A novel mode of enhancer evolution: The Tal1 stem cell enhancer recruited a MIR element to specifically boost its activity

Abstract

Altered cis-regulation is thought to underpin much of metazoan evolution, yet the underlying mechanisms remain largely obscure. The stem cell leukemia TAL1 (also known as SCL) transcription factor is essential for the normal development of blood stem cells and we have previously shown that the Tal1 +19 enhancer directs expression to hematopoietic stem cells, hematopoietic progenitors, and to endothelium. Here we demonstrate that an adjacent region 1 kb upstream (+18 element) is in an open chromatin configuration and carries active histone marks but does not function as an enhancer in transgenic mice. Instead, it boosts activity of the +19 enhancer both in stable transfection assays and during differentiation of embryonic stem (ES) cells carrying single-copy reporter constructs targeted to the Hprt locus. The +18 element contains a mammalian interspersed repeat (MIR) which is essential for the +18 function and which was transposed to the Tal1 locus ∼160 million years ago at the time of the mammalian/marsupial branchpoint. Our data demonstrate a previously unrecognized mechanism whereby enhancer activity is modulated by a transposon exerting a "booster" function which would go undetected by conventional transgenic approaches.

Induction of a detoxification gene in Drosophila melanogaster requires an interaction between tissue specific enhancers and a novel cis-regulatory element

“…CREs have been described as modular and independent from each other (Rebeiz et al, 2009). CREs that have no intrinsic activity but require interaction with existing enhancers have been discovered by transgenic studies in sea urchin and mouse (Smith et al, 2008;Yuh et al, 1996). These CREs, called boosters, do not direct transcription on their own but instead interact with adjacent enhancers to increase transcriptional output constitutively.…”

Comparative studies of gene expression and the evolution of gene regulation

“…Recent experimental results in model systems 74, 97-99 are also resurrecting the classical idea that transposable elements, containing pre-existing transcription factor binding sites, could insert in the vicinity of regulatory loci, and serve as a source of novel regulatory elements 6 . It appears that latent regulatory activity can be located in introns 75 and even deteriorating coding sequences 100 .…”

Identification of Biologically Relevant Enhancers in Human Erythroid Cells

“…Previous studies, such as those of the globin gene loci (77)(78)(79)(80)(81), the GATA1 and SCL/Tal1 gene loci (82)(83)(84)(85)(86)(87)(88)(89)(90)(91)(92)(93), and the erythropoietin gene locus (83), characterized enhancers as distantly located, positively acting cis-regulatory elements (77,80). Recent studies have shown that enhancers have additional, complex roles in cellular gene regulation.…”