A comparative analysis of transcription factor binding models learned from PBM, HT-SELEX and ChIP data

By Yaron Orenstein, Ron Shamir. 2014

96 citations recorded by the source corpus.

Understanding gene regulation is a key challenge in today's biology. The new technologies of protein-binding microarrays (PBMs) and high-throughput SELEX (HT-SELEX) allow measurement of the binding intensities of one transcription factor (TF) to numerous synthetic double-stranded DNA sequences in a single experiment. Recently, Jolma et al. reported the results of 547 HT-SELEX experiments covering human and mouse TFs. Because 162 of these TFs were also covered by PBM technology, for the first time, a large-scale comparison between implementations of these two in vitro technologies is possible. Here we assessed the similarities and differences between binding models, represented as position weight matrices, inferred from PBM and HT-SELEX, and also measured how well these models predict in vivo binding. Our results show that HT-SELEX- and PBM-derived models agree for most TFs. For some TFs, the HT-SELEX-derived models are longer versions of the PBM-derived models, whereas for other TFs, the HT-SELEX models match the secondary PBM-derived models. Remarkably, PBM-based 8-mer ranking is more accurate than that of HT-SELEX, but models derived from HT-SELEX predict in vivo binding better. In addition, we reveal several biases in HT-SELEX data including nucleotide frequency bias, enrichment of C-rich k-mers and oligos and underrepresentation of palindromes.

Subfields: Molecular Biology

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

1. Dirk Schübeler
2. Jussi Taipale
3. Paul Adrian Ginno
4. P. Beachy
5. Benjamin L. Ebert
6. Siddhartha Jaiswal

Citations in the corpus

• Impact of cytosine methylation on DNA binding specificities of human transcription factors (2017, methodology): “We (21, 26, 27) and others have previously established that motifs generated using HT-SELEX are similar to those obtained using other state-of-the-art methods, such as protein-binding microarrays or bacterial one-hybrid assays (28, 29), and are biologically relevant on the basis of their ability to ”
• Conservation of transcription factor binding specificities across 600 million years of bilateria evolution (2015, background): “We and others have shown earlier that inclusion of dimeric sites and the extended flanking specificity improve prediction of in vivo occupied sites (Jolma et al., 2013; Orenstein and Shamir, 2014), indicating that the extended specificity information revealed by HT-SELEX is biologically relevant.”