title: The LMO2 -25 Region Harbours GATA2-Dependent Myeloid Enhancer and RUNX-Dependent T-Lymphoid Repressor Activity.
abstract: Lim domain only 2 (LMO2) is a transcriptional co-factor required for angiogenesis and the specification of haematopoietic cells during development. LMO2 is widely expressed within haematopoiesis with the exception of T-cells. Failure to downregulate LMO2 during T-cell maturation leads to leukaemia, thus underlining the critical nature of context-dependent regulation of LMO2 expression. We previously identified a distal regulatory element of LMO2 (element -25) that cooperates with the proximal promoter in directing haematopoietic expression. Here we dissected the functional activity of element -25 and showed it to consist of two modules that conferred independent and cell-type specific activities: a 3' myeloid enhancer and a 5' T-cell repressor. The myeloid enhancer was bound by GATA2 in progenitors and its activity depended on a highly conserved GATA motif, whereas the T-cell repressor moiety of element -25 was bound by the Core Binding Factor in T-cells and its repressive activity depended on a highly conserved RUNT motif. Since the myeloid enhancer and nearby downstream region is recurrently involved in oncogenic translocations, our data suggest that the -25 enhancer region provides an open chromatin environment prone to translocations, which in turn cause aberrant LMO2 expression in T-cells due to the removal of the adjacent T-cell repressor.
authors.affiliation: Department of Haematology, Wellcome Trust and MRC Cambridge Stem Cell Institute, Cambridge Institute for Medical Research, Cambridge University, Cambridge, United Kingdom.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bonadies
authors.affiliation: Department of Haematology, Wellcome Trust and MRC Cambridge Stem Cell Institute, Cambridge Institute for Medical Research, Cambridge University, Cambridge, United Kingdom.
authors.forename: Berthold
authors.initials: B
authors.lastname: Göttgens
authors.affiliation: Department of Haematology, Wellcome Trust and MRC Cambridge Stem Cell Institute, Cambridge Institute for Medical Research, Cambridge University, Cambridge, United Kingdom.
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Calero-Nieto
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D050657:Core Binding Factor alpha Subunits / Q000378:metabolism*; D004742:Enhancer Elements, Genetic / Q000235:genetics; D050989:GATA2 Transcription Factor / Q000378:metabolism*; D005786:Gene Expression Regulation; D006410:Hematopoiesis / Q000235:genetics; D006801:Humans; D019169:Jurkat Cells; D060588:LIM Domain Proteins / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D023461:Myeloid Progenitor Cells / Q000378:metabolism; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D012689:Sequence Homology, Nucleic Acid; D037941:Silencer Elements, Transcriptional / Q000235:genetics; D013601:T-Lymphocytes / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D050657:Core Binding Factor alpha Subunits; D050989:GATA2 Transcription Factor; D060588:LIM Domain Proteins; C085117:LMO2 protein, human; D011518:Proto-Oncogene Proteins