Abstract
The SCL (TAL1) transcription factor is a critical regulator of haematopoiesis and its expression is tightly controlled by multiple cis-acting regulatory elements. To elaborate further the DNA elements which control its regulation, we used genomic tiling microarrays covering 256 kb of the human SCL locus to perform a concerted analysis of chromatin structure and binding of regulatory proteins in human haematopoietic cell lines. This approach allowed us to characterise further or redefine known human SCL regulatory elements and led to the identification of six novel elements with putative regulatory function both up and downstream of the SCL gene. They bind a number of haematopoietic transcription factors (GATA1, E2A LMO2, SCL, LDB1), CTCF or components of the transcriptional machinery and are associated with relevant histone modifications, accessible chromatin and low nucleosomal density. Functional characterisation shows that these novel elements are able to enhance or repress SCL promoter activity, have endogenous promoter function or enhancer-blocking insulator function. Our analysis opens up several areas for further investigation and adds new layers of complexity to our understanding of the regulation of SCL expression.
Highlights
Understanding the molecular events which occur as stem cells differentiate into committed cell lineages is a fundamental issue in cell biology
It has been shown that the SCL (TAL1) gene is central to the mechanisms whereby pluripotent stem cells differentiate into haematopoietic stem cells (HSCs) that give rise to the various blood lineages
We describe here the first comprehensive analysis using chromatin immunoprecipitation (ChIP)-chip approaches and downstream analyses to facilitate the characterization of a further set of genomic cis-acting sequences which underlie the regulation of gene expression at the human SCL locus
Summary
Understanding the molecular events which occur as stem cells differentiate into committed cell lineages is a fundamental issue in cell biology. It has been shown that the SCL (TAL1) gene is central to the mechanisms whereby pluripotent stem cells differentiate into haematopoietic stem cells (HSCs) that give rise to the various blood lineages. While this process is thought to be tightly regulated at the level of gene expression, the exact ways in which SCL helps direct this process are not well understood. SCL expression is required for normal differentiation of erythroid and megakaryocytic lineages [7,9], whereas inappropriate expression during T-cell differentiation leads to T-cell acute lymphoblastic leukemia (T-ALL) [10]
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