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How Orphan Motifs Impact Gene Expression in Pluripotent Stem Cells

Review of “BANP opens chromatin and activates CpG-island-regulated genes” from Nature by Stuart P. Atkinson

An incomplete understanding of transcription factors, their DNA-binding motifs, and the cell-specific functionality of genomic binding sites [1-3] represent just some of the factors that we still do not fully understand when considering gene transcription by RNA polymerase II controlled by CpG island promoters [4, 5]. Orphan motifs without known binding factors represent one of the confounding factors; this lack of knowledge is typified by the CGCG element present at a subset of CpG island promoters associated with highly expressed genes in a range of cell types [6-8].

In a recent Nature article, researchers led by Dirk Schübeler (FMI/University of Basel, Switzerland) reported on the identification of BTG3-associated nuclear protein, or BANP, as the transcription factor binding the human and mouse the CGCG elements [9]. Overall, the authors describe how orphan motifs may impact gene expression in cells such as pluripotent stem cells.

Grand et al. combined two cutting-edge molecular techniques - single-molecule footprinting and interaction proteomics - to establish the binding of BANP to the human and mouse CGCG elements, where the transcription factor robustly activated CpG islands that controlled the expression of metabolism-associated genes both in pluripotent stem cells and terminally differentiated neurons. Interestingly, while DNA methylation of the CGCG elements inhibited BANP binding (accounting for its variable binding in cancer cell lines), BANP binding to an unmethylated CGCG element prompted the formation of an open chromatin domain and strong nucleosome phasing at CpG islands.

These findings describe BANP as a crucial transcriptional regulator, and the authors state that this provides further evidence for the DNA methylation-modulated binding of specific transcription factors that can induce chromatin opening.

For more on the potentially important role of BANP in regulating gene expression in pluripotent stem cells, stay tuned to the Stem Cells Portal!


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