DNA binding analysis of rare variants in homeodomains reveals novel homeodomain specificity-determining residues
Kian Hong Kock,Patrick K. Kimes,Stephen S. Gisselbrecht,Sachi Inukai,Sabrina K. Phanor,James T. Anderson,Gayatri Ramakrishnan,Colin H. Lipper,Dongyuan Song,Jesse V. Kurland,Julia M. Rogers,Raehoon Jeong,Stephen C. Blacklow,Rafael A. Irizarry,Martha L. Bulyk +14 more
TL;DR: In this article , the second largest class of DNA binding domains (DBDs) among eukaryotic sequence-specific transcription factors (TFs) were analyzed for their effects on DNA binding activity.
read more
Abstract: Homeodomains (HDs) are the second largest class of DNA binding domains (DBDs) among eukaryotic sequence-specific transcription factors (TFs) and play important roles in regulating development, body patterning, and cellular differentiation. Here, we analyzed 92 human HD mutants, including disease-associated variants and variants of unknown significance (VUSs), for their effects on DNA binding activity. Many of the variants altered DNA binding affinity and/or specificity. Biochemical analysis and structural modeling identified 14 novel specificity-determining positions, 5 of which do not contact DNA. The same missense substitution at analogous positions within different HDs often exhibited different effects on DNA binding. Variant effect prediction tools perform moderately well in distinguishing variants with altered binding affinity, but poorly in identifying those with altered specificity. Our results highlight the need for biochemical assays of TF coding variants and prioritize dozens of variants for further investigations into their pathogenicity and development of clinical diagnostics and precision therapies.
read more
Chat with Paper
AI Agents for this Paper
Find similar papers on Google Scholar, PubMed and Arxiv
Write a critical review of this paper
Analyze citations of this paper to find unaddressed research gaps
Citations
Widespread variation in molecular interactions and regulatory properties among transcription factor isoforms
Luke Lambourne,Kaia Mattioli,Clarissa Stephanie Santoso,Gloria Sheynkman,Sachi Inukai,Babita Kaundal,A. Berenson,Kerstin Spirohn-Fitzgerald,Anukana Bhattacharjee,Elisabeth Rothman,Shaleen Shrestha,Florent Laval,Zhipeng Yang,Deepa Bisht,J. Sewell,Guangyuan Li,Anisa Prasad,Sabrina K. Phanor,Ryan Lane,Devlin M. Campbell,Toby Hunt,Dawit Balcha,Marinella Gebbia,Jean-Claude Twizere,Tong Hao,Adam Frankish,Josh A. Riback,Nathan Salomonis,Michael A. Calderwood,David E. Hill,Nidhi Sahni,Marc Vidal,Martha L. Bulyk,Juan I. Fuxman Bass +33 more
TL;DR: The widespread variation in molecular interactions and regulatory properties among transcription factor isoforms results in functional differences in gene regulation.
References
Fast gapped-read alignment with Bowtie 2
TL;DR: Bowtie 2 combines the strengths of the full-text minute index with the flexibility and speed of hardware-accelerated dynamic programming algorithms to achieve a combination of high speed, sensitivity and accuracy.
limma powers differential expression analyses for RNA-sequencing and microarray studies
Matthew E. Ritchie,Belinda Phipson,Di Wu,Yifang Hu,Charity W. Law,Wei Shi,Gordon K. Smyth,Gordon K. Smyth +7 more
TL;DR: The philosophy and design of the limma package is reviewed, summarizing both new and historical features, with an emphasis on recent enhancements and features that have not been previously described.
Model-based Analysis of ChIP-Seq (MACS)
Yong Zhang,Tao Liu,Clifford A. Meyer,Jérôme Eeckhoute,David S. Johnson,Bradley E. Bernstein,Bradley E. Bernstein,Chad Nusbaum,Richard M. Myers,Myles Brown,Wei Li,X. Shirley Liu +11 more
TL;DR: This work presents Model-based Analysis of ChIP-Seq data, MACS, which analyzes data generated by short read sequencers such as Solexa's Genome Analyzer, and uses a dynamic Poisson distribution to effectively capture local biases in the genome, allowing for more robust predictions.
An integrated encyclopedia of DNA elements in the human genome
TL;DR: The Encyclopedia of DNA Elements project provides new insights into the organization and regulation of the authors' genes and genome, and is an expansive resource of functional annotations for biomedical research.
•Journal Article
An integrated encyclopedia of DNA elements in the human genome.
TL;DR: The Encyclopedia of DNA Elements project provides new insights into the organization and regulation of the authors' genes and genome, and is an expansive resource of functional annotations for biomedical research.
12.5K