# Impact of Coding Variation on Transcription Factor - DNA Recognition

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $867,757

## Abstract

ABSTRACT
Binding by sequence-specific transcription factors (TFs) to their recognition sites is a
primary step in gene regulation. In-depth characterization of the DNA binding
specificities of TFs is essential for understanding how transcriptional regulation is
specified. Technologies developed in the past decade for highly parallel analysis of TF
DNA binding specificities have been used to survey the DNA binding specificities of TFs
from a variety of TF DNA binding domain (DBD) structural classes (e.g., homeodomains)
and species. Nevertheless, despite the generation of these large datasets, a detailed
understanding of TF-DNA binding specificity determinants is still lacking for most TFs.
Disease mutations and naturally occurring coding variation in TFs, especially those
within DBDs, have the potential to alter TF DNA binding activity. However, there is
insufficient understanding of the determinants of TF-DNA binding activity to allow for
accurate prediction of the effects of such coding mutations on DNA binding activity. This
is an important problem, since mutations or coding variation that damage TF DNA
binding activity have the potential to disrupt the regulation of 1,000s of genes in the
human genome.
The goals of this project are to investigate novel DNA binding activity determinants for
major structural classes of human TFs, to determine how heterodimeric protein partners
might modulate the effects of TF coding variants on DNA binding activity, and to
determine the extent to which coding variation that damages intrinsic TF-DNA
recognition alters TF genomic targeting and gene regulation. We anticipate our results
and datasets will reveal determinants of TF-DNA binding specificity, identify what
mutations damage DNA binding specificity or affinity, inform future interpretations of
exome and whole-genome sequence data, and open new areas of investigation into
studies of how TF coding variation impacts transcriptional gene regulation and human
phenotypes.

## Key facts

- **NIH application ID:** 10112946
- **Project number:** 5R01HG010501-03
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** MARTHA L BULYK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $867,757
- **Award type:** 5
- **Project period:** 2019-05-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10112946

## Citation

> US National Institutes of Health, RePORTER application 10112946, Impact of Coding Variation on Transcription Factor - DNA Recognition (5R01HG010501-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10112946. Licensed CC0.

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