A mechanism for Ikaros regulation of human globin gene switching
BRITISH JOURNAL OF HAEMATOLOGY
Authors: Keys, Janelle R.; Tallack, Michael R.; Zhan, Ye; Papathanasiou, Peter; Goodnow, Christopher C.; Gaensler, Karin M.; Crossley, Merlin; Dekker, Job; Perkins, Andrew C.
Abstract
The human beta globin locus consists of an upstream LCR and functional genes arranged sequentially in the order of their expression during development: 5'-HBE1, HBG2, HBG1, HBD, HBB-3'. Haemoglobin switching entails the successive recruitment of these genes into an active chromatin hub (ACH). Here we show that the transcription factor Ikaros plays a major role in the formation of the beta-globin ACH, and in haemoglobin switching. In Plastic mice, where the DNA-binding region of Ikaros is disrupted by a point mutation, there is concomitant marked down-regulation of HBB, and up-regulation of HBG expression. We show for the first time Ikaros and its family member Eos, bind to critical cis elements implicated in haemoglobin switching and deletional hereditary persistence of fetal haemoglobin (HPFH). Chromatin conformation capture (3C) data demonstrated that Ikaros facilitates long-distance DNA looping between the LCR and a region upstream of HBD. This study provides new insights into the mechanism of stage-specific assembly of the beta-globin ACH, and HPFH.
Transcriptional regulation of tracheo-bronchial mucin (TBM) gene by ethanol
GENE
Authors: Verma, M; Davidson, EA
Abstract
The epithelia of the respiratory tract are protected by a mucin glycoprotein. The expression of mucin changes when epithelia come in contact with toxic agents such as ethanol. Previously, we have identified and characterized the expression of a tracheobronchial mucin (TBM) gene. In the present study, we observed that ethanol regulates TBM expression at the transcription level. Ethanol enhanced the expression of TBM mRNA in a dose- and time-dependent manner in HBE1 cells. At 100 mM concentration (a concentration reported to be present in alcoholics), ethanol induced an eight-fold increase in TBM transcription as determined by reporter gene expression analysis. (C) 1997 Elsevier Science B.V.