Complexity of in-vivo DNA binding preferences of human C2H2 zinc finger transcription factors
Abstract/Contents
- Abstract
- The Cys2-His2 (C2H2)-Zinc Finger (ZF) transcription factors (TFs) constitute approximately half of all human TFs. These TFs contain multiple ZF DNA binding domains, giving rise to the possibility of multiple complex DNA binding motifs arising from the usage of different subsets of ZFs at different binding sites. Although they are the most abundant TF family in the human genome, the C2H2-ZF TFs also remain the most understudied. The lack of antibodies for them combined with their usage of different ZFs in different binding sites have made their in-vivo DNA binding preferences challenging to characterize fully. In this study, we fill this gap by generating genome-wide ChIP-seq profiles for 344 human C2H2-ZF TFs to complement previously published ChIP-seq and ChIP-exo datasets. We then trained neural networks (NNs) to learn high-performance sequence models of base-resolution binding profiles of 509 C2H2-ZF TFs. We discovered 100s of previously uncharacterized novel motifs. Intriguingly, several TFs exhibited complex binding preferences involving secondary motifs, motifs with variable spacing, and alternate motifs within bound Transposable Elements (TEs). Comparisons of these motifs with the commonly used bacterial one hybrid (B1H) ``Recognition Code'' revealed variable context-specific combinatorial usage of ZF domains, including frequent ``skipping'' of individual ZFs. We corroborated these findings by in-vitro characterization of protein-DNA interaction specificity using Spec-seq, HT-SELEX, and Genomic HT-SELEX. The detailed in-vitro measurements of TF-DNA interactions by Spec-seq elucidate the energetic differences across alternate binding modes. Alternative binding modes that are context-specific also reveal the biophysical mechanism behind highly targeted binding to Transposable Elements(TE) by KRAB-ZFs and give us a motif-centric window into KRAB-ZF evolution.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2022; ©2022 |
| Publication date | 2022; 2022 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Banerjee, Abhimanyu |
|---|---|
| Degree supervisor | Doniach, S |
| Degree supervisor | Kundaje, Anshul, 1980- |
| Thesis advisor | Doniach, S |
| Thesis advisor | Kundaje, Anshul, 1980- |
| Thesis advisor | Fordyce, Polly |
| Thesis advisor | Greenleaf, William James |
| Degree committee member | Fordyce, Polly |
| Degree committee member | Greenleaf, William James |
| Associated with | Stanford University, Department of Physics |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Abhimanyu Banerjee. |
|---|---|
| Note | Submitted to the Department of Physics. |
| Thesis | Thesis Ph.D. Stanford University 2022. |
| Location | https://purl.stanford.edu/nx506wd8560 |
Access conditions
- Copyright
- © 2022 by Abhimanyu Banerjee
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
Also listed in
Loading usage metrics...