Chromatin occupation changes associated with IRF4 silencing
Ontology highlight
ABSTRACT: TMD8 cells were treated with either shIRF4 or control shRNA. Cells were lysed and the DNA was subjected to ATAC-sequencing to assess the changes in chromatin occupation.
Project description:A gene expression study was conducted to understand the role of IRF4 in ABC like lymphomas. For this, IRF4 was silenced in TMD8 cell line alongside a control vector. Treated and control cell lines were subjected to gene expression measurement. Pathway analysis of differentially expressed gens showed antigen presentation pathways to be differentially regulated.
Project description:To investigate the genomic occupation of the transcription factor BmGATA, and the impact of BmNPV infection on its genomic occupation
Project description:To assess the timing and scope of IRF4–dependent reprogramming in vivo, CTV-labeled IRF4–sufficient and –deficient B cells were transferred into mMT hosts. One day later, hosts were challenged with 50 mg LPS. Three days post-LPS challenge, transferred cells were recovered and sorted from divisions 0, 1, 3, 4, 5, and 6 as determined by CTV dilution for ATAC–seq.
Project description:Interferon regulatory factor 4 (IRF4) is a transcriptional regulator with critical roles in the normal development and malignant transformation of lymphocytes. Recently we have shown that plasma cell cancers (multiple myeloma, MM) are addicted to an aberrant gene expression program ochestrated by wild-type IRF4 for their survival. Here we show that an aggressive malignancy of mature B cells, the activated B cell for of Diffuse Large B Cell lymphoma (ABC-DLBC), also depends on IRF4 for survival. With genome-wide expression profiling and localization (ChIP-Seq) assays, we identified IRF4 target genes in ABC-DLBCL as members of diverse pathways related to B cell biology and malignant behavior, distinct from IRF4 targets in MM. For example, we find the gene encoding the NFkB signal transduction adapter protein CARD11 is a target of IRF4 activation, driving the critical NFkB pathway in ABC-DLBCL. Further, we find enrichment of DNA binding motifs for ETS-IRF factors in regions of IRF4 binding in ABC-DLBCL suggesting cooperative activity between IRF4 and an ETS family transcription factor. Through complementation assays we show that IRF4 and the critical ABC-DLBCL ETS factor SPIB interact with one another and are key to ABC-DLBCL survival. Together our data show that ABC-DLBCL is addicted to the interaction between IRF4 and SPIB, in part through a positive feedback loop invovling CARD11 and the activation of the NFkB pathway. These data suggest theraepeutic potential in targeting the IRF4:SPIB interface in ABC-DLBCL. Gene expression was analyzed using Agilent human 4X44K oligo gene expression arrays. Cell lines (HBL1, OCILY3, TMD8-ABC-DLBCL; KMS12-MM) were infected with control (shControl, Cy3) or shIRF4_3'UTR (Cy5) constructs, and changes in gene expression were monitored over time after induction of the shRNA with doxycyclin. For each of the three ABC-DLBCL cell line a four timepoint series (24, 48, 72, 96 hrs) of shRNA induction was analyzed, for a total of 12 arrays. In HBL-1 a second shRNA targeting the IRF4 cds (shIRF4_cds) was used in a similar time course of shRNA induction (4 arrays). For the KMS12 MM cell line a three point time course was analyzed using the shIRF4_3'UTR with one technical (using the same RNA sample) duplicate time point measurement (4 arrays). ChIP-Seq data not provided.
Project description:MALT1 Small Molecule Inhibitors Specifically Suppress ABC-DLBCL In Vitro and In Vivo Total RNA was obtained from HBL-1 and TMD8 cell lines subjected to 8 hours treatment with MI-2, z-VRPR-fmk or vehicle.
Project description:The extreme environments of the Tibetan Plateau offer significant challenges to human survival, demanding novel adaptations. While the role of biological and agricultural adaptations in enabling early human colonization of the plateau has been widely discussed, the contribution of pastoralism is less well understood, especially the dairy pastoralism that has historically been central to Tibetan diets. Here, we analyze preserved proteins from the dental calculus of 40 ancient individuals to report the earliest direct evidence of dairy consumption on the Tibetan Plateau. Our palaeoproteomic results demonstrate that dairy pastoralism began on the higher plateau by approximately 3,500 years ago, more than 2,000 years earlier than the recording of dairying in historical sources. With less than 1% of the Tibetan Plateau dedicated to farmland, pastoralism and the milking of ruminants were essential for large-scale human expansion into agriculturally-marginal regions that make up the majority of the plateau. Dairy pastoralism allowed conversion of abundant grasslands into nutritional human food, which facilitating adaptation in the face of extreme climatic and altitudinal pressures, and maximizing the land area available for long-term human occupation of the “roof of the world”.