title: A far downstream enhancer for murine Bcl11b controls its T-cell specific expression.
abstract: Bcl11b is a T-cell specific gene in hematopoiesis that begins expression during T-lineage commitment and is required for this process. Aberrant expression of BCL11B or proto-oncogene translocation to the vicinity of BCL11B can be a contributing factor in human T-ALL. To identify the mechanism that controls its distinctive T-lineage expression, we corrected the identified Bcl11b transcription start site and mapped a cell-type-specific differentially methylated region bracketing the Bcl11b promoter. We identified a 1.9-kb region 850 kb downstream of Bcl11b, "Major Peak," distinguished by its dynamic histone marking pattern in development that mirrors the pattern at the Bcl11b promoter. Looping interactions between promoter-proximal elements including the differentially methylated region and downstream elements in the Major Peak are required to recapitulate the T-cell specific expression of Bcl11b in stable reporter assays. Functional dissection of the Major Peak sequence showed distinct subregions, in which TCF-1 sites and a conserved element were required for T-lineage-specific activation and silencing in non-T cells. A bacterial artificial chromosome encompassing the full Bcl11b gene still required the addition of the Major Peak to exhibit T-cell specific expression. Thus, promoter-proximal and Major Peak sequences are cis-regulatory elements that interact over 850 kb to control expression of Bcl11b in hematopoietic cells.
authors.affiliation: Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Long
authors.initials: L
authors.lastname: Li
authors.forename: Jingli A
authors.initials: JA
authors.lastname: Zhang
authors.forename: Marei
authors.initials: M
authors.lastname: Dose
authors.forename: Hao Yuan
authors.initials: HY
authors.lastname: Kueh
authors.forename: Ruzbeh
authors.initials: R
authors.lastname: Mosadeghi
authors.forename: Fotini
authors.initials: F
authors.lastname: Gounari
authors.forename: Ellen V
authors.initials: EV
authors.lastname: Rothenberg
mesh_terms: D000818:Animals; D019070:Cell Lineage; D018899:CpG Islands; D019175:DNA Methylation; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D020868:Gene Silencing; D017930:Genes, Reporter; D006412:Hematopoietic Stem Cells; D006657:Histones / Q000378:metabolism; D051379:Mice; D011401:Promoter Regions, Genetic; D000090063:Proto-Oncogene Mas; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C511143:Bcl11b protein, mouse; D006657:Histones; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D012097:Repressor Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins