35 results found
Roman-Trufero M, Ito CM, Pedebos C, et al., 2020, Evolution of an amniote-specific mechanism for modulating ubiquitin signalling via phosphoregulation of the E2 enzyme UBE2D3, Molecular Biology and Evolution, Vol: 37, Pages: 1986-2001, ISSN: 0737-4038
Genetic variation in the enzymes that catalyse post-translational modification of proteins is a potentially important source of phenotypic variation during evolution. Ubiquitination is one such modification that affects turnover of virtually all of the proteins in the cell in addition to roles in signalling and epigenetic regulation. UBE2D3 is a promiscuous E2 enzyme, which acts as a ubiquitin donor for E3 ligases that catalyse ubiquitination of developmentally important proteins. We have used protein sequence comparison of UBE2D3 orthologues to identify a position in the C-terminal α-helical region of UBE2D3 that is occupied by a conserved serine in amniotes and by alanine in anamniote vertebrate and invertebrate lineages. Acquisition of the serine (S138) in the common ancestor to modern amniotes created a phosphorylation site for Aurora B. Phosphorylation of S138 disrupts the structure of UBE2D3 and reduces the level of the protein in mouse ES cells (ESCs). Substitution of S138 with the anamniote alanine (S138A) increases the level of UBE2D3 in ESCs as well as being a gain of function early embryonic lethal mutation in mice. When mutant S138A ESCs were differentiated into extra-embryonic primitive endoderm (PrE), levels of the PDGFRα and FGFR1 receptor tyrosine kinases (RTKs) were reduced and PreE differentiation was compromised. Proximity ligation analysis showed increased interaction between UBE2D3 and the E3 ligase CBL and between CBL and the RTKs. Our results identify a sequence change that altered the ubiquitination landscape at the base of the amniote lineage with potential effects on amniote biology and evolution.
Cordonnier G, Mandoli A, Cagnard N, et al., 2020, CBF beta-SMMHC Affects Genome-wide Polycomb Repressive Complex 1 Activity in Acute Myeloid Leukemia, CELL REPORTS, Vol: 30, Pages: 299-+, ISSN: 2211-1247
Beagrie RA, Scialdone A, Schueler M, et al., 2017, Complex multi-enhancer contacts captured by genome architecture mapping, NATURE, Vol: 543, Pages: 519-+, ISSN: 0028-0836
Bond J, Domaschenz R, Roman-Trufero M, et al., 2016, Direct interaction of Ikaros and Foxp1 modulates expression of the G protein-coupled receptor G2A in B-lymphocytes and acute lymphoblastic leukemia, Oncotarget, Vol: 7, Pages: 65923-65936, ISSN: 1949-2553
Ikaros and Foxp1 are transcription factors that play key roles in normal lymphopoiesis and lymphoid malignancies. We describe a novel physical and functional interaction between the proteins, which requires the central zinc finger domain of Ikaros. The Ikaros-Foxp1 interaction is abolished by deletion of this region, which corresponds to the IK6 isoform that is commonly associated with high-risk acute lymphoblastic leukemia (ALL). We also identify the Gpr132 gene, which encodes the orphan G protein-coupled receptor G2A, as a novel target for Foxp1. Increased expression of Foxp1 enhanced Gpr132 transcription and caused cell cycle changes, including G2 arrest. Co-expression of wild-type Ikaros, but not IK6, displaced Foxp1 binding from the Gpr132 gene, reversed the increase in Gpr132 expression and inhibited G2 arrest. Analysis of primary ALL samples revealed a significant increase in GPR132 expression in IKZF1-deleted BCR-ABL negative patients, suggesting that levels of wild-type Ikaros may influence the regulation of G2A in B-ALL. Our results reveal a novel effect of Ikaros haploinsufficiency on Foxp1 functioning, and identify G2A as a potential modulator of the cell cycle in Ikaros-deleted B-ALL.
Pombo A, Dillon N, 2015, Three-dimensional genome architecture: players and mechanisms, NATURE REVIEWS MOLECULAR CELL BIOLOGY, Vol: 16, Pages: 245-257, ISSN: 1471-0072
Kunowska N, Rotival M, Yu L, et al., 2015, Identification of protein complexes that bind to histone H3 combinatorial modifications using super-SILAC and weighted correlation network analysis, NUCLEIC ACIDS RESEARCH, Vol: 43, Pages: 1418-1432, ISSN: 0305-1048
Sabbattini P, Sjoberg M, Nikic S, et al., 2014, An H3K9/S10 methyl-phospho switch modulates Polycomb and Pol II binding at repressed genes during differentiation, MOLECULAR BIOLOGY OF THE CELL, Vol: 25, Pages: 904-915, ISSN: 1059-1524
Auner HW, Moody AM, Ward TH, et al., 2013, Combined Inhibition of p97 and the Proteasome Causes Lethal Disruption of the Secretory Apparatus in Multiple Myeloma Cells, PLOS One, Vol: 8, ISSN: 1932-6203
Inhibition of the proteasome is a widely used strategy for treating multiple myeloma that takes advantage of the heavy secretory load that multiple myeloma cells (MMCs) have to deal with. Resistance of MMCs to proteasome inhibition has been linked to incomplete disruption of proteasomal endoplasmic-reticulum (ER)-associated degradation (ERAD) and activation of non-proteasomal protein degradation pathways. The ATPase p97 (VCP/Cdc48) has key roles in mediating both ERAD and non-proteasomal protein degradation and can be targeted pharmacologically by small molecule inhibition. In this study, we compared the effects of p97 inhibition with Eeyarestatin 1 and DBeQ on the secretory apparatus of MMCs with the effects induced by the proteasome inhibitor bortezomib, and the effects caused by combined inhibition of p97 and the proteasome. We found that p97 inhibition elicits cellular responses that are different from those induced by proteasome inhibition, and that the responses differ considerably between MMC lines. Moreover, we found that dual inhibition of both p97 and the proteasome terminally disrupts ER configuration and intracellular protein metabolism in MMCs. Dual inhibition of p97 and the proteasome induced high levels of apoptosis in all of the MMC lines that we analysed, including bortezomib-adapted AMO-1 cells, and was also effective in killing primary MMCs. Only minor toxicity was observed in untransformed and non-secretory cells. Our observations highlight non-redundant roles of p97 and the proteasome in maintaining secretory homeostasis in MMCs and provide a preclinical conceptual framework for dual targeting of p97 and the proteasome as a potential new therapeutic strategy in multiple myeloma.
Frangini A, Sjoeberg M, Roman-Trufero M, et al., 2013, The Aurora B Kinase and the Polycomb Protein Ring1B Combine to Regulate Active Promoters in Quiescent Lymphocytes, MOLECULAR CELL, Vol: 51, Pages: 647-661, ISSN: 1097-2765
Dillon N, 2012, Factor mediated gene priming in pluripotent stem cells sets the stage for lineage specification, BIOESSAYS, Vol: 34, Pages: 194-204, ISSN: 0265-9247
O'Loghlen A, Munoz-Cabello AM, Gaspar-Maia A, et al., 2012, MicroRNA Regulation of Cbx7 Mediates a Switch of Polycomb Orthologs during ESC Differentiation, CELL STEM CELL, Vol: 10, Pages: 33-46, ISSN: 1934-5909
Auner HW, Beham-Schmid C, Dillon N, et al., 2010, The life span of short-lived plasma cells is partly determined by a block on activation of apoptotic caspases acting in combination with endoplasmic reticulum stress, BLOOD, Vol: 116, Pages: 3445-3455, ISSN: 0006-4971
Liber D, Domaschenz R, Holmqvist P-H, et al., 2010, Epigenetic Priming of a Pre-B Cell-Specific Enhancer through Binding of Sox2 and Foxd3 at the ESC Stage, CELL STEM CELL, Vol: 7, Pages: 114-126, ISSN: 1934-5909
Dillon N, 2008, The impact of gene location in the nucleus on transcriptional regulation, DEVELOPMENTAL CELL, Vol: 15, Pages: 182-186, ISSN: 1534-5807
Parelho V, Hadjur S, Spivakov M, et al., 2008, Cohesins functionally associate with CTCF on mammalian chromosome arms, CELL, Vol: 132, Pages: 422-433, ISSN: 0092-8674
Sabbattini P, Canzonetta C, Sjoberg M, et al., 2007, Novel role for the Aurora B kinase in epigenetic marking of silent chromatin in differentiated postmitotic cells, EMBO JOURNAL, Vol: 26, Pages: 4657-4669, ISSN: 0261-4189
Thompson EC, Cobb BS, Sabbattini P, et al., 2007, Ikaros DNA-binding proteins as integral components of B cell developmental-stage-specific regulatory circuits., Immunity, Vol: 26, Pages: 335-344, ISSN: 1074-7613
Ikaros DNA-binding proteins are critical for the development of lymphocytes and other hematopoietic lineages, but it remains unclear how they cooperate with other regulators of signaling and transcription to achieve ordered gene expression during development. Here, we show that Ikaros proteins regulate the pre-BCR component lambda5 in a stage-specific manner. In pre-BI cells, Ikaros modulated lambda5 expression in competition with the transcriptional activator EBF. This required Ikaros binding to the Igll1 (lambda5) promoter and was abolished either by mutation of the Ikaros DNA-binding domain or by deletion of a single Ikaros site from the Igll1 promoter. At the transition from the pre-BI to pre-BII stage, the expression of the Ikaros family member Aiolos was upregulated and required for the efficient silencing of Igll1. Aiolos expression was controlled by pre-BCR signals via the adaptor protein SLP-65. Thus, pre-BCR signaling regulates Aiolos and the silencing of Igll1 via a developmental-stage-specific feedback loop.
Szutorisz H, Georgiou A, Tora L, et al., 2006, The proteasome restricts permissive transcription at tissue-specific gene loci in embryonic stem cells, CELL, Vol: 127, Pages: 1375-1388, ISSN: 0092-8674
Dillon N, 2006, Gene regulation and large-scale chromatin organization in the nucleus, CHROMOSOME RESEARCH, Vol: 14, Pages: 117-126, ISSN: 0967-3849
Szutorisz H, Dillon N, 2005, The epigenetic basis for embryonic stem cell pluripotency, BIOESSAYS, Vol: 27, Pages: 1286-1293, ISSN: 0265-9247
Szutorisz H, Dillon N, Tora L, 2005, The role of enhancers as centres for general transcription factor recruitment, TRENDS IN BIOCHEMICAL SCIENCES, Vol: 30, Pages: 593-599, ISSN: 0968-0004
Minaee S, Farmer D, Georgiou A, et al., 2005, Mapping and functional analysis of regulatory sequences in the mouse lambda 5-VpreB1 domain, MOLECULAR IMMUNOLOGY, Vol: 42, Pages: 1283-1292, ISSN: 0161-5890
Chow CM, Georgiou A, Szutorisz H, et al., 2005, Variant histone H3.3 marks promoters of transcriptionally active genes during mammalian cell division, EMBO REPORTS, Vol: 6, Pages: 354-360, ISSN: 1469-221X
Sabbattini P, Dillon N, 2005, The lambda 5-VpreB1 locus - a model system for studying gene regulation during early B cell development, SEMINARS IN IMMUNOLOGY, Vol: 17, Pages: 121-127, ISSN: 1044-5323
Szutorisz H, Canzonetta C, Georgiou A, et al., 2005, Formation of an active tissue-specific chromatin domain initiated by epigenetic marking at the embryonic stem cell stage, MOLECULAR AND CELLULAR BIOLOGY, Vol: 25, Pages: 1804-1820, ISSN: 0270-7306
Takacs K, Du Roure C, Nabarro S, et al., 2004, The regulated long-term delivery of therapeutic proteins by using antigen-specific B lymphocytes, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 101, Pages: 16298-16303, ISSN: 0027-8424
Dillon N, 2004, Heterochromatin structure and function, BIOLOGY OF THE CELL, Vol: 96, Pages: 631-637, ISSN: 0248-4900
Dillon N, 2003, Positions, please ..., NATURE, Vol: 425, Pages: 457-457, ISSN: 0028-0836
Azuara V, Brown KE, Williams RRE, et al., 2003, Heritable gene silencing in lymphocytes delays chromatid resolution without affecting the timing of DNA replication, NATURE CELL BIOLOGY, Vol: 5, Pages: 668-U49, ISSN: 1465-7392
Dillon N, Festenstein R, 2002, Unravelling heterochromatin: competition between positive and negative factors regulates accessibility, TRENDS IN GENETICS, Vol: 18, Pages: 252-258, ISSN: 0168-9525
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