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October 11, 2021 | ESCs/iPSCsHow 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!
References
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- Vaquerizas JM, Kummerfeld SK, Teichmann SA, et al., A census of human transcription factors: function, expression and evolution. Nature Reviews Genetics 2009;10:252-263.
- Slattery M, Zhou T, Yang L, et al., Absence of a simple code: how transcription factors read the genome. Trends in Biochemical Sciences 2014;39:381-399.
- Mohn F and Schübeler D, Genetics and epigenetics: stability and plasticity during cellular differentiation. Trends in Genetics 2009;25:129-136.
- Deaton AM and Bird A, CpG islands and the regulation of transcription. Genes & Development 2011;25:1010-1022.
- Ernst J, Melnikov A, Zhang X, et al., Genome-scale high-resolution mapping of activating and repressive nucleotides in regulatory regions. Nature Biotechnology 2016;34:1180-1190.
- FitzGerald PC, Shlyakhtenko A, Mir AA, et al., Clustering of DNA Sequences in Human Promoters. Genome Research 2004;14:1562-1574.
- Pique-Regi R, Degner JF, Pai AA, et al., Accurate inference of transcription factor binding from DNA sequence and chromatin accessibility data. Genome Research 2011;21:447-455.
- Grand RS, Burger L, Gräwe C, et al., BANP opens chromatin and activates CpG-island-regulated genes. Nature 2021;596:133-137.