Bhlhe40 mediates tissue-specific control of macrophage proliferation in homeostasis and type 2 immunity
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ABSTRACT:
PROVIDER: PRJNA517405 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8494734.fastq.gz | Fastqsanger.gz | |||
| SRR8494735.fastq.gz | Fastqsanger.gz | |||
| SRR8494736.fastq.gz | Fastqsanger.gz | |||
| SRR8494737.fastq.gz | Fastqsanger.gz |
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Project description:Most tissue-resident macrophage populations develop during embryogenesis, self-renew in the steady state and expand during type 2 immunity. Whether shared mechanisms regulate the proliferation of macrophages in homeostasis and disease is unclear. Here we found that the transcription factor Bhlhe40 was required in a cell-intrinsic manner for the self-renewal and maintenance of large peritoneal macrophages (LPMs), but not that of other tissue-resident macrophages. Bhlhe40 was necessary for the proliferation, but not the polarization, of LPMs in response to the cytokine IL-4. During infection with the helminth Heligmosomoides polygyrus bakeri, Bhlhe40 was required for cell cycling of LPMs. Bhlhe40 repressed the expression of genes encoding the transcription factors c-Maf and Mafb and directly promoted expression of transcripts encoding cell cycle-related proteins to enable the proliferation of LPMs. In LPMs, Bhlhe40 bound to genomic sites co-bound by the macrophage lineage-determining factor PU.1 and to unique sites, including Maf and loci encoding cell-cycle-related proteins. Our findings demonstrate a tissue-specific control mechanism that regulates the proliferation of resident macrophages in homeostasis and type 2 immunity.
| S-EPMC6531324 | biostudies-literature
Project description:Most tissue-resident macrophage populations develop during embryogenesis, self-renew in the steady state, and can expand during type 2 immunity. Whether shared mechanisms regulate macrophage proliferation in homeostasis and disease is unclear. We found that the transcription factor Bhlhe40 was cell-intrinsically required in large peritoneal macrophages (LPMs) for self-renewal and maintenance, but was not required in other resident macrophages. Bhlhe40 was selectively necessary in LPMs for proliferation, but not polarization, in response to IL-4. During a helminth infection, Bhlhe40 was required for normal LPM cell cycling. Bhlhe40 repressed the expression of Maf and Mafb and directly promoted expression of cell cycle-related transcripts to enable proliferation of LPMs. Genomic sites bound by Bhlhe40 in LPMs included some co-bound by the macrophage lineage-determining factor PU.1 and others uniquely bound by Bhlhe40, including Maf and cell cycle-related loci. Our findings demonstrate a tissue-specific control mechanism regulating resident macrophage proliferation in homeostasis and type 2 immunity.
2019-04-30 | GSE125727 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2019-04-30 | GSE125730 | GEO
Project description:BHLHE40 is a member of basic helix-loop-helix family transcription factors and highly conserved across mammalian species. Structurally, BHLHE40 consists of an N-terminal basic DNA binding domain, a helix-loop-helix dimerization domain, and a protein interacting orange domain. BHLHE40 is known to regulate a wide variety of essential cellular processes, including cell cycle, cellular proliferation, programmed cell death, cellular development and differentiation, and circadian rhythm. Here we isolated thioglycollate-elicited peritoneal macrophages (PMs) from 3 mice per group (Lyz2cre and Lyz2cre:BHLHE40Fl/Fl). These cells were stimulated with 100ng/ml LPS for 4 hours. Total RNA was isolated and subjected to RNAseq analyses.
2021-09-24 | GSE176174 | GEO
Project description:Most tissue-resident macrophage populations develop during embryogenesis, self-renew in the steady state, and can expand during type 2 immunity. Whether shared mechanisms regulate macrophage proliferation in homeostasis and disease is unclear. We found that the transcription factor Bhlhe40 was cell-intrinsically required in large peritoneal macrophages (LPMs) for self-renewal and maintenance, but was not required in other resident macrophages. Bhlhe40 was selectively necessary in LPMs for proliferation, but not polarization, in response to IL-4. During a helminth infection, Bhlhe40 was required for normal LPM cell cycling. Bhlhe40 repressed the expression of Maf and Mafb and directly promoted expression of cell cycle-related transcripts to enable proliferation of LPMs. Genomic sites bound by Bhlhe40 in LPMs included some co-bound by the macrophage lineage-determining factor PU.1 and others uniquely bound by Bhlhe40, including Maf and cell cycle-related loci. Our findings demonstrate a tissue-specific control mechanism regulating resident macrophage proliferation in homeostasis and type 2 immunity.
2019-04-30 | GSE125729 | GEO
Project description:Microarray data on TH17 cells from Bhlhe40-GFP reporter mice We used microarrays to detail the global programme of gene expression in polarized Bhlhe40-GFPneg and Bhlhe40-GFPpos TH17 cells Purified naïve CD4 T cells from spleen were polarized under TH17 condition in vitro. On day 4, cells were stimulated with PMA and ionomycin, and sorted by their Bhlhe40-GFP expression prior to microarray analysis
2016-01-04 | E-GEOD-75407 | biostudies-arrayexpress
Project description:Tissues in multicellular organisms are ‘serviced’ by resident macrophages, which perform both generic and tissue-specific functions. The latter relies on unique tissue-specific molecular programs induced by signals from the microenvironment and executed through a combinatorial action of tissue-specific and broadly expressed transcriptional regulators. Here, we identify the transcription factors Bhlhe40 and Bhlhe41 as novel regulators of alveolar macrophages (AMs) – a population that provides the first line of immune defense and executes homeostatic functions in lung alveoli. In the absence of these factors, AMs exhibited decreased proliferation that resulted in a severe disadvantage of knockout AMs in a competitive setting. Gene expression analyses revealed a broad cell-intrinsic footprint of Bhlhe40/Bhlhe41-deficiency manifested by a downregulation of AM signature genes and induction of signature genes of other macrophage lineages. Genome-wide characterization of Bhlhe40 DNA binding suggested that these transcription factors directly repress the expression of lineage-inappropriate genes in AMs. Taken together, these results identify Bhlhe40 and Bhlhe41 as key regulators of AM self-renewal and guardians of their identity.
2019-07-30 | GSE135018 | GEO
Project description:Microarray data on TH17 cells from Bhlhe40-GFP reporter mice We used microarrays to detail the global programme of gene expression in polarized Bhlhe40-GFPneg and Bhlhe40-GFPpos TH17 cells
2016-01-04 | GSE75407 | GEO
Project description:The androgen receptor (AR) is a therapeutic target of prostate cancer (PCa). Targeted AR therapy commonly uses androgen deprivation therapy (ADT) and AR antagonists to reduce androgen levels and inhibit tumor growth. Surprisingly, treatment with supraphysiological androgen level (SAL) can also inhibit the growth of PCa. SAL (R1881) was shown to induce cellular senescence in PCa. Knockdown of BHLHE40 in C4-2 and LNCaP cell lines indicates that BHLHE40 mediates SAL-induced cellular senescence as a possible tumor suppressive pathway. The RNA-seq from BHLHE40 knocked down C4-2 cells confirmed that BHLHE40 regulates cellular senescence and associated pathways. Interestingly, a large overlap of differentially expressed gene sets was identified between BHLHE40 regulated transcriptome and the SAL-changed transcriptome leading to four classes of up-and downregulated BHLHE40 transcriptome landscapes overlapping with that of AR. Further RNA-seq analyses revealed that the tumor suppressive cyclin G2 (CCNG2) emerged as a novel downstream target of BHLHE40. Knockdown of CCNG2 suggests that it mediates SAL-induced cellular senescence providing evidence of a novel pathway by the AR-BHLHE40-CCNG2 axis to mediate androgen-induced cellular senescence as a novel tumor suppressive pathway in PCa cells.
2024-06-21 | GSE262117 | GEO
Project description:NK cells represent a cellular component of the mammalian innate immune system, and mount rapid responses against viral infection, including the secretion of the potent anti-viral effector cytokine IFN-g. Following mouse cytomegalovirus (MCMV) infection, Bhlhe40 was the most highly induced transcription factor in NK cells among the basic helix-loop-helix family. Bhlhe40 upregulation in NK cells depended upon IL-12 and IL-18 signals, with the promoter of Bhlhe40 enriched for STAT4 and the permissive histone H3K4me3, and STAT4-deficient NK cells showing an impairment of Bhlhe40 induction and diminished H3K4me3. Transcriptomic and protein analysis of Bhlhe40-deficient NK cells revealed a defect in IFN-g production during MCMV infection, resulting in diminished protective immunity following viral challenge. Finally, we provide evidence that Bhlhe40 directly promotes IFN-g by binding throughout the Ifng loci in activated NK cells. Thus, our study reveals how STAT4-mediated control of Bhlhe40 drives protective IFN-g secretion by NK cells during viral infection.
2023-09-13 | GSE242900 | GEO