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The long non-coding RNA Morrbid regulates Bim and short-lived myeloid cell lifespan (ChIP-Seq)

ABSTRACT: Neutrophils, eosinophils and “classical” monocytes collectively account for ~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 while minimizing the deleterious consequences of prolonged inflammation. However, how the lifespan of these cells is strictly controlled remains largely unknown. Here, we identify a novel long non-coding RNA (lncRNA) that we termed Morrbid, which tightly controls the survival of neutrophils, eosinophils and “classical” monocytes in response to pro-survival cytokines. To control the lifespan of these cells, Morrbid regulates the transcription of its neighboring pro-apoptotic gene, Bcl2l11 (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 for rapid control of apoptosis in response to extracellular pro-survival signals. As MORRBID is also present in humans and dysregulated in patients with hypereosinophilic syndrome, this lncRNA may represent a potential therapeutic target for inflammatory disorders characterized by aberrant short-lived myeloid cell lifespan.

ORGANISM(S): Mus musculus

PROVIDER: GSE85072 | GEO | 2016/09/02

SECONDARY ACCESSION(S): PRJNA336059

REPOSITORIES: GEO

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The long non-coding RNA Morrbid regulates Bim and short-lived myeloid cell lifespan (ATAC-Seq)

Project description:Neutrophils, eosinophils and “classical” monocytes collectively account for ~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 while minimizing the deleterious consequences of prolonged inflammation. However, how the lifespan of these cells is strictly controlled remains largely unknown. Here, we identify a novel long non-coding RNA (lncRNA) that we termed Morrbid, which tightly controls the survival of neutrophils, eosinophils and “classical” monocytes in response to pro-survival cytokines. To control the lifespan of these cells, Morrbid regulates the transcription of its neighboring pro-apoptotic gene, Bcl2l11 (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 for rapid control of apoptosis in response to extracellular pro-survival signals. As MORRBID is also present in humans and dysregulated in patients with hypereosinophilic syndrome, this lncRNA may represent a potential therapeutic target for inflammatory disorders characterized by aberrant short-lived myeloid cell lifespan.

2016-09-02 | GSE85071 | GEO

Transcriptomics of circulating human eosinophils

Project description:Global expression pattern in eosinophils in various conditions such as eosinophilic asthma, hypereosinophilic dermatological diseases, parasitosis and pulmonary aspergillosis. Eosinophil were isolated from peripheral blood by FACS from 4 hypereosinophilic conditions: eosinophilic asthma (4 replicates), hypereosinophilic dermatological diseases (3 replicates), parasitosis (3 replicates) and pulmonary aspergillosis (4 replicates).

2015-12-10 | E-GEOD-65239 | biostudies-arrayexpress

Transcriptomics of circulating human eosinophils

Project description:Global expression pattern in eosinophils in various conditions such as eosinophilic asthma, hypereosinophilic dermatological diseases, parasitosis and pulmonary aspergillosis.

2015-12-10 | GSE65239 | GEO

Transcription factor C/EBP⍺ is required for the development of Ly6Chi monocytes but not Ly6Clo monocytes

Project description:Monocytes comprise two major subsets, Ly6Chi classical monocytes and Ly6Clo non-classical monocytes. Notch2 signaling in Ly6Chi monocytes triggers transition to Ly6Clo monocytes, which require Nr4a1, Bcl6, Irf2 and Cebpb. By comparison, less is known about transcriptional requirements for Ly6Chi monocytes. We find transcription factor CCAAT/enhancer-binding protein alpha (C/EBPα) is highly expressed in Ly6Chi monocytes, but down-regulated in Ly6Clo monocytes. A few previous studies described the requirement of C/EBPα in the development of neutrophils and eosinophils. However, role of C/EBPα for in vivo monocyte development has not been understood. We deleted the Cebpa +37 kb enhancer in mice, eliminating hematopoietic expression of C/EBPα, reproducing the expected neutrophil defect. Surprisingly, we also discovered a severe and selective loss of Ly6Chi monocytes, while preserving Ly6Clo monocytes. We find that BM progenitors from Cebpa +37–/– mice rapidly progress through the cMoP stage to develop directly into Ly6Clo monocytes even in the absence of Notch2 signaling. These results identify a previously unrecognized role for C/EBPα in maintaining Ly6Chi monocyte identity.

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Monocytic cell differentiation from band-stage neutrophils under inflammatory conditions

Project description:During inflammation, neutrophils are rapidly mobilized from the bone marrow storage pool into peripheral blood to subsequently enter lesional sites where most of them rapidly undergo apoptosis. Monocytes constitute a second wave of inflammatory immigrates giving rise to long-lived macrophages and dendritic cell subsets. According to descriptive immunophenotypic and cell culture studies, neutrophils may directly M-bM-^@M-^\transdifferentiateM-bM-^@M-^] into monocytes/macrophages. We here provide mechanistic data in human supporting the existence of this cellular pathway. Global transcriptional profiling of neutrophil-dervived monocytic cells revealed close resemblance of gene expression with monocytes and a clear separation of these cells from neutrophils. G-CSF mobilized neutrophils from peripheral blood were isolated and in vitro stimulated with GM-CSF, TNFa, and Il-1b for 5 days to generate monocytic cells. RNA were isolated from these cells and freshly isolated blood neutrophils and monocytes.

2014-07-11 | E-GEOD-58920 | biostudies-arrayexpress

Transcriptional analysis of TREM-1+ and TREM-1- airway eosinophils during allergic inflammation

Project description:Triggering Receptor Expressed on Myeloid cells 1 (TREM-1) an innate receptor that canonically amplifies inflammatory signaling in neutrophils and monocytes, plays a central role in regulating lung inflammation. Utilizing a murine model of asthma, flow cytometry revealed TREM-1+ eosinophils in the lung tissue and airway during allergic airway inflammation. TREM-1 expression was restricted to recruited, inflammatory eosinophils. Expression was induced on bone marrow derived eosinophils by incubation with IL-33, LPS, or GM-CSF. Compared to TREM-1- airway eosinophils, TREM-1+ eosinophils were enriched for pro-inflammatory gene sets including migration, respiratory burst, and cytokine production. Unexpectedly, eosinophil-specific ablation of TREM-1 increased airway IL-5 and lung tissue eosinophil accumulation. Further investigation of transcriptional data revealed apoptosis related gene sets were enriched in TREM-1+ eosinophils. Annexin V staining demonstrated higher rates of apoptosis among TREM-1+ eosinophils compared to TREM-1- eosinophils in the inflammatory airway. In vitro, Trem1/3-/- eosinophils were protected from apoptosis. Finally, inhibition of reactive oxygen species production with diphenyleneiodonium protected WT bone marrow derived eosinophils from apoptosis more than Trem1/3-/- eosinophils, suggesting that superoxide accounted for more apoptosis in WT cells. These data demonstrate protein level expression of TREM-1 by eosinophils for the first time, define a population of TREM-1+ inflammatory eosinophils, and reveal that eosinophil TREM-1 restricts key features of type 2 lung inflammation.

2023-12-15 | GSE246389 | GEO

Expression data from adult left ventricular heart tissue of hypereosinophilic mice and controls

Project description:Hypereosinophilic syndrome is a progressive disease with extensive eosinophilia that results in organ damage. Patients suffer from frequent cardiac pathologies and a high mortality rate. A better understanding of the mechanisms of eosinophil-mediated tissue damage would benefit the development of new therapies. Here, we describe the cardiac pathologies that develop in a mouse model of hypereosinophilic syndrome. These IL-5 transgenic mice exhibited decreased left ventricular function already at a young age. Cardiac function worsened with age and heart weight increased. Moreover, hypereosinophilic mice developed different pathologies of the cardiac conductive system, including 2nd degree atrioventricular block and atrioventricular reentry. Cardiomyocytes from IL-5 transgenic mice showed reduced contractility. Despite immune infiltrates in the lungs, doppler echocardiography revealed no signs of pulmonary hypertension in these mice. Mechanistically, we demonstrated eosinophil infiltration of the heart tissue that lead to an inflammatory environment. Eosinophils were 100-fold more abundant in the hearts of hypereosinophilic mice than controls. Gene expression signatures showed tissue damage as well as repair and remodeling processes. Our results suggest that hypereosinophilia leads to infiltration of the heart tissue by eosinophils and tissue damage. The ongoing remodeling and repair processes are insufficient or maladapted to maintain heart function resulting in progressive deterioration.

2023-10-25 | GSE185300 | GEO

Monocytic cell differentiation from band-stage neutrophils under inflammatory conditions

Project description:During inflammation, neutrophils are rapidly mobilized from the bone marrow storage pool into peripheral blood to subsequently enter lesional sites where most of them rapidly undergo apoptosis. Monocytes constitute a second wave of inflammatory immigrates giving rise to long-lived macrophages and dendritic cell subsets. According to descriptive immunophenotypic and cell culture studies, neutrophils may directly “transdifferentiate” into monocytes/macrophages. We here provide mechanistic data in human supporting the existence of this cellular pathway. Global transcriptional profiling of neutrophil-dervived monocytic cells revealed close resemblance of gene expression with monocytes and a clear separation of these cells from neutrophils.

2014-07-11 | GSE58920 | GEO

Expression data from middle-aged and old Drosophila females

Project description:The mechanisms underlying natural variation in lifespan and ageing rate remain largely unknown. We performed microarray experiment to characterise genome-wide expression patterns of a long-lived, natural variant of Drosophila melanogaster resulting from selection for starvation resistance (SR) and compare it with normal-lived control flies (C). We sampled adult females at two time points representing middle age (90% survival) and old age (10% survival) respectively, in three adult diets (malnutrition, optimal food, and overfeeding).

2012-03-31 | E-GEOD-36582 | biostudies-arrayexpress

The germline regulates longevity and somatic repair in a sex-specific manner (RNA-Seq)

Project description:Classical evolutionary theories propose tradeoffs between reproduction, damage repair, and lifespan. However, the specific role of the germline in shaping vertebrate aging remains largely unknown. Here, we use the turquoise killifish (N. furzeri) to genetically arrest germline differentiation at discrete stages, and examine how different ‘flavors’ of infertility impact life-history. We first constructed a comprehensive single-cell gonadal atlas, providing cell-type-specific markers for downstream phenotypic analysis. Next, investigating our genetic models revealed that only germline ablation enhanced female damage repair, while arresting germline differentiation did not. Conversely, germline-ablated males were significantly long-lived, indicating that the mere presence of the germline can negatively affect lifespan. Transcriptomic analysis highlighted enrichment of pro-longevity pathways and genes, with functional conservation in germline-ablated C. elegans. Finally, germline depletion extended male healthspan through rejuvenated metabolic functions. Our results suggest that different germline manipulation paradigms can yield pronounced sexually dimorphic phenotypes, implying alternative mechanisms to classical evolutionary tradeoffs.

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