Single Transcriptional Factor (PU.1) Efficiently Leads Human iPS Cells to Functional Microglia
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE178284 | GEO | 2022/07/07
REPOSITORIES: GEO
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Project description:Single Transcriptional Factor (PU.1) Efficiently Leads Human iPS Cells to Functional Microglia
| PRJNA738361 | ENA
Project description:More than forty loci contribute to genetic risk for Alzheimer’s disease (AD). These risk alleles are enriched in myeloid cell enhancers suggesting that microglia, the brain-resident macrophages, contribute to AD risk. We have previously identified SPI1/PU.1, a master regulator of myeloid cell development in the brain and periphery, as a genetic risk factor for AD. Higher expression of SPI1 is associated with increased risk for AD, while lower expression is protective. To investigate the molecular and cellular phenotypes associated with higher and lower expression of PU.1 in microglia, we used stable overexpression and knock-down of PU.1 in BV2, an immortalized mouse microglial cell line. Transcriptome analysis suggests that reduced PU.1 expression suppresses expression of homeostatic genes similar to the disease-associated microglia response to amyloid plaques in mouse models of AD. Moreover, PU.1 knock-down resulted in activation of protein translation, antioxidant action and cholesterol/lipid metabolism pathways with a concomitant decrease of pro-inflammatory gene expression. PU.1 overexpression upregulated and knock-down downregulated phagocytic uptake in BV2 cells independent of the nature of the engulfed material. However, cells with reduced PU.1 expression retained their ability to internalize myelin similar to control albeit with a delay, which aligns with their anti-inflammatory profile. Here we identified several microglial responses that are modulated by PU.1 expression levels and propose that risk association of PU.1 to AD is driven by increased pro-inflammatory response due to increased viability of cells under cytotoxic conditions. In contrast, low expression of PU.1 leads to increased cell death under cytotoxic conditions accompanied by reduced pro-inflammatory signaling that decreased A1 reactive astrocytes signature supporting the protective effect of SPI1 genotype in AD. These findings inform future in vivo validation studies and design of small molecule screens for therapeutic discovery in AD.
2020-12-07 | GSE162526 | GEO
Project description:We characterized Pu-miR172d, a miRNA that negatively regulates stomatal differentiation in Populus ussuriensis. Overexpression of Pu-miR172d significantly decreased stomatal density in P. ussuriensis. Molecular analysis indicated that PuGTL1 as a major target of Pu-miR172d by cleavage. Moreover, chimeric dominant repressor version of PuGTL1 (PuGTL1-SRDX) lines resembled the Pu-miR172d overexpression (Pu-miR172d-OE) lines, resulting in reduced stomatal density, net photosynthetic rate, stomatal conductance, transpiration and enhanced instantaneous water use efficiency, and thus improving tolerance to drought stress. QRT-PCR analysis showed that PuSDD1 transcript abundance in young leaves of PuGTL1-SRDX and Pu-miR172d-OE plants compared to WT plants, suggesting that Pu-miR172d positively regulates PuSDD1 expression through repression of PuGTL1. RNA-seq analysis showed Pu-miR172d overexpression significantly reduced the expression of many genes related to photosynthesis under drought stress. Overall, the present results demonstrate that Pu-miR172d/PuGTL1/PuSDD1 module plays an important role in stomatal differentiation and regulate WUE, illustrating its capacity for engineering drought tolerance improvement in poplar under future drier environments.
2022-06-13 | GSE133658 | GEO
Project description:Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized by progressive decline of cognitive ability. An important component of AD, and other chronic neurodegenerative diseases, is generation of an innate inflammatory response within the CNS, characterized by activation of microglia, the resident immune cells of the brain. Transcription factor PU.1 has been known to play an important role in myeloid and lymphoid cell development, however its function in microglia and how it contributes to disease pathology is not well understood. Using transcriptional and chromatin state profiles during AD-like pathology in the CK-p25 mouse model of neurodegeneration, we showed that PU.1 specifically targets noncoding regions which regulate expression changes of immune response genes during AD, suggesting it may act as master regulator of microglia activation. Here, we examine the role of PU.1 in neurodegeneration by using a conditional knockout (cKO) cassette (Cx3cr1CreER+/-) to inducibly deplete PU.1 from microglia in the CK-p25 mouse model of neurodegeneration. We found that knocking out PU.1 rescues multiple neurodegenerative phenotypes. Specifically, PU.1 inhibition reduces neurodegeneration-specific increase in microglia cell number, improves neuronal survival and reverses functional synaptic plasticity deficits in the hippocampus of the CK-p25 mouse.
2021-01-01 | GSE117868 | GEO
Project description:Microglia are versatile regulators in brain development and disorders. Emerging evidence links miRNA-mediated regulation to microglial function; however, the exact underlying mechanism remains largely unknown. Here, we discover that miR-137, a neuropsychiatric disorders-associated miRNA, is abundant in the microglial nucleus and exhibits unexpected epigenetic functions in maintaining the global transcriptomic state, core properties, and functions of microglia. Mechanistically, microglial Mir137 deletion increases the accessibility of chromatin, which harbors binding motifs of microglial master transcription factor Pu.1. Our biochemical and bioinformatics analyses suggest that miR-137 can interact with Pu.1, thus influencing Pu.1-mediated gene expression. Importantly, we find that increased Pu.1 binding upregulates the target gene Jdp2, and Jdp2 knockdown markedly suppresses the impaired cellular phenotypes in Mir137 knockout microglia. Collectively, our study provides evidence supporting a notion that miR-137 acts as an epigenetic regulator, and this microglia-specific function is essential to maintain normal adult brain function.
2024-02-22 | GSE254802 | GEO
Project description:Impairment of microglial clearance activity contributes to beta-amyloid (Aβ) pathology in Alzheimer disease (AD). While the transcriptome profile of microglia directs microglial functions, how the microglial transcriptome can be regulated to alleviate AD pathology is largely unknown. Here, we show that injection of interleukin (IL)-33 in an AD transgenic mouse model ameliorates Aβ pathology by reprogramming microglial epigenetic and transcriptomic profiles to induce a microglial subpopulation with enhanced phagocytic activity. These IL-33–responsive microglia (IL-33RM) express distinct transcriptome signature, highlighted by major histocompatibility complex class II genes, and restored homeostatic signature genes. IL-33–induced remodeling of chromatin accessibility and PU.1 transcription factor binding at the signature genes of IL-33RM control their transcriptome reprogramming. Specifically, disrupting PU.1–DNA interaction abolishes the microglial state transition and Aβ clearance induced by IL-33. Thus, we define a PU.1-dependent transcriptional pathway that drives the IL-33–induced functional state transition of microglia, resulting in enhanced Aβ clearance.
2020-05-01 | GSE147495 | GEO
Project description:PU.1 is a prototype master transcription factor (TF) of hematopoietic cell differentiation with diverse roles in different lineages. Analysis of its genome-wide binding pattern across PU.1 expressing cell types revealed manifold cell type-specific binding patterns. They are not consistent with the epigenetic and chromatin constraints to PU.1 binding observed in vitro, suggesting that PU.1 requires auxiliary factors to access DNA in vivo. Using a model of transient mRNA expression we show that PU.1 induction leads to the extensive remodeling of chromatin, redistribution of partner transcription factors and rapid initiation of a myeloid gene expression program in heterologous cell types. By probing PU.1 mutants for defects in chromatin access and screening for PU.1 proximal proteins in vivo, we found that its N-terminal acidic domain was required for the recruitment of SWI/SNF remodeling complexes, de novo chromatin access and stable binding as well as the redistribution of partner TFs.
2019-11-20 | PXD013167 | Pride
Project description:PU.1 is an Ets family transcription factor that is essential for the differentiation of both myeloid and lymphoid cells. PU.1 is down-regulated in classical Hodgkin lymphoma cells via methylation of the PU.1 promoter. To evaluate whether down-regulation of PU.1 is essential for the growth of cHL cells, we generated L428 derived cell lines conditionally express PU.1 by tet-off system (designated L428tetPU.1). Conditonally expressed PU.1 by tetracycline removal induced complete growth arrest and apoptosis in L428 cells. To elucidate the mechanisms underlying cell cycle arrest and apoptosis induced by PU.1, we compared gene expression profiles of L428tetPU.1 cells 0, 1 and 3 days after PU.1 induction, by DNA microarray. We extracted total RNA from L428tetPU.1 cells 0, 1 and 3 days after PU.1 induction by tetracycline removal. We compared gene expression profiles of KL428tetPU.1 cells 0, 1 and 3 days after PU.1 induction using DNA microarray analysis. 4 independent experiments were performed with each RNA samples.
2012-11-22 | E-GEOD-42437 | biostudies-arrayexpress
Project description:PU.1 is an Ets family transcription factor that is essential for the differentiation of both myeloid and lymphoid cells. PU.1 is down-regulated in classical Hodgkin lymphoma cells via methylation of the PU.1 promoter. To evaluate whether down-regulation of PU.1 is essential for the growth of cHL cells, we generated KM-H2 derived cell lines conditionally express PU.1 by tet-off system (designated KM-H2tetPU.1). Conditonally expressed PU.1 by tetracycline removal induced complete growth arrest and apoptosis in KM-H2 cells. To elucidate the mechanisms underlying cell cycle arrest and apoptosis induced by PU.1, we compared gene expression profiles of KM-H2tetPU.1 cells 0, 1 and 3 days after PU.1 induction, by DNA microarray. We extracted total RNA from KM-H2tetPU.1 cells 0, 1 and 3 days after PU.1 induction by tetracycline removal. We compared gene expression profiles of KM-H2tetPU.1 cells 0, 1 and 3 days after PU.1 induction using DNA microarray analysis. 4 independent experiments were performed with each RNA samples.
2012-11-22 | E-GEOD-42440 | biostudies-arrayexpress