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Long terminal repeat (LTR) elements are wide-spread in the human genome and have the potential to act as promoters and enhancers. Their expression is therefore under tight epigenetic control. We previously reported in classical Hodgkin Lymphoma (cHL) that a member of the THE1B class of LTR elements acted as a promoter for the proto-oncogene and growth factor receptor gene CSF1R and that expression of this gene is required for cHL tumour survival. However, to which extent and how such elements participate in globally shaping the unique cHL gene expression programme is unknown. To address this question we mapped the genome-wide activation of THE1-LTRs in cHL cells using a targeted next generation sequencing approach (RACE-Seq). Integration of these data with global gene expression data from cHL and control B cell lines showed a unique pattern of LTR activation impacting on gene expression, including genes associated with the cHL phenotype. We also show that global LTR activation is induced by strong inflammatory stimuli. Together these results demonstrate that LTR activation provides an additional layer of gene deregulation in classical Hodgkin lymphoma and highlight the potential impact of genome-wide LTR activation in other inflammatory diseases.

Summary Acute myeloid leukemia (AML) is a heterogeneous disease caused by mutations in transcriptional regulator genes, but how different mutant regulators shape the chromatin landscape is unclear. Here, we compared the transcriptional networks of two types of AML with chromosomal translocations of the RUNX1 locus that fuse the RUNX1 DNA-binding domain to different regulators, the t(8;21) expressing RUNX1-ETO and the t(3;21) expressing RUNX1-EVI1. Despite containing the same DNA-binding domain, the two fusion proteins display distinct binding patterns, show differences in gene expression and chromatin landscape, and are dependent on different transcription factors. RUNX1-EVI1 directs a stem cell-like transcriptional network reliant on GATA2, whereas that of RUNX1-ETO-expressing cells is more mature and depends on RUNX1. However, both types of AML are dependent on the continuous expression of the fusion proteins. Our data provide a molecular explanation for the differences in clinical prognosis for these types of AML., Graphical Abstract, Highlights • t(8;21) and t(3;21) AML are regulated by unique gene regulatory networks • RUNX1-ETO and RUNX1-EVI1 have different binding patterns and binding partners • Depletion of each fusion protein initiates C/EBPα-dependent myeloid differentiation • t(8;21) AML survival depends on RUNX1, whereas t(3;21) AML survival requires GATA2, Loke et al. compare the regulatory signature of two related types of acute myeloid leukemia, t(8;21) expressing RUNX1-ETO and t(3;21) expressing RUNX1-EVI1. Each fusion protein displays a distinct binding pattern and cooperates with different transcription factors to impact the epigenome, but both downregulate the myeloid differentiation regulator C/EBPα.

A feasibility study presenting results from acoustic monitoring from marine autonomous vehicles in typical coastal ocean conditions (i.e. 50-­100m depth) to investigate current capability in measuring marine noise levels and detection of vocalisation of marine mammals and to provide guidance on future use

Summary During somatic reprogramming, Yamanaka’s pioneer factors regulate a complex sequence of molecular events leading to the activation of a network of pluripotency factors, ultimately resulting in the acquisition and maintenance of a pluripotent state. Here, we show that, contrary to the pluripotency factors studied so far, overexpression of Mybl2 inhibits somatic reprogramming. Our results demonstrate that Mybl2 levels are crucial to the dynamics of the reprogramming process. Mybl2 overexpression changes chromatin conformation, affecting the accessibility of pioneer factors to the chromatin and promoting accessibility for early immediate response genes known to be reprogramming blockers. These changes in the chromatin landscape ultimately lead to a deregulation of key genes that are important for the mesenchymal-to-epithelial transition. This work defines Mybl2 level as a gatekeeper for the initiation of reprogramming, providing further insights into the tight regulation and required coordination of molecular events that are necessary for changes in cell fate identity during the reprogramming process., Graphical Abstract, Highlights • Deletion and overexpression of MYBL2 pluripotency factor inhibit somatic reprogramming • Mybl2 overexpression affects the accessibility of pioneer factors to the chromatin • Mybl2 overexpression promotes accessibility of reprogramming blockers to the chromatin • High Mybl2 levels deregulate key genes for proper MET, a requirement for reprogramming, Ward et al. show that Mybl2 expression level is a gatekeeper for the initiation of reprogramming. They find that Mybl2 overexpression leads to changes in the chromatin landscape, affecting the accessibility of pioneer factors to the chromatin and promoting accessibility for the AP1 family of transcription factors, known to be reprogramming blockers.

TCR signaling pathways cooperate to activate the inducible transcription factors NF-κB, NFAT, and AP-1. In this study, using the calcium ionophore ionomycin and/or PMA on Jurkat T cells, we show that the gene expression program associated with activation of TCR signaling is closely related to specific chromatin landscapes. We find that calcium and kinase signaling cooperate to induce chromatin remodeling at ∼2100 chromatin regions, which demonstrate enriched binding motifs for inducible factors and correlate with target gene expression. We found that these regions typically function as inducible enhancers. Many of these elements contain composite NFAT/AP-1 sites, which typically support cooperative binding, thus further reinforcing the need for cooperation between calcium and kinase signaling in the activation of genes in T cells. In contrast, treatment with PMA or ionomycin alone induces chromatin remodeling at far fewer regions (∼600 and ∼350, respectively), which mostly represent a subset of those induced by costimulation. This suggests that the integration of TCR signaling largely occurs at the level of chromatin, which we propose plays a crucial role in regulating T cell activation.

TCR signaling pathways cooperate to activate the inducible transcription factors NF-B, NFAT and AP-1. Here, using the calcium ionophore ionomycin and/or PMA on Jurkat T cells, we show that the gene expression program associated with activation of TCR signaling is closely related to specific chromatin landscapes. We find that calcium and kinase signaling cooperate to induce chromatin remodeling at ~2100 chromatin regions, which demonstrate enriched binding motifs for inducible factors and correlate with target gene expression. We found that these regions typically function as inducible enhancers. Many of these elements contain composite NFAT/AP-1 sites, which typically support cooperative binding, thus further reinforcing the need for cooperation between calcium and kinase signaling in the activation of genes in T cells. In contrast, treatment with PMA or ionomycin alone induces chromatin remodeling at far fewer regions (~600 and ~350, respectively), which mostly represent a subset of those induced by co-stimulation. This suggests that the integration of T cell receptor signaling largely occurs at the level of chromatin, which we propose plays a crucial role in regulating T cell activation.