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Inactivation of the nuclear interacting SET domain protein 1 (NSD1) impairs GATA1-regulated erythroid differentiation and causes erythroleukemia.

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE136811 | GEO | 2020/04/07

REPOSITORIES: GEO

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Nuclear interacting SET domain protein 1 inactivation impairs GATA1-regulated erythroid differentiation and causes erythroleukemia.

Project description:The nuclear receptor binding SET domain protein 1 (NSD1) is recurrently mutated in human cancers including acute leukemia. We show that NSD1 knockdown alters erythroid clonogenic growth of human CD34+ hematopoietic cells. Ablation of Nsd1 in the hematopoietic system of mice induces a transplantable erythroleukemia. In vitro differentiation of Nsd1-/- erythroblasts is majorly impaired despite abundant expression of GATA1, the transcriptional master regulator of erythropoiesis, and associated with an impaired activation of GATA1-induced targets. Retroviral expression of wildtype NSD1, but not a catalytically-inactive NSD1N1918Q SET-domain mutant induces terminal maturation of Nsd1-/- erythroblasts. Despite similar GATA1 protein levels, exogenous NSD1 but not NSDN1918Q significantly increases the occupancy of GATA1 at target genes and their expression. Notably, exogenous NSD1 reduces the association of GATA1 with the co-repressor SKI, and knockdown of SKI induces differentiation of Nsd1-/- erythroblasts. Collectively, we identify the NSD1 methyltransferase as a regulator of GATA1-controlled erythroid differentiation and leukemogenesis.

| S-EPMC7293310 | biostudies-literature

Inactivation of the nuclear interacting SET domain protein 1 (NSD1) impairs GATA1-regulated erythroid differentiation and causes erythroleukemia

Project description:Nuclear receptor binding SET domain protein 1 (NSD1) is recurrently mutated in human cancers including acute leukemia. We found that NSD1 knockdown altered erythroid clonogenic growth of human CD34+ hematopoietic cells. Ablation of Nsd1 in the hematopoietic system induced a transplantable erythroleukemia in mice. Despite abundant expression of the transcriptional master regulator GATA1, in vitro differentiation of Nsd1-/- erythroblasts was majorly impaired associated with reduced activation of GATA1-induced targets, while GATA1-repressed target genes were less affected. Retroviral expression of wildtype Nsd1, but not a catalytically-inactive Nsd1N1918Q SET-domain mutant induced terminal maturation of Nsd1-/- erythroblasts. Despite similar GATA1 levels, exogenous Nsd1 but not Nsd1N1918Q significantly increased GATA1 chromatin occupancy and target gene activation. Notably, Nsd1 expression reduced the association of GATA1 with the co-repressor SKI, and knockdown of SKI induced differentiation of Nsd1-/- erythroblasts. Collectively, we identified the NSD1 methyltransferase as a novel regulator of GATA1-controlled erythroid differentiation and leukemogenesis.

2020-04-08 | PXD017657 | Pride

Inactivation of the nuclear interacting SET domain protein 1 (NSD1) impairs GATA1-regulated erythroid differentiation and causes erythroleukemia. NSD1 Add-back experiment, mRNASeq cultured erythroblasts.

Project description:In vitro differentiation of Nsd1-/- erythroblasts with retroviral expression of wildtype Nsd1, or a catalytically-inactive Nsd1N1918Q SET-domain

2020-04-07 | GSE136810 | GEO

Project description:In vitro differentiation of Nsd1-/- erythroblasts with retroviral expression of wildtype Nsd1, or a catalytically-inactive Nsd1N1918Q SET-domain

2020-04-07 | GSE136808 | GEO

Inactivation of the nuclear interacting SET domain protein 1 (NSD1) impairs GATA1-regulated erythroid differentiation and causes erythroleukemia. KO experiement, mRNASeq whole bone-marrow.

Project description:Bone marrow of lin-neg erythroblasts either diseased Nsd1-/- or healthy Nsd1fl/fl

2020-04-07 | GSE136809 | GEO

Inactivation of the nuclear interacting SET domain protein 1 (NSD1) impairs GATA1-regulated erythroid differentiation and causes erythroleukemia.

Project description:Inactivation of the nuclear interacting SET domain protein 1 (NSD1) impairs GATA1-regulated erythroid differentiation and causes erythroleukemia.

| PRJNA563705 | ENA

Project description:Inactivation of the nuclear interacting SET domain protein 1 (NSD1) impairs GATA1-regulated erythroid differentiation and causes erythroleukemia. NSD1 Add-back experiment, mRNASeq cultured erythroblasts.

| PRJNA563709 | ENA

| PRJNA563707 | ENA

Inactivation of the nuclear interacting SET domain protein 1 (NSD1) impairs GATA1-regulated erythroid differentiation and causes erythroleukemia. KO experiement, mRNASeq whole bone-marrow.

| PRJNA563708 | ENA

FAM122A Inhibits Erythroid Differentiation through GATA1.

Project description:FAM122A is a highly conserved housekeeping gene, but its physiological and pathophysiological roles remain greatly elusive. Based on the fact that FAM122A is highly expressed in human CD71+ early erythroid cells, herein we report that FAM122A is downregulated during erythroid differentiation, while its overexpression significantly inhibits erythrocytic differentiation in primary human hematopoietic progenitor cells and erythroleukemia cells. Mechanistically, FAM122A directly interacts with the C-terminal zinc finger domain of GATA1, a critical transcriptional factor for erythropoiesis, and reduces GATA1 chromatin occupancy on the promoters of its target genes, thus resulting in the decrease of GATA1 transcriptional activity. The public datasets show that FAM122A is abnormally upregulated in patients with ?-thalassemia. Collectively, our results demonstrate that FAM122A plays an inhibitory role in the regulation of erythroid differentiation, and it would be a potentially therapeutic target for GATA1-related dyserythropoiesis or an important regulator for amplifying erythroid cells ex vivo.

| S-EPMC7486200 | biostudies-literature

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