Chromatin looping defines expression of TAL1, its flanking genes, and regulation in T-ALL

Zhou, Y., Kurukuti, S., Saffrey, P., Vukovic, M., Michie, A.M. , Strogantsev, R., West, A.G. and Vetrie, D. (2013) Chromatin looping defines expression of TAL1, its flanking genes, and regulation in T-ALL. Blood, 122(26), pp. 4199-4209. (doi: 10.1182/blood-2013-02-483875)

Abstract

TAL1 is an important regulator of hematopoiesis and its expression is tightly controlled despite complexities in its genomic organization. It is frequently misregulated in T-cell acute lymphoblastic leukemia (T-ALL), often due to deletions between TAL1 and the neighboring STIL gene. To better understand the events that lead to TAL1 expression in hematopoiesis and in T-ALL, we studied looping interactions at the TAL1 locus. In TAL1-expressing erythroid cells, the locus adopts a looping “hub” which brings into close physical proximity all known TAL1 cis-regulatory elements including CTCF-bound insulators. Loss of GATA1 results in disassembly of the hub and loss of CTCF/RAD21 from one of its insulators. Genes flanking TAL1 are partly dependent on hub integrity for their transcriptional regulation. We identified looping patterns unique to TAL1-expressing T-ALL cells, and, intriguingly, loops occurring between the TAL1 and STIL genes at the common TAL1/STIL breakpoints found in T-ALL. These findings redefine how TAL1 and neighboring genes communicate within the nucleus, and indicate that looping facilitates both normal and aberrant TAL1 expression and may predispose to structural rearrangements in T-ALL. We also propose that GATA1-dependent looping mechanisms may facilitate the conservation of TAL1 regulation despite cis-regulatory remodeling during vertebrate evolution.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: West, Dr Adam and Saffrey, Dr Peter and Michie, Professor Alison and Strogantsev, Mr Ruslan and Vetrie, Professor David and Kurukuti, Dr Sreenivasulu and Vukovic, Ms Milica and Zhou, Mr Yan
• Authors: Zhou, Y., Kurukuti, S., Saffrey, P., Vukovic, M., Michie, A.M., Strogantsev, R., West, A.G., and Vetrie, D.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Blood
• Publisher: American Society of Hematology
• ISSN: 0006-4971
• ISSN (Online): 1528-0020