The Properties of Genome Conformation and Spatial Gene Interaction and Regulation Networks of Normal and Malignant Human Cell Types
Ontology highlight
ABSTRACT: In this work, we generated hundreds of millions of Hi-C paired end sequence reads for three different human cells (RL follicular lymphoma cell line, primary tumor B-cells from an acute lymphoblastic leukemia patient, and MHH-CALL-4 B-cell acute lymphoblastic leukemia cell line) using the Hi-C technique. An in-house Bioinformatics software pipeline was developed and applied to map sequence reads to the human reference genome, producing a large data set of high-quality and high-resolution chromosome contacts. Our computational analysis on these data reveal some interesting properties of human genome conformation, including conformational conservation and variation of the genomes of different cells, intra- and inter-chromosomal interactions, aberrant chromosomal translocation, spatial gene clusters, spatial gene-gene interactions, and spatial gene-regulatory-element interaction. Furthermore, we derived spatial interactions between functional elements (genes, transcription factor binding sites) from the chromosomal interaction data. The data were then used to generate chromosome-/genome-wide gene-gene interaction networks, transcription factor binding site (TFBS) â TFBS networks, and gene-TFBS networks. Remarkably, the connectivity in both networks shows the hallmark features of scale-free networks, suggesting that spatial interactions of gene-gene, gene-TFBS, and TFBS-TFBS in a genome are far from random. Three different human cells (RL follicular lymphoma cell line, primary tumor B-cells from an acute lymphoblastic leukemia patient, and MHH-CALL-4 B-cell acute lymphoblastic leukemia cell line) were analyzed
Project description:In this work, we generated hundreds of millions of Hi-C paired end sequence reads for three different human cells (RL follicular lymphoma cell line, primary tumor B-cells from an acute lymphoblastic leukemia patient, and MHH-CALL-4 B-cell acute lymphoblastic leukemia cell line) using the Hi-C technique. An in-house Bioinformatics software pipeline was developed and applied to map sequence reads to the human reference genome, producing a large data set of high-quality and high-resolution chromosome contacts. Our computational analysis on these data reveal some interesting properties of human genome conformation, including conformational conservation and variation of the genomes of different cells, intra- and inter-chromosomal interactions, aberrant chromosomal translocation, spatial gene clusters, spatial gene-gene interactions, and spatial gene-regulatory-element interaction. Furthermore, we derived spatial interactions between functional elements (genes, transcription factor binding sites) from the chromosomal interaction data. The data were then used to generate chromosome-/genome-wide gene-gene interaction networks, transcription factor binding site (TFBS) – TFBS networks, and gene-TFBS networks. Remarkably, the connectivity in both networks shows the hallmark features of scale-free networks, suggesting that spatial interactions of gene-gene, gene-TFBS, and TFBS-TFBS in a genome are far from random.
Project description:Gene expression profiling (GEP) can reveal characteristic signatures associated with distinct biologic subtypes of acute lymphoblastic leukemia (ALL). We performed GEP on Down syndrome (DS) and comparison non-Down syndrome (NDS) ALL cases to identify biologic differences between these groups. Ficoll-enriched, cryopreserved diagnostic bone marrow samples were obtained from patients with newly diagnosed B-precursor acute lymphoblastic leukemia.
Project description:This SuperSeries is composed of the following subset Series: GSE28460: Expression data from ALL diagnosis and relapse pediatric acute lymphoblastic leukemia cases GSE28461: Promoter methylation data from ALL diagnosis and relapse pediatric acute lymphoblastic leukemia cases Refer to individual Series
Project description:Chromosomal aneuploidy and translocations are hallmarks of acute lymphoblastic leukemia (ALL), but many patients lack a recurring chromosomal alteration. Here we report a recurring interstitial deletion of the pseudoautosomal region 1 of chromosomes X and Y in B-progenitor ALL that results in the expression of a novel fusion that juxtaposes the first non-coding exon of P2RY8 to the coding region of the CRLF2 (cytokine receptor like factor 2, or thymic stromal lymphopoietin receptor) gene. The P2RY8-CRLF2 fusion was identified in 7% of B-ALL cases, and was very common in ALL associated with Down syndrome (55% of cases) and was associated with the presence of JAK mutations. The P2RY8-CRLF2 fusion results in increased expression of CRLF2, a lymphoid signaling molecule that forms a heterodimeric complex with interleukin receptor 7 alpha. These findings identify a novel recurring chromosomal alteration in B-ALL, and suggest that perturbed CRLF2-mediated signaling is a key event in leukemogenesis in these cases. Profiling of tumor acquired DNA copy number alterations in 2 patients with Down syndrome associated B-progenitor acute lymphoblastic leukemia. Matched tumor and normal DNA was used for each array hybridization in each case.
Project description:We wanted to identify regions of active and open chromatin in a pre-B-cell model of Acute Lymphoblastic Leukemia (ALL). We did not stimulate or treat the cells, we merely maintained them in culture. We chose these conditions because we were building a computational model and needed a baseline read of histone activation. For each histone mark, we had one sample where we immunoprecipitated with an antibody for the histone mark of interest and we had one control where we immunoprecipitated with an IgG control.
Project description:SNP profiling can reveal copy number abnormalities and loss of heterozygosity associated with distinct biologic subtypes of acute lymphoblastic leukemia (ALL). We performed SNP profiling of Down syndrome ALL cases and controls to identify unique biologic features of this ALL subgroup. Ficoll-enriched, cryopreserved bone marrow aspirate samples were obtained from patients with B-precursor ALL at diagnosis and in remission; and from control patients without leukemia.
Project description:Genome wide expression profiling was used to detect cases of adult T-ALL lacking GATA3 expression. GATA3low T-ALL exhibited enrichment of myeloid/lymphoid progenitor (MLP) and granulocyte/monocyte progenitor (GMP) genes, while T-cell specific signatures were downregulated. Among upregulated genes FLT3 was identified and mutational analyses revealed a high rate of FLT3 mutations. Analysis of 83 samples of bone marrow mononuclear cells (39x HGU-133 2.0 plus chip; 44x HGU-133 A&B Set) from adult patients with acute T-cell lymphoblastic leukemia (T-ALL)
Project description:Acute lymphoblastic leukaemia with early T-cell precursor immunophenotype (ETP ALL) is a highly aggressive subtype of ALL of unknown aetiology. To gain insights into the genetic basis of this disease, we performed whole genome sequencing of tumour and normal DNA of 12 children with ETP ALL. Analysis of structural and sequence variants in this discovery cohort, and mutation recurrence screening in a panel of 51 ETP and 43 non ETP ALL samples identified a high frequency of activating mutations in genes regulating cytokine receptor and Ras signalling, including IL7R, NRAS, KRAS, FLT3, BRAF, JAK1 and JAK3 in ETP ALL. Moreover, we identified multiple new targets of mutation in including GATA3, EP300, RUNX1, DNM2, ECT2L, HNRNPA1 and HNRNPR, as well as genes known to be mutated in T-ALL, including NOTCH1, PHF6, and WT1.. Five of 12 ETP ALL cases harboured novel chromosomal translocations, several of which accompanied complex multichromosomal rearrangements and resulted in the expression of chimeric in-frame fusion genes disrupting hematopoietic regulators, including ETV6-INO80D, NAP1L1-MLLT10 and RUNX1-EVX1. These results indicate that although ETP ALL is genetically heterogeneous, activation of Ras and cytokine receptor signalling distinguishes this disease from non-ETP ALL. These findings suggest that targeting this pathway may improve the currently dismal outcome of this disease. Gene expression profiling of an extended panel of childhood B-lineage and T-lineage acute lymphoblastic leukemia samples was performed using Affymetrix U133A arrays.
Project description:Methylation profiling can reveal patterns of hypermethlation and hypomethylation associated with distinct biologic subtypes of acute lymphoblastic leukemia (ALL). We performed methylation profiling of Down syndrome ALL cases and controls to identify unique biologic features of this ALL subgroup. Ficoll-enriched, cryopreserved bone marrow aspirate samples were obtained from patients with B-precursor ALL at diagnosis and in remission
Project description:Acute lymphoblastic leukaemia with early T-cell precursor immunophenotype (ETP ALL) is a highly aggressive subtype of ALL of unknown aetiology. To gain insights into the genetic basis of this disease, we performed whole genome sequencing of tumour and normal DNA of 12 children with ETP ALL. Analysis of structural and sequence variants in this discovery cohort, and mutation recurrence screening in a panel of 51 ETP and 43 non ETP ALL samples identified a high frequency of activating mutations in genes regulating cytokine receptor and Ras signalling, including IL7R, NRAS, KRAS, FLT3, BRAF, JAK1 and JAK3 in ETP ALL. Moreover, we identified multiple new targets of mutation in including GATA3, EP300, RUNX1, DNM2, ECT2L, HNRNPA1 and HNRNPR, as well as genes known to be mutated in T-ALL, including NOTCH1, PHF6, and WT1.. Five of 12 ETP ALL cases harboured novel chromosomal translocations, several of which accompanied complex multichromosomal rearrangements and resulted in the expression of chimeric in-frame fusion genes disrupting hematopoietic regulators, including ETV6-INO80D, NAP1L1-MLLT10 and RUNX1-EVX1. These results indicate that although ETP ALL is genetically heterogeneous, activation of Ras and cytokine receptor signalling distinguishes this disease from non-ETP ALL. These findings suggest that targeting this pathway may improve the currently dismal outcome of this disease. Gene expression profiling of an extended panel of childhood B-lineage and T-lineage acute lymphoblastic leukemia samples was performed using Affymetrix U133A arrays.