title: Aberrant TAL1 activation is mediated by an interchromosomal interaction in human T-cell acute lymphoblastic leukemia.
abstract: Long-range chromatin interactions control metazoan gene transcription. However, the involvement of intra- and interchromosomal interactions in development and oncogenesis remains unclear. TAL1/SCL is a critical transcription factor required for the development of all hematopoietic lineages; yet, aberrant TAL1 transcription often occurs in T-cell acute lymphoblastic leukemia (T-ALL). Here, we report that oncogenic TAL1 expression is regulated by different intra- and interchromosomal loops in normal hematopoietic and leukemic cells, respectively. These intra- and interchromosomal loops alter the cell-type-specific enhancers that interact with the TAL1 promoter. We show that human SET1 (hSET1)-mediated H3K4 methylations promote a long-range chromatin loop, which brings the +51 enhancer in close proximity to TAL1 promoter 1 in erythroid cells. The CCCTC-binding factor (CTCF) facilitates this long-range enhancer/promoter interaction of the TAL1 locus in erythroid cells while blocking the same enhancer/promoter interaction of the TAL1 locus in human T-cell leukemia. In human T-ALL, a T-cell-specific transcription factor c-Maf-mediated interchromosomal interaction brings the TAL1 promoter into close proximity with a T-cell-specific regulatory element located on chromosome 16, activating aberrant TAL1 oncogene expression. Thus, our study reveals a novel molecular mechanism involving changes in three-dimensional chromatin interactions that activate the TAL1 oncogene in human T-cell leukemia.
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: B
authors.initials: B
authors.lastname: Patel
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL, USA [2] College of Life Science, Jilin University, Changchun, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Kang
authors.affiliation: Center for System Biology, NHLBI, National Institute of Health, Bethesda, MD, USA.
authors.forename: K
authors.initials: K
authors.lastname: Cui
authors.affiliation: Medical Education Center, Ball State University, Muncie, IN, USA.
authors.forename: M
authors.initials: M
authors.lastname: Litt
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: M S J
authors.initials: MS
authors.lastname: Riberio
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: C
authors.initials: C
authors.lastname: Deng
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: T
authors.initials: T
authors.lastname: Salz
authors.affiliation: Medical Education Center, Ball State University, Muncie, IN, USA.
authors.forename: S
authors.initials: S
authors.lastname: Casada
authors.affiliation: College of Life Science, Jilin University, Changchun, China.
authors.forename: X
authors.initials: X
authors.lastname: Fu
authors.affiliation: 1] Department of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, FL, USA [2] Shands Cancer Center, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Center for System Biology, NHLBI, National Institute of Health, Bethesda, MD, USA.
authors.forename: K
authors.initials: K
authors.lastname: Zhao
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL, USA [2] Shands Cancer Center, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: S
authors.initials: S
authors.lastname: Huang
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D000076246:CCCTC-Binding Factor; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D002885:Chromosomes, Human, Pair 16; D004742:Enhancer Elements, Genetic; D004843:Epistasis, Genetic; D015672:Erythroid Precursor Cells / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D023061:Gene Order; D056426:Genetic Loci; D006410:Hematopoiesis / Q000235:genetics; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D009928:Organ Specificity / Q000235:genetics; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D051257:Proto-Oncogene Proteins c-maf / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D012097:Repressor Proteins / Q000378:metabolism; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D015533:Transcriptional Activation; D050880:p300-CBP Transcription Factors / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D000076246:CCCTC-Binding Factor; D002843:Chromatin; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones; D011518:Proto-Oncogene Proteins; D051257:Proto-Oncogene Proteins c-maf; D012097:Repressor Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D050880:p300-CBP Transcription Factors; C000619697:CTCF protein, human; C067143:TAL1 protein, human; C526068:Setd1A protein, human