Transcription of the SCL gene in erythroid and CD34 positive primitive myeloid cells is controlled by a complex network of lineage-restricted chromatin-dependent and chromatin-independent regulatory elements.
The SCL gene (also known as TAL-1) encodes a basic helix-loop-helix transcription factor that is essential for the development of all haematopoietic lineages, and ectopic expression of which results in T cell leukaemia. SCL is expressed in normal pluripotent haematopoietic stem cells and its expression is maintained during differentiation along erythroid, mast and megakaryocytic lineages, but is extinguished following commitment to other cell types. The mechanisms responsible for this pattern of expression are poorly understood, but are likely to illuminate the molecular basis for stem cell development and lineage commitment. We have identified multiple lineage-restricted DNase I hypersensitive sites in a 45 kb region spanning the murine SCL locus. Committed erythroid cells and CD34 positive primitive myeloid cells exhibited both shared and unique DNase I hypersensitive sites whereas none were found in T cells. The function of each hypersensitive site was studied using both transient and stable reporter assays in erythroid, primitive myeloid and T cells. Multiple positive and negative regulatory elements were characterised and found to display lineage-specificity, promoter-specificity and/or chromatin-dependence. These results represent the first description of key components of a complex network of regulatory elements controlling SCL expression during haematopoiesis.
Göttgens
B
B
University of Cambridge, Department of Haematology, MRC Centre, UK.
McLaughlin
F
F
Bockamp
E O
EO
Fordham
J L
JL
Begley
C G
CG
Kosmopoulos
K
K
Elefanty
A G
AG
Green
A R
AR
D000818:Animals; D018952:Antigens, CD34 / Q000032:analysis; D051792:Basic Helix-Loop-Helix Proteins; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D002843:Chromatin / Q000502:physiology* / Q000648:ultrastructure; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D003850:Deoxyribonuclease I / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D004915:Leukemia, Erythroblastic, Acute / Q000235:genetics / Q000473:pathology; D051379:Mice; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins; D012045:Regulatory Sequences, Nucleic Acid; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D018952:Antigens, CD34; D051792:Basic Helix-Loop-Helix Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; D003850:Deoxyribonuclease I; D011518:Proto-Oncogene Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors; C489366:Tal1 protein, mouse