The LMO2 -25 region harbours GATA2-dependent myeloid enhancer and RUNX-dependent T-lymphoid repressor activity
Calero-Nieto, Fernando J
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Bonadies, N., Gottgens, B., & Calero-Nieto, F. J. (2015). The LMO2 -25 region harbours GATA2-dependent myeloid enhancer and RUNX-dependent T-lymphoid repressor activity. PLOS ONE, 10 (e0131577)https://doi.org/10.1371/journal.pone.0131577
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.
This work was supported by Leukaemia and Lymphoma Research (BG) (http://leukaemialymphomaresearch.org.uk/, grants number 07060 and 12029), a fellowship from the Swiss National Science Foundation (NB) (http://www.snf.ch/) and Wellcome Trust Infrastructure support funding for the Cambridge Institute for Medical Research ((http://www.wellcome.ac.uk/) grant number 100140/Z/12/Z) and the Wellcome Trust and MRC Cambridge Stem Cell Institute (http://www.mrc.ac.uk/, grant number 097922/Z/11/Z).
Wellcome Trust (097922/Z/11/Z)
Wellcome Trust (100140/Z/12/Z)
Cancer Research UK (12765)
Leukaemia & Lymphoma Research (12029)
Leukemia & Lymphoma Society (7001-12)
MEDICAL RESEARCH COUNCIL (MR/M008975/1)
External DOI: https://doi.org/10.1371/journal.pone.0131577
This record's URL: https://www.repository.cam.ac.uk/handle/1810/248662
Attribution 2.0 UK: England & Wales
Licence URL: http://creativecommons.org/licenses/by/2.0/uk/