title: Chromatin looping defines expression of TAL1, its flanking genes, and regulation in T-ALL.
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.
authors.affiliation: Epigenetics Unit and.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.forename: Sreenivasulu
authors.initials: S
authors.lastname: Kurukuti
authors.forename: Peter
authors.initials: P
authors.lastname: Saffrey
authors.forename: Milica
authors.initials: M
authors.lastname: Vukovic
authors.forename: Alison M
authors.initials: AM
authors.lastname: Michie
authors.forename: Ruslan
authors.initials: R
authors.lastname: Strogantsev
authors.forename: Adam G
authors.initials: AG
authors.lastname: West
authors.forename: David
authors.initials: D
authors.lastname: Vetrie
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D002843:Chromatin / Q000737:chemistry / Q000235:genetics*; D004742:Enhancer Elements, Genetic / Q000235:genetics; D050982:GATA1 Transcription Factor / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D019169:Jurkat Cells; D020014:K562 Cells; D008214:Lymphocytes / Q000166:cytology; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008813:Mice, Inbred ICR; D009703:Nucleoside-Phosphate Kinase / Q000235:genetics; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011487:Protein Conformation; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002843:Chromatin; D050982:GATA1 Transcription Factor; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009703:Nucleoside-Phosphate Kinase; D011518:Proto-Oncogene Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; C494688:GATA1 protein, human; C509768:PDZK1IP1 protein, human; C071236:STIL protein, human; C067143:TAL1 protein, human; C019979:cytidylate kinase