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A zebrafish model of Granulin deficiency reveals essential roles in myeloid cell differentiation

ABSTRACT: A zebrafish model of Granulin deficiency reveals essential roles in myeloid cell differentiation

PROVIDER: PRJNA649208 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12338624.fastq.gz	Fastqsanger.gz
	SRR12338625.fastq.gz	Fastqsanger.gz
	SRR12338626.fastq.gz	Fastqsanger.gz
	SRR12338627.fastq.gz	Fastqsanger.gz
	SRR12338628.fastq.gz	Fastqsanger.gz

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A zebrafish model of Granulin deficiency reveals essential roles in myeloid cell differentiation

Project description:Granulin (GRN) is a pleiotropic protein involved in inflammation, wound healing, neurodegenerative disease, and tumorigenesis. These roles in human health have prompted research efforts to utilize Granulin in the treatment of rheumatoid arthritis, frontotemporal dementia, and to enhance wound healing. How granulin contributes to each of these diverse biological functions, however, remains largely unknown. Here, we have uncovered a new role for granulin during myeloid cell differentiation. Using a zebrafish model of granulin deficiency, we reveal that myeloid progenitors are unable to terminally differentiate into neutrophils and macrophages in the absence of granulin a (grna), and fail to express the myeloid genes cebpa, rgs2, lyz, mpx, mpeg1, mfap4, and apoeb. Pathology studies in combination with RNA-sequencing show that in addition to facilitating myeloid cell differentiation, granulin actively inhibits the erythroid program. Moreover, grna deficient myeloid progenitors are incapable of triggering a myelopoiesis emergency response, resulting in decreased recruitment of macrophages to the wound and therefore abnormal healing showing aberrant collagen depositions. Mechanistically, we have performed CUT&RUN for the first time in zebrafish, and identified that Pu.1 directly binds grna enhancers, triggering its expression. Similarly, mammalian granulin is also upregulated in myeloid cells, and its expression is controlled by the myeloid transcription factors PU.1 and IRF8, demonstrating a conserved regulatory mechanism among the zebrafish and mammalian genes. Altogether, our findings uncover a previously unrecognized role for granulin during myeloid cell differentiation, opening a new field of study that will help elucidate how granulin impacts inflammation, wound healing, tumor progression, and neurodegenerative disease.

2020-07-28 | GSE155258 | GEO

A zebrafish model of granulin deficiency reveals essential roles in myeloid cell differentiation.

Project description:Granulin is a pleiotropic protein involved in inflammation, wound healing, neurodegenerative disease, and tumorigenesis. These roles in human health have prompted research efforts to use granulin to treat rheumatoid arthritis and frontotemporal dementia and to enhance wound healing. But how granulin contributes to each of these diverse biological functions remains largely unknown. Here, we have uncovered a new role for granulin during myeloid cell differentiation. We have taken advantage of the tissue-specific segregation of the zebrafish granulin paralogues to assess the functional role of granulin in hematopoiesis without perturbing other tissues. By using our zebrafish model of granulin deficiency, we revealed that during normal and emergency myelopoiesis, myeloid progenitors are unable to terminally differentiate into neutrophils and macrophages in the absence of granulin a (grna), failing to express the myeloid-specific genes cebpa, rgs2, lyz, mpx, mpeg1, mfap4, and apoeb. Functionally, macrophages fail to recruit to the wound, resulting in abnormal healing. Our CUT&RUN experiments identify Pu.1, which together with Irf8, positively regulates grna expression. In vivo imaging and RNA sequencing experiments show that grna inhibits the expression of gata1, leading to the repression of the erythroid program. Importantly, we demonstrated functional conservation between the mammalian granulin and the zebrafish ortholog grna. Our findings uncover a previously unrecognized role for granulin during myeloid cell differentiation, which opens a new field of study that can potentially have an impact on different aspects of human health and expand the therapeutic options for treating myeloid disorders such as neutropenia or myeloid leukemia.

| S-EPMC7876888 | biostudies-literature

TREM1 deficiency alters the tumor myeloid landscape

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Pediatric Study to Evaluate Risk of Developing Essential Fatty Acid Deficiency When Receiving Clinolipid or Standard-of-Care Lipid Emulsion

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TREM1 deficiency alters the tumor myeloid landscape

Project description:TREM1 deficiency alters the tumor myeloid landscape

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The proteomics effects of HSP60 chaperone deficiency in zebrafish larvae

Project description:To understand the effects of Hsp60 deficiency in developing vertebrates, we generated CRISPR/Cas9-mediated hspd1 knockout zebrafish lines by targeting exon 2 to induce a frameshift mutation. We selected an allele with a 56 base pair deletion inducing a frameshift mutation leading to loss of protein functions. We examined the proteome changes in zebrafish larvae at 5 days post fertilization (DPF). Wildtype control and hspd1-/- larvae at 5dpf, were analyzed by TMT and nanoLC-MS/MS based proteomcis. For this purpose, we studied five pools from each genotype, and each pool consisted of five larvae.

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Project description:This will be a descriptive study designed to evaluate the propensity for hospitalized pediatric patients treated adequately with Clinolipid or standard of care (Intralipid) from 7 up to 90 days to develop Essential Fatty Acid Deficiency (EFAD). Additionally, this study design will evaluate the safety and efficacy of using Clinolipid or Intralipid in a pediatric population.

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Distinct GAB2 signaling pathways are essential for myeloid and lymphoid transformation and leukemogenesis by BCR-ABL1

Project description:Tyrosine kinase inhibitors (TKIs) directed against BCR-ABL1, the product of the Philadelphia (Ph) chromosome, have revolutionized treatment of patients with chronic myeloid leukemia (CML). However, acquired resistance to TKIs is a significant clinical problem in CML, and TKI therapy is much less effective against Ph+ B-cell acute lymphoblastic leukemia (B-ALL). BCR-ABL1, via phosphorylated Tyr177, recruits the adapter GAB2 as part of a GRB2/GAB2 complex. We showed previously that GAB2 is essential for BCR-ABL1-evoked myeloid transformation in vitro. Using a genetic strategy and mouse models of CML and B-ALL, we show here that GAB2 is essential for myeloid and lymphoid leukemogenesis by BCR-ABL1. In the mouse model, recipients of BCR-ABL1-transduced Gab2-/- bone marrow failed to develop CML-like myeloproliferative neoplasia. Leukemogenesis was restored by expression of GAB2 but not by GAB2 mutants lacking binding sites for its effectors PI3K or SHP2. GAB2 deficiency also attenuated BCR-ABL1-induced B-ALL, but only the SHP2 binding site was required. The SHP2 and PI3K binding sites were differentially required for signaling downstream of GAB2. Hence, GAB2 transmits critical transforming signals from Tyr177 to PI3K and SHP2 for CML pathogenesis, whereas only the GAB2-SHP2 pathway is essential for lymphoid leukemogenesis. Given that GAB2 is dispensable for normal hematopoiesis, GAB2 and its effectors PI3K and SHP2 represent promising targets for therapy in Ph+ hematologic neoplasms. RNA-Seq expression profiling of 6 mouse bone marrow samples: 3 GAB2 WT (+/+) and 3 GAB2 NULL (-/-)

2016-01-17 | E-GEOD-75615 | biostudies-arrayexpress

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