Transcriptional regulation of the stem cell leukaemia gene (SCL/TAL1) via chromatin looping

RB Pathology

Zhou, Yan ; Vetrie, David

University:University of Glasgow

Department:Institute of Cancer Sciences

关键词: TAL1/SCL, LYL1, chromosome conformation capture(3C), 4C-array, T-cell acute lymphoblastic leukemia, chromatin looping, transcriptional regulation;   

Others  :  http://theses.gla.ac.uk/4004/1/2012zhouphd.pdf

来源: University of Glasgow

【 摘 要 】

The bHLH protein TAL1 (SCL) is a critical regulator of vertebrate hematopoiesis and is misregulated in T-cell acute lymphoblastic leukemia (T-ALL). This thesis studied chromatin looping interactions at the TAL1 locus – defining the first structural model which accounts for a number of phenomena associated with TAL1, its flanking genes and its relationship with its functional paralogue LYL1. The chromosome conformation capture (3C) and its high-throughput variant 4C-array technologies have been applied to characterise the chromatin interactions. Intriguing chromatin organisations have been identified at the TAL1 and LYL1 loci, which are closely associated with transcriptional regulation, chromosomal abnormality and regulatory remodelling through evolution. Firstly, in TAL1 expressing cells, the locus adopts a “cruciform” configuration – forming an active chromatin hub which brings together the TAL1 promoters, its stem cell and erythroid enhancers, and two CTCF/Rad21-bound insulators.Secondly, loss of a GATA1-containing complex bound by the TAL1 erythroid enhancer and its promoter is sufficient to disrupt the formation of the hub and the entire cruciform structure and results in decreased TAL1 expression. Thirdly, it demonstrates that genes flanking TAL1 are also dependent on this hub and that TAL1 promoters interact directly with intron 1 of the neighbouring STIL gene. This TAL1/STIL interaction also provides a structural link between the DNA sequences which mediate micro-deletions in 25% of cases of T-ALL. Finally, it demonstrates that a GATA1-dependent chromatin looping mechanism also exists at the LYL1 locus which is strikingly similar to that mediating contact between the TAL1 promoter and its erythroid enhancer. Conservation of core chromatin looping at the TAL1 and LYL1 loci may account for some aspects of their functional relationships. It also suggests that looping mechanisms at both loci could also facilitate cis-regulatory maintenance and/or remodelling during vertebrate evolution.