Project description:Three-dimensional disorganisation of the cancer genome occurs coincident with long range genetic and epigenetic alterations [RNA-seq]
Project description:Lymphocyte development consists of sequential and mutually exclusive cell states of proliferative selection and antigen receptor gene recombination. Transitions between each state require large, coordinated changes in epigenetic landscapes and transcriptional programs. How this occurs remains unclear. Herein, we demonstrate that in small pre-B cells, the lineage and stage-specific epigenetic reader BRWD1 reorders three-dimensional chromatin topology to affect transition between proliferative and gene recombination molecular programs. BRWD1 regulated the switch between poised and active enhancers interacting with promoters and coordinated this with Igk locus contraction. BRWD1 did so by converting chromatin-bound static cohesin to dynamic complexes competent to mediate long-range looping. Remarkably, ATP depletion recapitulated cohesin distributions observed in Brwd1-/- cells. Therefore, in small pre-B cells, cohesin conversion appears to be the main energetic mechanism dictating where dynamic looping occurs in the genome. Our findings provide a new mechanism of cohesin regulation and reveal how cohesin function can be regulated by lineage contextual mechanisms to facilitate specific cell fate transitions.
Project description:Lymphocyte development consists of sequential and mutually exclusive cell states of proliferative selection and antigen receptor gene recombination. Transitions between each state require large, coordinated changes in epigenetic landscapes and transcriptional programs. How this occurs remains unclear. Herein, we demonstrate that in small pre-B cells, the lineage and stage-specific epigenetic reader BRWD1 reorders three-dimensional chromatin topology to affect transition between proliferative and gene recombination molecular programs. BRWD1 regulated the switch between poised and active enhancers interacting with promoters and coordinated this with Igk locus contraction. BRWD1 did so by converting chromatin-bound static cohesin to dynamic complexes competent to mediate long-range looping. Remarkably, ATP depletion recapitulated cohesin distributions observed in Brwd1-/- cells. Therefore, in small pre-B cells, cohesin conversion appears to be the main energetic mechanism dictating where dynamic looping occurs in the genome. Our findings provide a new mechanism of cohesin regulation and reveal how cohesin function can be regulated by lineage contextual mechanisms to facilitate specific cell fate transitions.
Project description:The 3D organization of the genome is important for regulation of diverse nuclear processes ranging from transcription to DNA replication. Knowledge of the higher order chromatin structure is critical for understanding mechanisms of gene regulation by long-range control elements such as enhancers and insulators. We describe high resolution, genome-wide dynamic chromatin interaction maps in human embryonic stem cells (hESC) as they differentiate into four distinct embryonic cell lineages. Extensive reorganization of higher-order chromatin structure occurs during hESC differentiation. In this process, topological domains remain largely intact but inter-domain association patterns change dramatically, coincident with widespread changes in chromatin state and gene expression. Moreover, using proximity ligation sequencing to generate chromosome span haplotypes, widespread allele biased gene activities are detected. The allelic gene expression patterns can be correlated to epigenetic state at distal enhancers, supporting the role of these elements in regulating gene expression over a distance. Two biological replicates of Hi-C experiment and one replicate of CTCF ChIP-Seq experiment in embryonic stem cells and 4 other differentiated cell-types from H1 cell line. Re-analysis of data from GSE16256 in an allele specific manner is linked as supplementary data.
Project description:Genomic sequences, as well as its covalent epigenetic modifications, are spatially organized into three-dimensional structures. Here, we developed Methyl-HiC by combining in situ Hi-C and whole genome bisulfite sequencing (WGBS) to simultaneously capture genome-wide chromosome conformation changes and DNA methylation within the same DNA molecule. Methyl-HiC generated consistent information compared with in situ Hi-C and WGBS from the same cell line. We detected long-range DNA methylation concordance in general but varied in different chromatin states. We extended Methyl-HiC to single cell level and applied it on 103 primed and 47 naïve mouse embryonic stem cells (mESCs). We revealed the heterogeneity of chromosomal conformation changes by grouping cells in their DNA methylation level alone. We also observed increases of DNA methylation stochasticity and decreases of contact frequency together in late replication timing regions. Our method here paves the road to evaluate the direct long-range effect of epigenetic alterations in different pathological and healthy conditions at genome-wide and single cell level.
Project description:Primary outcome(s): Correlation between image evaluation/clinical data and molecular predictive and/or prognostic factors including genetic and epigenetic alterations derived from colorectal cancer tissues
Project description:This SuperSeries is composed of the following subset Series: GSE17768: An integrative multi-dimensional genetic and epigenetic strategy to identify aberrant genes and pathways in cancer: gene expression GSE17769: An integrative multi-dimensional genetic and epigenetic strategy to identify aberrant genes and pathways in cancer: DNA methylation GSE21347: An integrative multi-dimensional genetic and epigenetic strategy to identify aberrant genes and pathways in cancer: allelic status GSE21540: An integrative multi-dimensional genetic and epigenetic strategy to identify aberrant genes and pathways in cancer: CGH Refer to individual Series
Project description:To identify genomic regions which display concordant epigenetics alterations in prostate cancer, we performed MeDIP and ChIP-on-chip profiling of normal prostate epithelial cells (PrEC) and the prostate cancer cell line LNCaP. These promoter arrays were integrated with expression arrays of the same cells to discover and characterise regions of Long Range Epigenetic Silencing (LRES) in prostate cancer.