Chromatin accessibility landscape of cutaneous T cell lymphoma and dynamic response to HDAC inhibitors
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE85853 | GEO | 2017/04/20
SECONDARY ACCESSION(S): PRJNA339552
REPOSITORIES: GEO
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Project description:Various types of HDAC inhibitor are now planned or on going to use against non-Hodgkin’s lymphoma including CTCL. However there is a lack of molecular based evidence not only for which HDACi might be effective to use against advanced CTCL but also for which genes might be pivotal target gene(s) of HDACi. To investigate expression changes of miRNAs by HDACis, we conducted miRNA microarray by using CTCL cell lines.
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Project description:We surveyed the variation and dynamics of active regulatory elements genome-wide in CD4+ T cells, using Assay of Transposase Accessible Chromatin with sequencing (ATAC-seq) in longitudinal samples from healthy volunteers and during T cell activation. We created robust pipelines that enable accurate single molecule counting and allelic discrimination from clinical material. Over 4000 regulatory elements (7.2%) showed reproducible personal variation in activity. Gender was the most significant attributable source of regulome variation. ATAC-seq revealed novel elements that escape X chromosome inactivation and predicted gender-specific gene regulatory networks across autosomes, which coordinately impact genes with immune function. Noisy regulatory elements with personal variation in accessibility are significantly enriched for autoimmune disease loci. Over one third of regulome variation lacked genetic variation in cis, suggesting contributions from environmental or epigenetic factors. These results refine concepts of human individuality and provide foundational reference to compare disease-associated regulomes. We examined chromatin structure using ATAC-seq in purified human CD4+ T cells in 33 samples from 12 healthy donors and 15 samples from 3 patients with cutaneous T cell leukemia (CTCL). For T cell activation (TCA) time course, CD4+ cells from healthy donor 1 isolated as above were stimulated with ionomycin (1 ug/mL) and Phorbol Myristate Acetate (PMA; 20 ng/mL) and collected at 0, 1, 2, 4 hours in duplicate.
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Project description:TOX is a nuclear factor essential for the development of CD4+ T cells in the thymus. TOX is found to be aberrantly up-regulated in the skin biopsies and in the blood CD4+ T cells of cutaneous T cell lymphoma. The goal of this study is to identify potential transcriptional targets of TOX in CTCL by comparison between TOX shRNA transfected CTCL cells (Hut78 and HH) and control CTCL cells. Two color experiment. Lentivirus transduced control vector vs. TOX shRNA vectors on Hut78 and HH cell lines. Biological replicates: 3 control replicates, 3 shRNA tansduced replicates for each cell line.
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Project description:AHI-1 is an oncogene often targeted by provirus insertional mutagenesis in murine leukemias and lymphomas. Aberrant expression of human AHI-1 occurs in cutaneous T-cell lymphoma (CTCL) cells and in CD4+CD7- Sezary cells from patients with Sezary syndrome (SS). Stable knockdown of AHI-1 using retroviral-mediated RNA interference in CTCL cells inhibits their transforming activity in vitro and in vivo. To identify genes involved in AHI-1-mediated transformation, microarray analysis was performed to identify differentially expressed genes in AHI-1 suppressed CTCL cells. Fifteen up-regulated and six down-regulated genes were identified and confirmed by Q-RT-PCR. Seven were further confirmed in a microarray analysis of CD4+CD7- Sezary cells from SS patients. HCK and BIN1 emerged as new candidate cooperative genes, with differential protein expression which correlates with observed transcript changes. Interestingly, changes in HCK phosphorylation and biological response to its inhibitor, dasatinib, were observed in AHI-1 suppressed or overexpressed cells. The tumor suppressor BIN1 physically interacts with MYC in CTCL cells, which also exhibit differential MYC protein expression. In addition, aberrant expression of alternative splicing forms of BIN1 was observed in primary and transformed CTCL cells. These findings indicate that HCK and BIN1 may play critical roles in AHI-1-mediated leukemic transformation of human CTCL cells. Experiment Overall Design: Two groups, each with two subgroups, subgroups having 2 or 3 replicates each
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Project description:<p>Sezary syndrome is a leukemic and aggressive form of cutaneous T-cell lymphoma (CTCL) resulting from the malignant transformation of skin-homing central memory CD4+ T cells. To identify new genetic alterations involved in Sezary syndrome and CTCL transformation we performed whole-exome sequencing of tumor-normal sample pairs from 26 Sezary syndrome and 16 CTCL patients. These analyses revealed a distinctive pattern of somatic copy number alterations in Sezary syndrome including highly prevalent recurrent chromosomal deletions involving the TP53, RB1, PTEN, DNMT3A, and CDKN1B tumor suppressor genes. Mutation analysis identified a broad spectrum of somatic mutations involving key genes involved in epigenetic regulation (TET2, CREBBP, MLL3, BRD9, SMARCA4 and CHD3) and signaling, including mutations in MAPK1, BRAF, CARD11 and PRKG1 driving increased MAPK, NFKB and NFAT activity upon T-cell receptor stimulation. Collectively, our findings provide new insights into the genetics of Sezary syndrome and CTCL and support the development of personalized therapies targeting key oncogenically activated signaling pathways for the treatment of these diseases.</p>
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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
Project description:AHI-1 is an oncogene often targeted by provirus insertional mutagenesis in murine leukemias and lymphomas. Aberrant expression of human AHI-1 occurs in cutaneous T-cell lymphoma (CTCL) cells and in CD4+CD7- Sezary cells from patients with Sezary syndrome (SS). Stable knockdown of AHI-1 using retroviral-mediated RNA interference in CTCL cells inhibits their transforming activity in vitro and in vivo. To identify genes involved in AHI-1-mediated transformation, microarray analysis was performed to identify differentially expressed genes in AHI-1 suppressed CTCL cells. Fifteen up-regulated and six down-regulated genes were identified and confirmed by Q-RT-PCR. Seven were further confirmed in a microarray analysis of CD4+CD7- Sezary cells from SS patients. HCK and BIN1 emerged as new candidate cooperative genes, with differential protein expression which correlates with observed transcript changes. Interestingly, changes in HCK phosphorylation and biological response to its inhibitor, dasatinib, were observed in AHI-1 suppressed or overexpressed cells. The tumor suppressor BIN1 physically interacts with MYC in CTCL cells, which also exhibit differential MYC protein expression. In addition, aberrant expression of alternative splicing forms of BIN1 was observed in primary and transformed CTCL cells. These findings indicate that HCK and BIN1 may play critical roles in AHI-1-mediated leukemic transformation of human CTCL cells. Keywords: Cell type comparison
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Project description:A detailed understanding of the gene-regulatory network in ankylosing spondylitis (AS) is vital for elucidating the mechanisms of AS pathogenesis. Assaying transposase-accessible chromatin in single cell sequencing (scATAC-seq) is a suitable method for revealing such networks. Thus, scATAC-seq was applied to define the landscape of active regulatory DNA in AS. As a result, there was a significant change in the percent of CD8+ T cells in PBMCs, and 37 differentially accessible transcription factor (TF) motifs were identified. T cells, monocytes-1 and dendritic cells were found to be crucial for the IL-17 signaling pathway and TNF signaling pathway, since they had 73 potential target genes regulated by 8 TF motifs with decreased accessibility in AS. Moreover, natural killer cells were involved in AS by increasing the accessibility to TF motifs TEAD1 and JUN to induce cytokine-cytokine receptor interactions. In addition, CD4+ T cells and CD8+ T cells may be vital for altering host immune functions through increasing the accessibility of TF motifs NR1H4 and OLIG (OLIGI and OLIG2), respectively. These results explain clear gene regulatory variation in PBMCs from AS patients, providing a foundational framework for the study of personal regulomes and delivering insights into epigenetic therapy.
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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
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.
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