Functional genetic variants can mediate their regulatory effects through alteration of transcription factor binding
Year: 2019
Type: article
Abstract: Functional variants in the genome are usually identified by their association with local gene expression, DNA methylation or chromatin states. DNA sequence motif analysis and chromatin immunoprecipitation studies have provided indirect support for the hypothesis that functional variants alter transcription factor binding to exert their effects. In this study, we provide direct evidence that functional variants can alter transcription factor binding. We identify a multifunctional variant within the TBC1D4 gene encoding a canonical NFκB binding site, and edited it using CRISPR-Cas9 to remove this site. We show that this editing reduces TBC1D4 expression, local chromatin accessibility and binding of the p65 component of NFκB. We then used CRISPR without genomic editing to guide p65 back to the edited locus, demonstrating that this re-targeting, occurring ~182 kb from the gene promoter, is enough to restore the function of the locus, supporting the central role of transcription factors mediating the effects of functional variants.
Source: Nature Communications
Institution: Albert Einstein College of Medicine
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,200
Awards: G1457338957, G3522119324, Targeting CRISPR-based HDAC inhibitors to histones: a new tool for assessing mechanisms of class I HDAC inhibitors and developing chemical probes., G434337789, UNDERSTANDING CELLULAR AND TRANSCRIPTIONAL REGULATORY CHANGES IN HUMAN AGING, Medical Scientist Training Program, NYR-Diabetes Research Center (NYR-DRC)
OpenAlex ID: W2966433686