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Unstranded RNA sequencing data

ABSTRACT: A single hematopoietic stem cell can give rise to all blood cells with remarkable fidelity. Here, we define the chromatin accessibility and transcriptional landscape controlling this process in thirteen primary cell types that traverse the hematopoietic hierarchy. Exploiting the finding that enhancer landscapes better reflect cell identity than mRNA levels, we enable "enhancer cytometry" for accurate enumeration of pure cell types from complex populations. We further reveal the lineage ontogeny of genetic elements linked to diverse human diseases. In acute myeloid leukemia, chromatin accessibility reveals distinctive regulatory evolution in pre-leukemic HSCs (pHSCs), leukemia stem cells, and leukemic blasts. These leukemic cells demonstrate unique lineage infidelity, confirmed by single cell regulomes. We further show that pHSCs have a competitive advantage that is conferred by reduced chromatin accessibility at HOXA9 targets and is associated with adverse patient outcomes. Thus, regulome dynamics can provide diverse insights into human hematopoietic development and disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE74246 | GEO | 2016/06/01

SECONDARY ACCESSION(S): PRJNA299579

REPOSITORIES: GEO

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Unstranded RNA sequencing data

Project description:A single hematopoietic stem cell can give rise to all blood cells with remarkable fidelity. Here, we define the chromatin accessibility and transcriptional landscape controlling this process in thirteen primary cell types that traverse the hematopoietic hierarchy. Exploiting the finding that enhancer landscapes better reflect cell identity than mRNA levels, we enable "enhancer cytometry" for accurate enumeration of pure cell types from complex populations. We further reveal the lineage ontogeny of genetic elements linked to diverse human diseases. In acute myeloid leukemia, chromatin accessibility reveals distinctive regulatory evolution in pre-leukemic HSCs (pHSCs), leukemia stem cells, and leukemic blasts. These leukemic cells demonstrate unique lineage infidelity, confirmed by single cell regulomes. We further show that pHSCs have a competitive advantage that is conferred by reduced chromatin accessibility at HOXA9 targets and is associated with adverse patient outcomes. Thus, regulome dynamics can provide diverse insights into human hematopoietic development and disease. Transcription profiles of hematopoietic and leukemic cell types, assayed using unstranded RNA-seq, across 13 normal hematopoietic cell types and 3 acute myeloid leukemia cell types. The complete data set contains a total of 81 samples.

2016-06-01 | E-GEOD-74246 | biostudies-arrayexpress

Single-cell chromatin accessibility data using scATAC-seq

Project description:A single hematopoietic stem cell can give rise to all blood cells with remarkable fidelity. Here, we define the chromatin accessibility and transcriptional landscape controlling this process in thirteen primary cell types that traverse the hematopoietic hierarchy. Exploiting the finding that enhancer landscapes better reflect cell identity than mRNA levels, we enable "enhancer cytometry" for accurate enumeration of pure cell types from complex populations. We further reveal the lineage ontogeny of genetic elements linked to diverse human diseases. In acute myeloid leukemia, chromatin accessibility reveals distinctive regulatory evolution in pre-leukemic HSCs (pHSCs), leukemia stem cells, and leukemic blasts. These leukemic cells demonstrate unique lineage infidelity, confirmed by single cell regulomes. We further show that pHSCs have a competitive advantage that is conferred by reduced chromatin accessibility at HOXA9 targets and is associated with adverse patient outcomes. Thus, regulome dynamics can provide diverse insights into human hematopoietic development and disease. Single-cell ATAC-seq of LMPPs, Monocytes, LSCs and Luekemic blast cells.

2016-06-01 | E-GEOD-74310 | biostudies-arrayexpress

ATAC-seq data

Project description:A single hematopoietic stem cell can give rise to all blood cells with remarkable fidelity. Here, we define the chromatin accessibility and transcriptional landscape controlling this process in thirteen primary cell types that traverse the hematopoietic hierarchy. Exploiting the finding that enhancer landscapes better reflect cell identity than mRNA levels, we enable "enhancer cytometry" for accurate enumeration of pure cell types from complex populations. We further reveal the lineage ontogeny of genetic elements linked to diverse human diseases. In acute myeloid leukemia, chromatin accessibility reveals distinctive regulatory evolution in pre-leukemic HSCs (pHSCs), leukemia stem cells, and leukemic blasts. These leukemic cells demonstrate unique lineage infidelity, confirmed by single cell regulomes. We further show that pHSCs have a competitive advantage that is conferred by reduced chromatin accessibility at HOXA9 targets and is associated with adverse patient outcomes. Thus, regulome dynamics can provide diverse insights into human hematopoietic development and disease. ATAC-seq profiles of hematopoietic and leukemic cell types, across 13 normal hematopoietic cell types and 3 acute myeloid leukemia cell types. The complete data set contains a total of 132 samples.

2016-06-01 | E-GEOD-74912 | biostudies-arrayexpress

ATAC-seq data

2016-06-01 | GSE74912 | GEO

Single-cell chromatin accessibility data using scATAC-seq

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The alternative Nucleosome Remodeling Factor complex sustains acute myeloid leukemia by regulating the accessibility of insulator regions

Project description:Efficient treatment of Acute Myeloid Leukemia (AML) patients remains a challenge despite recent advances. Here using a CRISPRi screen targeting chromatin factors, we identified BPTF as an essential regulator of AML cell survival. We demonstrate that BPTF forms an alternative NURF chromatin remodeling complex with SMARCA5 and BAP18, which regulates the accessibility of a large set of insulator regions in leukemic cells. This ensures efficient CTCF binding and boundary formation between topologically associated domains that is essential for maintaining the leukemic transcriptional programs. We also demonstrate that the well-studied PHD2-BROMO chromatin reader modules of BPTF, while contributing to complex recruitment to chromatin, are dispensable for leukemic cell growth. Taken together, our results uncover how the alternative NURF complex contributes to leukemia and provide a rationale for its targeting in AML.

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IDH1-mutant preleukemic hematopoietic stem cells can be eliminated by oxphos inhibition

Project description:Rare preleukemic hematopoietic stem cells (pHSCs) harboring only the initiating mutations can be detected at the time of AML diagnosis. pHSCs are likely the origin of leukemia and a potential reservoir for relapse but remain challenging to eradicate. Using primary human samples and gene-editing to model isocitrate dehydrogenase 1 (IDH1) mutant pHSCs, we show biological, transcriptional, and metabolic differences between pHSCs and healthy hematopoietic stem cells (HSCs). We confirm that IDH1 mutations are present in patients with clonal cytopenia of undetermined significance, but not in individuals with clonal hematopoiesis of indeterminate potential, suggesting an inherent defect to fully reconstitute hematopoiesis. Despite giving rise to multilineage engraftment, IDH1-mutant pHSCs exhibited reduced proliferation with a block in differentiation, downregulation of MHC Class II genes and reprogramming of oxphos metabolism. Critically, IDH1-mutant pHSCs showed reduced metabolic activity distinct from normal HSCs and inhibition of oxphos resulted in complete eradication of IDH1-mutant pHSCs but not IDH2-mutant pHSCs or wildtype HSCs. Our results indicate that IDH1-mutant preleukemic clones can be targeted with complex I inhibitors to prevent development and relapse of leukemia.

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Chromatin accessibility promotes hematopoietic and leukemia stem cell activity

Project description:Chromatin organization is a highly orchestrated process that influences gene expression, in part by modulating access of regulatory factors to DNA and nucleosomes. We found that the chromatin accessibility regulator HMGN1, a target of recurrent DNA copy gains in leukemia, controls myeloid differentiation. HMGN1 amplification was associated with increased accessibility, expression, and histone H3K27 acetylation of loci important for hematopoietic stem cell (HSC) function and AML, such as HoxA cluster genes. In vivo, HMGN1 overexpression was linked to decreased quiescence and increased HSC activity in bone marrow transplantation. HMGN1 overexpression also cooperated with the AML-ETO9a fusion oncoprotein to impair myeloid differentiation and enhance leukemia stem cell (LSC) activity. Inhibition of histone acetyltransferases CBP/p300 relieved the HMGN1-associated differentiation block. These data nominate factors that modulate chromatin accessibility as regulators of HSCs and LSCs and suggest that targeting HMGN1 or its downstream effects on histone acetylation could be therapeutically active in AML.

2020-02-25 | PXD017054 | Pride

Chromatin accessibility promotes hematopoietic and leukemia stem cell activity

Project description:Chromatin accessibility promotes hematopoietic and leukemia stem cell activity

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Chromatin accessibility, p300 and histone acetylation define PML-RARalpha- and AML1-ETO-binding sites

Project description:Chromatin accessibility is a key determinant of cell-type-specific gene expression. Here, we have investigated the chromatin architecture of different acute myeloid leukemia (AML) cells and the changes in accessibility when NB4 (APL) cells undergo the process of differentiation. For nuclease-accessible site sequencing (NA-seq; Gargiulo et al. 2009), chromatin-accessible libraries were generated in different AML leukemic cells by using restriction enzymes NlaIII and HpaII. In the case of NB4 cells, accessibility was mapped both before and after treatment with all-trans retinoic acid (ATRA) for 48hr. Differences were observed between the two conditions, and chromatin accessibility was correlated with underlying epigenetic modifications. For validation purposes, NA-seq libraries (using the NlaIII enzyme) were generated in APL and AML M1 patient's blasts. All of the ChIP-seq (Martens et al. 2010) studies were performed in leukemic NB4 and SKNO-1 cells. Supplementary file 'GSE30254_All_accessibleregions_ATRA_NB4_fseq.wig' includes data for Samples GSM749512, GSM749513, GSM749516, and GSM749517. Supplementary file 'GSE30254_All_accessibleregions_untreated_NB4_fseq.wig' includes data for Samples GSM749510, GSM749511, GSM749514, and GSM749515.

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