P., McCright, S. J., Kumar, D. B. U., Collet, M. A., Mowel, W. K., Elliott, E. N., Uyar, A., Makiya, M. A., Dunagin, M. C., Harman, C. C. D., Virtue, A. T., Zhu, S., Bailis, W., Stein, J., Hughes, C., Raj, A., Wherry, E. J., Goff, L. A., . . . Henao-Mejia, J. (2016). The long non-coding RNA Morrbid regulates Bim and short-lived myeloid cell lifespan. Nature. https://doi.org/10.1038/nature19346
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