A Nuclear factor I-X mediated regulatory network governs the balance of hematopoietic stem and progenitor cells during hematopoiesis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE166922 | GEO | 2022/12/02
REPOSITORIES: GEO
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Project description:Hematopoietic stem cells are both necessary and sufficient to sustain the complete blood system of vertebrates. Here we show that Nfix, a member of the nuclear factor I (Nfi) family of transcription factors, is highly expressed by hematopoietic stem and progenitor cells (HSPC) of murine adult bone marrow. Although shRNA mediated knockdown of Nfix expression in Lineage-Sca-1+c-Kit+ HSPC had no effect on in vitro cell growth or viability, Nfix-depleted HSPC displayed a significant loss of colony forming potential, as well as short- and long-term in vivo hematopoietic repopulating activity. Analysis of recipient mice 4-20 days post-transplant revealed that Nfix-depleted HSPC establish in the bone marrow but fail to persist due to increased apoptotic cell death. Gene expression profiling of Nfix-depleted HSPC reveals that loss of Nfix expression in HSPC is concomitant with a decrease in the expression of multiple genes known to be important for HSPC survival, such as Erg, Mecom, Mpl and Prdm16. These data reveal that Nfix is a novel regulator of HSPC survival post-transplantation and establish, for the first time, a role for Nfi genes in the regulation of this cellular compartment. 3 NFIX depleted samples are compared to 3 wt samples
2013-09-05 | E-GEOD-45492 | biostudies-arrayexpress
Project description:Hematopoietic stem cells are both necessary and sufficient to sustain the complete blood system of vertebrates. Here we show that Nfix, a member of the nuclear factor I (Nfi) family of transcription factors, is highly expressed by hematopoietic stem and progenitor cells (HSPC) of murine adult bone marrow. Although shRNA mediated knockdown of Nfix expression in Lineage-Sca-1+c-Kit+ HSPC had no effect on in vitro cell growth or viability, Nfix-depleted HSPC displayed a significant loss of colony forming potential, as well as short- and long-term in vivo hematopoietic repopulating activity. Analysis of recipient mice 4-20 days post-transplant revealed that Nfix-depleted HSPC establish in the bone marrow but fail to persist due to increased apoptotic cell death. Gene expression profiling of Nfix-depleted HSPC reveals that loss of Nfix expression in HSPC is concomitant with a decrease in the expression of multiple genes known to be important for HSPC survival, such as Erg, Mecom, Mpl and Prdm16. These data reveal that Nfix is a novel regulator of HSPC survival post-transplantation and establish, for the first time, a role for Nfi genes in the regulation of this cellular compartment.
2013-09-05 | GSE45492 | GEO
Project description:Hematopoietic stem cells sustain life-long blood production. While they are the known cellular origin of aging-associated myeloid malignancies, such as acute myeloid leukemia (AML), mechanisms driving their malignant transformation have remained elusive. Epigenetic dysregulation following acquired loss-of-function mutations of DNA methyl-cytosine dioxygenase Ten-Eleven Translocation-2 (TET2) occurs frequently in the elderly leading to cytosine hypermethylation in and around DNA binding sites of master transcription factors, including PU.1. Here we show that Tet2 deficient hematopoietic stem and progenitor cells (HSPC) undergo malignant transformation upon compromised PU.1 gene regulation. Leukemic stem and progenitor cells show hypermethylation at PU.1 binding sites and fail to activate PU.1-depenent myeloid enhancers, and are hallmarked by a defined signature of impaired genes shared with human AML. Our study demonstrates that Tet2 and PU.1 cooperate in suppressing leukemogenesis in HSPC and establishes a methylation sensitive PU.1-dependent gene network as a unifying feature in acute myeloid leukemia.
2022-07-31 | GSE191052 | GEO
Project description:Hematopoietic stem cells sustain life-long blood production. While they are the known cellular origin of aging-associated myeloid malignancies, such as acute myeloid leukemia (AML), mechanisms driving their malignant transformation have remained elusive. Epigenetic dysregulation following acquired loss-of-function mutations of DNA methyl-cytosine dioxygenase Ten-Eleven Translocation-2 (TET2) occurs frequently in the elderly leading to cytosine hypermethylation in and around DNA binding sites of master transcription factors, including PU.1. Here we show that Tet2 deficient hematopoietic stem and progenitor cells (HSPC) undergo malignant transformation upon compromised PU.1 gene regulation. Leukemic stem and progenitor cells show hypermethylation at PU.1 binding sites and fail to activate PU.1-depenent myeloid enhancers, and are hallmarked by a defined signature of impaired genes shared with human AML. Our study demonstrates that Tet2 and PU.1 cooperate in suppressing leukemogenesis in HSPC and establishes a methylation sensitive PU.1-dependent gene network as a unifying feature in acute myeloid leukemia.
2022-07-31 | GSE194170 | GEO
Project description:Hematopoietic stem cells sustain life-long blood production. While they are the known cellular origin of aging-associated myeloid malignancies, such as acute myeloid leukemia (AML), mechanisms driving their malignant transformation have remained elusive. Epigenetic dysregulation following acquired loss-of-function mutations of DNA methyl-cytosine dioxygenase Ten-Eleven Translocation-2 (TET2) occurs frequently in the elderly leading to cytosine hypermethylation in and around DNA binding sites of master transcription factors, including PU.1. Here we show that Tet2 deficient hematopoietic stem and progenitor cells (HSPC) undergo malignant transformation upon compromised PU.1 gene regulation. Leukemic stem and progenitor cells show hypermethylation at PU.1 binding sites and fail to activate PU.1-depenent myeloid enhancers, and are hallmarked by a defined signature of impaired genes shared with human AML. Our study demonstrates that Tet2 and PU.1 cooperate in suppressing leukemogenesis in HSPC and establishes a methylation sensitive PU.1-dependent gene network as a unifying feature in acute myeloid leukemia.
2022-07-31 | GSE186146 | GEO
Project description:The rapidly expanding information on the structural and functional characteristics of the human genome allows the development of genome-wide approaches to investigate the molecular circuitry wiring the genetic and epigenetic programs of clinically relevant stem/progenitor cells. Here, we define the transcriptional and epigenetic profile of human hematopoietic stem/progenitor cells (HSPC) and their committed, early myeloid and erythroid progeny. Cap Analysis of Gene Expression showed that the transcriptional state is largely maintained in the transition from early hematopoietic stem/progenitors to committed progenitor/precursors. A large fraction of differentially expressed active promoters in each cell type were classified as novel, possibly driving the expression of transcripts involved in HSPC commitment. Unannotated promoters harbored an enhancer chromatin signature, were enriched in cell-specific transcription factor binding sites, and were close to protein-coding cell-specific genes. To obtain a genome-wide description of regulatory regions, we performed ChIP-seq for histone modifications typical of promoters, enhancers and super-enhancers. ChIP-defined promoters were shared by HSPC and committed cells, whereas enhancer usage consistently changed upon commitment, thus indicating that the fine regulation of commitment is carried out by enhancer elements. The expression level of genes targeted by enhancers and super-enhancers was moderately higher in cells actively using these regulatory elements. However, functional annotation of targeted genes showed a low enrichment for cell-specific gene ontology categories. Finally, we used Moloney leukemia virus (MLV) to map functional regions of chromatin. Genomic regions targeted by MLV co-mapped with a fraction of epigenetically defined active regulatory elements, with two-third of MLV integrations falling in enhancers, and one-third in promoters. Most of MLV-targeted regulatory regions were differentially used between HSPC and their committed progeny. Analysis of the expression levels of promoters close to cell-specific MLV-targeted enhancers and functional assays indicated that MLV-defined regulatory regions are bona fide cell-specific enhancers. Finally, gene ontology analyses showed that MLV-targeted genes related to the peculiar cell identity. Overall, this study provided an overview of the differential transcriptional and epigenetic programs of HSPC and committed progenitors and represents a unique source of regulatory regions involved in HSPC commitment.
2016-04-20 | GSE70676 | GEO
Project description:The rapidly expanding information on the structural and functional characteristics of the human genome allows the development of genome-wide approaches to investigate the molecular circuitry wiring the genetic and epigenetic programs of clinically relevant stem/progenitor cells. Here, we define the transcriptional and epigenetic profile of human hematopoietic stem/progenitor cells (HSPC) and their committed, early myeloid and erythroid progeny. Cap Analysis of Gene Expression showed that the transcriptional state is largely maintained in the transition from early hematopoietic stem/progenitors to committed progenitor/precursors. A large fraction of differentially expressed active promoters in each cell type were classified as novel, possibly driving the expression of transcripts involved in HSPC commitment. Unannotated promoters harbored an enhancer chromatin signature, were enriched in cell-specific transcription factor binding sites, and were close to protein-coding cell-specific genes. To obtain a genome-wide description of regulatory regions, we performed ChIP-seq for histone modifications typical of promoters, enhancers and super-enhancers. ChIP-defined promoters were shared by HSPC and committed cells, whereas enhancer usage consistently changed upon commitment, thus indicating that the fine regulation of commitment is carried out by enhancer elements. The expression level of genes targeted by enhancers and super-enhancers was moderately higher in cells actively using these regulatory elements. However, functional annotation of targeted genes showed a low enrichment for cell-specific gene ontology categories. Finally, we used Moloney leukemia virus (MLV) to map functional regions of chromatin. Genomic regions targeted by MLV co-mapped with a fraction of epigenetically defined active regulatory elements, with two-third of MLV integrations falling in enhancers, and one-third in promoters. Most of MLV-targeted regulatory regions were differentially used between HSPC and their committed progeny. Analysis of the expression levels of promoters close to cell-specific MLV-targeted enhancers and functional assays indicated that MLV-defined regulatory regions are bona fide cell-specific enhancers. Finally, gene ontology analyses showed that MLV-targeted genes related to the peculiar cell identity. Overall, this study provided an overview of the differential transcriptional and epigenetic programs of HSPC and committed progenitors and represents a unique source of regulatory regions involved in HSPC commitment.
2016-04-20 | GSE70675 | GEO
Project description:The rapidly expanding information on the structural and functional characteristics of the human genome allows the development of genome-wide approaches to investigate the molecular circuitry wiring the genetic and epigenetic programs of clinically relevant stem/progenitor cells. Here, we define the transcriptional and epigenetic profile of human hematopoietic stem/progenitor cells (HSPC) and their committed, early myeloid and erythroid progeny. Cap Analysis of Gene Expression showed that the transcriptional state is largely maintained in the transition from early hematopoietic stem/progenitors to committed progenitor/precursors. A large fraction of differentially expressed active promoters in each cell type were classified as novel, possibly driving the expression of transcripts involved in HSPC commitment. Unannotated promoters harbored an enhancer chromatin signature, were enriched in cell-specific transcription factor binding sites, and were close to protein-coding cell-specific genes. To obtain a genome-wide description of regulatory regions, we performed ChIP-seq for histone modifications typical of promoters, enhancers and super-enhancers. ChIP-defined promoters were shared by HSPC and committed cells, whereas enhancer usage consistently changed upon commitment, thus indicating that the fine regulation of commitment is carried out by enhancer elements. The expression level of genes targeted by enhancers and super-enhancers was moderately higher in cells actively using these regulatory elements. However, functional annotation of targeted genes showed a low enrichment for cell-specific gene ontology categories. Finally, we used Moloney leukemia virus (MLV) to map functional regions of chromatin. Genomic regions targeted by MLV co-mapped with a fraction of epigenetically defined active regulatory elements, with two-third of MLV integrations falling in enhancers, and one-third in promoters. Most of MLV-targeted regulatory regions were differentially used between HSPC and their committed progeny. Analysis of the expression levels of promoters close to cell-specific MLV-targeted enhancers and functional assays indicated that MLV-defined regulatory regions are bona fide cell-specific enhancers. Finally, gene ontology analyses showed that MLV-targeted genes related to the peculiar cell identity. Overall, this study provided an overview of the differential transcriptional and epigenetic programs of HSPC and committed progenitors and represents a unique source of regulatory regions involved in HSPC commitment.
2016-04-20 | GSE64888 | GEO
Project description:The rapidly expanding information on the structural and functional characteristics of the human genome allows the development of genome-wide approaches to investigate the molecular circuitry wiring the genetic and epigenetic programs of clinically relevant stem/progenitor cells. Here, we define the transcriptional and epigenetic profile of human hematopoietic stem/progenitor cells (HSPC) and their committed, early myeloid and erythroid progeny. Cap Analysis of Gene Expression showed that the transcriptional state is largely maintained in the transition from early hematopoietic stem/progenitors to committed progenitor/precursors. A large fraction of differentially expressed active promoters in each cell type were classified as novel, possibly driving the expression of transcripts involved in HSPC commitment. Unannotated promoters harbored an enhancer chromatin signature, were enriched in cell-specific transcription factor binding sites, and were close to protein-coding cell-specific genes. To obtain a genome-wide description of regulatory regions, we performed ChIP-seq for histone modifications typical of promoters, enhancers and super-enhancers. ChIP-defined promoters were shared by HSPC and committed cells, whereas enhancer usage consistently changed upon commitment, thus indicating that the fine regulation of commitment is carried out by enhancer elements. The expression level of genes targeted by enhancers and super-enhancers was moderately higher in cells actively using these regulatory elements. However, functional annotation of targeted genes showed a low enrichment for cell-specific gene ontology categories. Finally, we used Moloney leukemia virus (MLV) to map functional regions of chromatin. Genomic regions targeted by MLV co-mapped with a fraction of epigenetically defined active regulatory elements, with two-third of MLV integrations falling in enhancers, and one-third in promoters. Most of MLV-targeted regulatory regions were differentially used between HSPC and their committed progeny. Analysis of the expression levels of promoters close to cell-specific MLV-targeted enhancers and functional assays indicated that MLV-defined regulatory regions are bona fide cell-specific enhancers. Finally, gene ontology analyses showed that MLV-targeted genes related to the peculiar cell identity. Overall, this study provided an overview of the differential transcriptional and epigenetic programs of HSPC and committed progenitors and represents a unique source of regulatory regions involved in HSPC commitment.
2016-04-20 | GSE70674 | GEO
Project description:Human erythropoiesis is a stepwise process in which multipotent hematopoietic stem/progenitor cells (HSPC) are initially committed towards the erythroid lineage and then differentiated into mature erythroid precursors. Commitment and differentiation are tightly regulated by the coordinated action of a host of transcription factors, including GATA2 and GATA1. Although the role of GATA factors in erythropoiesis has been extensively studied, how they regulate transcription from early to late stages of human erythropoiesis still remains underinvestigated. Here, we investigated GATA-mediated transcriptional regulation along erythroid development through the integrative analysis of gene expression, chromatin modifications, and GATA factors’ binding in human HSPC, early erythroid progenitors, and late precursors. A progressive loss of H3K27 acetylation, a mark of active regulatory elements, and diminished usage of active enhancers and super-enhancers was observed during erythroid lineage commitment and differentiation. We found that GATA factors mediate the transcriptional changes occurring during erythropoiesis through a stage-specific interplay with regulatory elements. In particular, GATA1 binds different sets of regulatory elements in early progenitors and late precursors, and controls the transcription of distinct genes in commitment and differentiation. By Chromosome Conformation Capture and CRISPR/Cas9-mediated genome editing, we demonstrated that the binding of GATA1 to a stage-specific super-enhancer sustains the expression of the stem cell factor receptor KIT in human erythroid progenitors. This study provides insights into the dynamics of epigenetic and transcriptional interactions during erythroid development and highlights a new layer of GATA1-mediated regulation in erythropoiesis.
2020-04-10 | GSE124164 | GEO