Project description:A high incidence of acute megakaryoblastic leukemia (AMKL) in Down syndrome patients implies that chromosome 21 genes have a pivotal role in AMKL development, but the functional contribution of individual genes remains elusive. Here, we report that SON, a chromosome 21-encoded DNA- and RNA-binding protein, inhibits megakaryocytic differentiation by suppressing RUNX1 and the megakaryocytic gene expression program. As megakaryocytic progenitors differentiate, SON expression is drastically reduced, with mature megakaryocytes having the lowest levels. In contrast, AMKL cells express an aberrantly high level of SON, and knockdown of SON induced the onset of megakaryocytic differentiation in AMKL cell lines. Genome-wide transcriptome analyses revealed that SON knockdown turns on the expression of pro-megakaryocytic genes while reducing erythroid gene expression. Mechanistically, SON represses RUNX1 expression by directly binding to the proximal promoter and two enhancer regions, the known +23 kb enhancer and the novel +139 kb enhancer, at the RUNX1 locus to suppress H3K4 methylation. In addition, SON represses the expression of the AP-1 complex subunits JUN, JUNB and FOSB which are required for late megakaryocytic gene expression. Our findings define SON as a negative regulator of RUNX1 and megakaryocytic differentiation, implicating SON overexpression in impaired differentiation during AMKL development.
Project description:Differentially expressed genes in the stomachs of type-1 gastric neuroendocrine tumour (NET) patients before, during and after treatment with netazepide (YF476)
Project description:Atopic eczema is an itchy inflammatory disorder characterised by skin barrier dysfunction. Loss-of-function mutations in the gene encoding filaggrin (FLG) are a major risk factor, but the mechanisms by which filaggrin haploinsufficiency leads to atopic inflammation remain incompletely understood. Skin as an organ which can be modelled using primary cells in vitro provides the opportunity for selected genetic effects to be investigated in detail.
Project description:SON inhibits megakaryocytic differentiation via repressing the megakaryocytic gene expression program in acute megakaryoblastic leukemia
Project description:This experiment is designed to compare the effects of Vitamin D3 treatment of mouse bone marrow derived dendritic cells with control, untreated cells, and additional effects of maturation of either treated or control cells with LPS.
Project description:Rheumatoid arthritis is an autoimmune inflammatory joint condition which primarily affects the synovium of joints, characterised by synovial inflammation as well as articular cartilage and underlying bone destruction. Within this study, the proteomes of serum obtained from rheumatoid arthritis patients, and appropriate human controls, were analysed using liquid chromatography-tandem mass spectrometry. ProteoMinerâ„¢ equalisation columns were used to deplete high abundant proteins and reduce the protein concentration dynamic range.
Project description:Thrombocytopenia is an independent prognostic indicator in patients with MDS (de Swart, L. et al, Br J Haematol, 2015) and we sought to evaluate the contribution of azacitidine to the worsening of this condition in patients with MDS and acute myeloid leukemia (AML). Since MDS/AML may have lower amounts of residual healthy cells, we sought to model this effect of AZA on healthy cord blood derived megakaryocytic cells. We used microarrays to detail the global programme of gene expression in the presence of azacitidine under megakaryocytic differentiation stimulants and identified distinct classes of dysregulated genes and pathways during this process.
Project description:Purpose: The goals of this study are to investigate the molecular mechanism by which MEIS1 controls megakaryocytic maturation and thrombopoiesis through compareing the mRNA profiling of Wild Type and MEIS1 deleted H1 drived cells at day6 of megakaryocytic differentiation.