TY  - JOUR
A1  - Telorac, Jonas
A1  - Prykhozhij, Sergey V.
A1  - Schöne, Stefanie
A1  - Meierhofer, David
A1  - Sauer, Sascha
A1  - Thomas-Chollier, Morgane
A1  - Meijsing, Sebastiaan H.
T1  - Identification and characterization of DNA sequences that prevent glucocorticoid receptor binding to nearby response elements
JF  - Nucleic Acids Research
N2  - Out of the myriad of potential DNA binding sites of the glucocorticoid receptor (GR) found in the human genome, only a cell-type specific minority is actually bound, indicating that the presence of a recognition sequence alone is insufficient to specify where GR binds. Cooperative interactions with other transcription factors (TFs) are known to contribute to binding specificity. Here, we reasoned that sequence signals preventing GR recruitment to certain loci provide an alternative means to confer specificity. Motif analyses uncovered candidate Negative Regulatory Sequences (NRSs) that interfere with genomic GR binding. Subsequent functional analyses demonstrated that NRSs indeed prevent GR binding to nearby response elements. We show that NRS activity is conserved across species, found in most tissues and that they also interfere with the genomic binding of other TFs. Interestingly, the effects of NRSs appear not to be a simple consequence of changes in chromatin accessibility. Instead, we find that NRSs interact with proteins found at sub-nuclear structures called paraspeckles and that these proteins might mediate the repressive effects of NRSs. Together, our studies suggest that the joint influence of positive and negative sequence signals partition the genome into regions where GR can bind and those where it cannot.
KW  - DNA sequencing
KW  - glucocorticoid receptor
KW  - DNA binding
KW  - transcription factors
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166330
VL  - 44
IS  - 13
ER  - 
TY  - JOUR
A1  - Klein-Hessling, Stefan
A1  - Rudolf, Ronald
A1  - Muhammad, Khalid
A1  - Knobeloch, Klaus-Peter
A1  - Maqbool, Muhammad Ahmad
A1  - Cauchy, Pierre
A1  - Andrau, Jean-Christophe
A1  - Avots, Andris
A1  - Talora, Claudio
A1  - Ellenrieder, Volker
A1  - Screpanti, Isabella
A1  - Serfling, Edgar
A1  - Patra, Amiya Kumar
T1  - A threshold level of NFATc1 activity facilitates thymocyte differentiation and opposes notch-driven leukaemia development
JF  - Nature Communications
N2  - NFATc1 plays a critical role in double-negative thymocyte survival and differentiation. However, the signals that regulate Nfatc1 expression are incompletely characterized. Here we show a developmental stage-specific differential expression pattern of Nfatc1 driven by the distal (P1) or proximal (P2) promoters in thymocytes. Whereas, preTCR-negative thymocytes exhibit only P2 promoter-derived Nfatc1β expression, preTCR-positive thymocytes express both Nfatc1β and P1 promoter-derived Nfatc1α transcripts. Inducing NFATc1α activity from P1 promoter in preTCR-negative thymocytes, in addition to the NFATc1β from P2 promoter impairs thymocyte development resulting in severe T-cell lymphopenia. In addition, we show that NFATc1 activity suppresses the B-lineage potential of immature thymocytes, and consolidates their differentiation to T cells. Further, in the pTCR-positive DN3 cells, a threshold level of NFATc1 activity is vital in facilitating T-cell differentiation and to prevent Notch3-induced T-acute lymphoblastic leukaemia. Altogether, our results show NFATc1 activity is crucial in determining the T-cell fate of thymocytes.
KW  - acute lymphocytic leukaemia
KW  - transcription factors
KW  - lymphocyte differentiation
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-172974
VL  - 7
ER  -