Similar Datasets
Project description:Broad domains of H3K4 methylation have been associated with tissue specific, cell identity and tumor suppressor genes. Here, we identified broad H3K4me3 domains (BH4D)-associated genes in human thymic T cell populations and a collection of T-Acute Lymphoblastic Leukemia (T-ALL) primary samples and cell lines. We found that BH4D are highly dynamic throughout T cell differentiation, flag key leukemia associated oncogenes and distinguish between normal and neoplastic cells. Leukemic cells loss broad domains at T cell identity genes and gain broad domains at cancer-related genes. Moreover, the expression of genes, both coding and non-coding, associated with BH4D is frequently deregulated in T-ALL. Using an ex-vivo model we demonstrated that the ectopic expression of TLX3 oncogenic factor preferentially impact on the expression of BH4D-associated genes in T cell leukemia. Finally, an H3K4me3 demethylase inhibitor differentially targets T-ALL cell lines depending on the extend of the broad domains. Our results show that regulation of BH4D-associated genes is critical for leukemogenesis and suggest that association with BH4D might be used as epigenetic prioritization of cancer-relevant genes, including long non-coding RNAs
2021-04-16 | GSE151297 | GEO
Project description:Dynamic of broad H3K4me3 domains uncover an epigenetic switch between cell identity and cancer-related genes
| PRJNA689588 | ENA
Project description:Dynamic of H3K4me3-broad domains uncover an epigenetic switch between cell identity and cancer-related genes
| PRJNA635406 | ENA
Project description:Transcriptionally active chromatin is marked by tri-methylation of histone H3 at lysine 4 (H3K4me3) located after first exons and around transcription start sites. This epigenetic mark is typically restricted to narrow regions at the 5`end of the gene body, though a small subset of genes have a broad H3K4me3 domain which extensively covers the coding region. Although most studies focus on the H3K4me3 mark, the broad H3K4me3 domain is associated with a plethora of histone modifications (e.g., H3 acetylated at K27) and is therein termed broad epigenetic domain. Genes marked with the broad epigenetic domain are involved in cell identity and essential cell functions and have clinical potential as biomarkers for patient stratification. Reducing expression of genes with the broad epigenetic domain may increase the metastatic potential of cancer cells. Enhancers and super-enhancers interact with the broad epigenetic domain marked genes forming a hub of interactions involving nucleosome-depleted regions. Together, the regulatory elements coalesce with transcription factors, chromatin modifying/remodeling enzymes, coactivators, and the Mediator and/or Integrator complex into a transcription factory which may be analogous to a liquid-liquid phase-separated condensate. The broad epigenetic domain has a dynamic chromatin structure which supports frequent transcription bursts. In this review, we present the current knowledge of broad epigenetic domains.
| S-EPMC8264473 | biostudies-literature
Project description:Maternal-to-zygotic transition (MZT) is essential for the formation of a new individual, but is still poorly understood despite recent progress in analysis of gene expression and DNA methylation in early embryogenesis. Dynamic histone modifications may have important roles in MZT, but direct measurements of chromatin states have been hindered by technical difficulties in profiling histone modifications from small quantities of cells. Recent improvements allow for 500 cell-equivalents of chromatin per reaction, but require 10,000 cells for initial steps or require a highly specialized microfluidics device that is not readily available. We developed a micro-scale chromatin immunoprecipitation and sequencing (μChIP-seq) method, which we used to profile genome-wide histone H3 lysine methylation (H3K4me3) and acetylation (H3K27ac) in mouse immature and metaphase II oocytes and in 2-cell and 8-cell embryos. Notably, we show that ~22% of the oocyte genome is associated with broad H3K4me3 domains that are anti-correlated with DNA methylation. The H3K4me3 signal becomes confined to transcriptional-start-site regions in 2-cell embryos, concomitant with the onset of major zygotic genome activation. Active removal of broad H3K4me3 domains by the lysine demethylases KDM5A and KDM5B is required for normal zygotic genome activation and is essential for early embryo development. Our results provide insight into the onset of the developmental program in mouse embryos and demonstrate a role for broad H3K4me3 domains in MZT.
| S-EPMC6283663 | biostudies-literature
Project description:Stretched histone regions, such as super-enhancers and broad H3K4me3 domains, are associated with maintenance of cell identity and cancer. We connected super-enhancers and broad H3K4me3 domains in the K562 chronic myelogenous leukemia cell line as well as the MCF-7 breast cancer cell line with chromatin interactions. Super-enhancers and broad H3K4me3 domains showed higher association with chromatin interactions than their typical counterparts. Interestingly, we identified a subset of super-enhancers that overlap with broad H3K4me3 domains and show high association with cancer-associated genes including tumor suppressor genes. Besides cell lines, we could observe chromatin interactions by a Chromosome Conformation Capture (3C)-based method, in primary human samples. Several chromatin interactions involving super-enhancers and broad H3K4me3 domains are constitutive and can be found in both cancer and normal samples. Taken together, these results reveal a new layer of complexity in gene regulation by super-enhancers and broad H3K4me3 domains.
| S-EPMC5438348 | biostudies-literature
Project description:Super-enhancers (SEs) and broad H3K4me3 domains (BDs) are crucial regulators in the control of tissue identity in human and mouse. However, their features in pig remain largely unknown. In this study, by integrative computational analyses of epigenomic and transcriptomic data, we have characterized SEs and BDs in six pig tissues and analyzed their conservation in comparison with human and mouse tissues. Similar to human and mouse, pig SEs and BDs display higher tissue specificity than their typical counterparts. Genes proximal to SEs and BDs are associated with tissue identity in most tissues. About 55-182 SEs (5-17% in total) and 99-309 BDs (8-16% in total) across pig tissues are considered as functionally conserved elements because they have orthologous SEs and BDs in human and mouse. However, these elements do not necessarily exhibit sequence conservation. The functionally conserved SEs are correlated to tissue identity in majority of pig tissues, while those conserved BDs are linked to tissue identity in a few tissues. Our study provides resources for future gene regulatory studies in pig. It highlights that SEs are more effective in defining tissue identity than BDs, which is contrasting to a previous study. It also provides novel insights on understanding the sequence features of functionally conserved elements.
| S-EPMC8652260 | biostudies-literature
Project description:Chromosomal translocations are important drivers of haematological malignancies whereby proto-oncogenes are activated by juxtaposition with super-enhancers, often called super-enhancer hijacking. We analysed the epigenomic consequences of rearrangements between the enhancers of the immunoglobulin heavy chain locus (IGH) and proto-oncogene CCND1 that are common in B-cell malignancies. By integrating BLUEPRINT epigenomic data with DNA breakpoint detection, we characterised the normal chromatin landscape of the human IGH locus and its dynamics after pathological genomic rearrangement. We detected an H3K4me3 broad domain (BD) within the IGH locus of healthy B-cells that was absent in samples with IGH-CCND1 translocations. The appearance of H3K4me3-BD over CCND1 in the latter was associated with overexpression and extensive chromatin accessibility of this locus. We observed similar cancer-specific H3K4me3-BDs associated with super-enhancer hijacking of other common oncogenes in B-cell (MAF, MYC and FGFR3) and in T-cell malignancies (LMO2, TLX3 and TAL1). Our analysis suggests that H3K4me3-BDs are created by super-enhancers and supports the new concept of epigenomic translocation, where the relocation of H3K4me3-BDs accompanies the translocation of super-enhancers.
2020-08-12 | GSE151556 | GEO
Project description:Regulators of the histone H3-trimethyl lysine-4 (H3K4me3) mark are significantly associated with the genetic risk architecture of common neurodevelopmental disease, including schizophrenia and autism. Typical H3K4me3 is primarily localized in the form of sharp peaks, extending in neuronal chromatin on average only across 500-1500 base pairs mostly in close proximity to annotated transcription start sites. Here, through integrative computational analysis of epigenomic and transcriptomic data based on next-generation sequencing, we investigated H3K4me3 landscapes of sorted neuronal and non-neuronal nuclei in human postmortem, non-human primate and mouse prefrontal cortex (PFC), and blood. To explore whether H3K4me3 peak signals could also extend across much broader domains, we examined broadest domain cell-type-specific H3K4me3 peaks in an unbiased manner with an innovative approach on 41+12 ChIP-seq and RNA-seq data sets. In PFC neurons, broadest H3K4me3 distribution ranged from 3.9 to 12 kb, with extremely broad peaks (~10 kb or broader) related to synaptic function and GABAergic signaling (DLX1, ELFN1, GAD1, IGSF9B and LINC00966). Broadest neuronal peaks showed distinct motif signatures and were centrally positioned in prefrontal gene-regulatory Bayesian networks and sensitive to defective neurodevelopment. Approximately 120 of the broadest H3K4me3 peaks in human PFC neurons, including many genes related to glutamatergic and dopaminergic signaling, were fully conserved in chimpanzee, macaque and mouse cortical neurons. Exploration of spread and breadth of lysine methylation markings could provide novel insights into epigenetic mechanism involved in neuropsychiatric disease and neuronal genome evolution.
| S-EPMC5068762 | biostudies-literature
Project description:Broad domain promoters and super enhancers are regulatory elements that govern cell-specific functions and harbor disease-associated sequence variants. These elements are characterized by distinct epigenomic profiles, such as expanded deposition of histone marks H3K27ac for super enhancers and H3K4me3 for broad domains, however little is known about how they interact with each other and the rest of the genome in three-dimensional chromatin space. Using network theory methods, we studied chromatin interactions between broad domains and super enhancers in three ENCODE cell lines (K562, MCF7, GM12878) obtained via ChIA-PET, Hi-C, and Hi-CHIP assays. In these networks, broad domains and super enhancers interact more frequently with each other compared to their typical counterparts. Network measures and graphlets revealed distinct connectivity patterns associated with these regulatory elements that are robust across cell types and alternative assays. Machine learning models showed that these connectivity patterns could effectively discriminate broad domains from typical promoters and super enhancers from typical enhancers. Finally, targets of broad domains in these networks were enriched in disease-causing SNPs of cognate cell types. Taken together these results suggest a robust and unique organization of the chromatin around broad domains and super enhancers: loci critical for pathologies and cell-specific functions.
| S-EPMC5663946 | biostudies-literature