Deletion of a Csf1r enhancer selectively impacts CSF1R expression and development of tissue macrophage populations

Rojo, Rocío; Raper, Anna; Ozdemir, Derya D.; Lefèvre, Lucas; Grabert, Kathleen; Wollscheid-Lengeling, Evi; Bradford, Barry; Caruso, Melanie; Gažová, Iveta; Sánchez, Alejandra; Lisowski, Zofia M.; Alves, Joana; Molina-González, Irene; Davtyan, Hayk; Lodge, R. J.; Glover, James D.; Wallace, Robert; Munro, David A. D.; David, Eyal; Amit, Ido; Miron, Véronique E.; Priller, Josef; Jenkins, Stephen J.; Hardingham, Giles E.; Blurton‐Jones, Mathew; Mabbott, Neil A.; Summers, Kim M.; Hohenstein, Peter; Hume, David; Pridans, Clare

doi:10.1038/s41467-019-11053-8

Cited by 251 publications

(327 citation statements)

References 81 publications

(162 reference statements)

Supporting

Mentioning

283

Contrasting

Order By: Relevance

“…Genes in Cluster 4 were strongly expressed in samples from brain and include microglia-enriched markers that are depleted in brains of Csf1r-deficient mice and rats such as Cx3cr1, Tmem119, P2ry12 and the key transcription factor genes Sall1, Sall2 and Sall3 [16,61]. Cluster 9 contains the S phase transcription factor gene Foxm1 and numerous cell cycle-associated transcripts [62] and the GO term enrichment supports the cell cycle association.…”

Section: Major Macrophage-enriched Co-regulated Clustersmentioning

confidence: 69%

“…Transcripts in Cluster 4 were enriched in the resident kidney macrophages compared to both splenic macrophages and other kidney myeloid populations. Interestingly, the resident kidney macrophage cluster includes many genes that are also highly-expressed in microglia and depleted in the brain in Csf1r mutant mice and rats, including Cx3cr1, C1qa/b/c, Csf3r, Ctss, Fcrls, Hexb, Laptm5, Tgfbr1, Tmem119 and Trem2 [16,61]. These were also detected in the isolated kidney macrophages in Table S1.…”

Section: Validation Of Co-expression Clustering With An Independent Kmentioning

confidence: 90%

“…Both populations of interstitial lung macrophages (and all the samples from other tissues in this BioProject) expressed very high levels of all of the IEG transcripts in Cluster 41. Whereas macrophageexpressed transcripts such as Adgre1 are readily detected in total tissue mRNA, and are CSF1Rdependent, inflammatory cytokines and IEG are not [16,61]. Accordingly, in each of these studies, the expression of IEG and inducible cytokines is most likely an artefact of tissue disaggregation.…”

Section: Resident Macrophage Activation During Isolationmentioning

confidence: 94%

“…Epidermal Langerhans cells (LC) have at times been considered as DC-like because of their migratory and APC properties but are now considered to be a specialized resident tissue macrophage [94]. Unlike most classical DC in lymphoid tissue, they are clearly Csf1r-dependent and share with several other macrophage populations dependence on the conserved enhancer in the Csf1r locus [16]. Cluster 43 did not include a transcriptional regulator specific to LC.…”

Section: Tissue-specific Macrophage Clustersmentioning

confidence: 99%

“…At least some of these transcription factors act by regulating Csf1r expression. Deletion of a conserved enhancer in the mouse Csf1r gene leads to selective loss of some tissue macrophage populations, whereas others express Csf1r normally [16]. In the mouse embryo, where abundant macrophage populations are engaged with phagocytosis of apoptotic cells [17], the macrophage transcriptome does not differ greatly between organs.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Transcriptional network analysis of transcriptomic diversity in resident tissue macrophages and dendritic cells in the mouse mononuclear phagocyte system

Hume

2020

Preprint

Self Cite

View full text Add to dashboard Cite

The mononuclear phagocyte system (MPS) is a family of cells including progenitors, circulating blood monocytes, resident tissue macrophages and dendritic cells (DC) present in every tissue in the body. To test the relationships between markers and transcriptomic diversity in the MPS, we collected from NCBI-GEO >500 quality RNA-seq datasets generated from mouse MPS cells isolated from multiple tissues. The primary data were randomly down-sized to a depth of 10 million reads and requantified. The resulting dataset was clustered using the network analysis tool Graphia. A sample-to-sample matrix revealed that MPS populations could be separated based upon tissue of origin. Cells identified as classical DC subsets, cDC1 and cDC2, and lacking Fcgr1 (CD64), were centrally-located within the MPS cluster and no more distinct than other MPS cell types. A gene-to-gene correlation matrix identified large generic co-expression clusters associated with MPS maturation and innate immune function. Smaller co-expression clusters including the transcription factors that drive them showed higher expression within defined isolated cells, including macrophages and DC from specific tissues. They include a cluster containing Lyve1 that implies a function in endothelial cell homeostasis, a cluster of transcripts enriched in intestinal macrophages and a generic cDC cluster associated with Ccr7. However, transcripts encoding many other putative MPS subset markers including Adgre1, Itgax, Itgam, Clec9a, Cd163, Mertk, Retnla and H2-A/E (class II MHC) clustered idiosyncratically and were not correlated with underlying functions. The data provide no support for the concept of markers of M2 polarization or the specific adaptation of DC to present antigen to T cells. Co-expression of immediate early genes (e.g. Egr1, Fos, Dusp1) and inflammatory cytokines and chemokines (Tnf, Il1b, Ccl3/4) indicated that all tissue disaggregation protocols activate MPS cells. Tissue-specific expression clusters indicated that all cell isolation procedures also co-purify other unrelated cell types that may interact with MPS cells in vivo. Comparative analysis of public RNA-seq and single cell RNA-seq data from the same lung cell populations showed that the extensive heterogeneity implied by the global cluster analysis may be even greater at a single cell level with few markers strongly correlated with each other. This analysis highlights the power of large datasets to identify the diversity of MPS cellular phenotypes, and the limited predictive value of surface markers to define lineages, functions or subpopulations.

show abstract

Section: Major Macrophage-enriched Co-regulated Clustersmentioning

confidence: 69%

Section: Validation Of Co-expression Clustering With An Independent Kmentioning

confidence: 90%

Section: Resident Macrophage Activation During Isolationmentioning

confidence: 94%

Section: Tissue-specific Macrophage Clustersmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Transcriptional network analysis of transcriptomic diversity in resident tissue macrophages and dendritic cells in the mouse mononuclear phagocyte system

Hume

2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

A Pathologically Friendly Strategy for Determining the Organ‐specific Spatial Tumor Microenvironment Topology in Lung Adenocarcinoma Through the Integration of snRandom‐seq and Imaging Mass Cytometry

Sun,

Teng,

Liu

et al. 2024

Advanced Science

View full text Add to dashboard Cite

Heterogeneous organ‐specific responses to immunotherapy exist in lung cancer. Dissecting tumor microenvironment (TME) can provide new insights into the mechanisms of divergent responses, the process of which remains poor, partly due to the challenges associated with single‐cell profiling using formalin‐fixed paraffin‐embedded (FFPE) materials. In this study, single‐cell nuclei RNA sequencing and imaging mass cytometry (IMC) are used to dissect organ‐specific cellular and spatial TME based on FFPE samples from paired primary lung adenocarcinoma (LUAD) and metastases. Single‐cell analyses of 84 294 cells from sequencing and 250 600 cells from IMC reveal divergent organ‐specific immune niches. For sites of LUAD responding well to immunotherapy, including primary LUAD and adrenal gland metastases, a significant enrichment of B, plasma, and T cells is detected. Spatially resolved maps reveal cellular neighborhoods recapitulating functional units of the tumor ecosystem and the spatial proximity of B and CD4+ T cells at immunogenic sites. Various organ‐specific densities of tertiary lymphoid structures are observed. Immunosuppressive sites, including brain and liver metastases, are deposited with collagen I, and T cells at these sites highly express TIM‐3. This study originally deciphers the single‐cell landscape of the organ‐specific TME at both cellular and spatial levels for LUAD, indicating the necessity for organ‐specific treatment approaches.

show abstract

Leukoencephalopathy with calcifications, developmental brain abnormalities and skeletal dysplasia due to homozygosity for a hypomorphic CSF1R variant: A report of three siblings

Beerepoot,

Verbeke,

Plantinga

et al. 2024

American J of Med Genetics Pt A

View full text Add to dashboard Cite

We report three siblings homozygous for CSF1R variant c.1969 + 115_1969 + 116del to expand the phenotype of “brain abnormalities, neurodegeneration, and dysosteosclerosis” (BANDDOS) and discuss its link with “adult leukoencephalopathy with axonal spheroids and pigmented glia” (ALSP), caused by heterozygous CSF1R variants. We evaluated medical, radiological, and laboratory findings and reviewed the literature. Patients presented with developmental delay, therapy‐resistant epilepsy, dysmorphic features, and skeletal abnormalities. Secondary neurological decline occurred from 23 years in sibling one and from 20 years in sibling two. Brain imaging revealed multifocal white matter abnormalities and calcifications during initial disease in siblings two and three. Developmental brain anomalies, seen in all three, were most severe in sibling two. During neurological decline in siblings one and two, the leukoencephalopathy was progressive and had the MRI appearance of ALSP. Skeletal survey revealed osteosclerosis, most severe in sibling three. Blood markers, monocytes, dendritic cell subsets, and T‐cell proliferation capacity were normal. Literature review revealed variable initial disease and secondary neurological decline. BANDDOS presents with variable dysmorphic features, skeletal dysplasia, developmental delay, and epilepsy with on neuro‐imaging developmental brain anomalies, multifocal white matter abnormalities, and calcifications. Secondary neurological decline occurs with a progressive leukoencephalopathy, in line with early onset ALSP. Despite the role of CSF1R signaling in myeloid development, immune deficiency is absent. Phenotype varies within families; skeletal and neurological manifestations may be disparate.

show abstract

Deletion of a Csf1r enhancer selectively impacts CSF1R expression and development of tissue macrophage populations

Cited by 251 publications

References 81 publications

Transcriptional network analysis of transcriptomic diversity in resident tissue macrophages and dendritic cells in the mouse mononuclear phagocyte system

Transcriptional network analysis of transcriptomic diversity in resident tissue macrophages and dendritic cells in the mouse mononuclear phagocyte system

A Pathologically Friendly Strategy for Determining the Organ‐specific Spatial Tumor Microenvironment Topology in Lung Adenocarcinoma Through the Integration of snRandom‐seq and Imaging Mass Cytometry

Leukoencephalopathy with calcifications, developmental brain abnormalities and skeletal dysplasia due to homozygosity for a hypomorphic CSF1R variant: A report of three siblings

Contact Info

Product

Resources

About