Work

Missense variants in human forkhead transcription factors reveal determinants of forkhead DNA bispecificity

Year: 2025

Type: article

Abstract: Recognition of specific DNA sequences by transcription factors (TFs) is a key step in transcriptional control of gene expression. While most forkhead (FH) TFs bind either an FKH (RYAAAYA) or an FHL (GACGC) recognition motif, some FHs can bind both motifs. Mechanisms that control whether a FH is monospecific versus bispecific have remained unknown. Screening a library of 12 reference FH proteins, 61 naturally occurring missense variants including clinical variants, and 22 designed mutant FHs for DNA binding activity using universal (“all 10-mer”) protein binding microarrays (PBMs) revealed non-DNA-contacting residues that control mono- versus bispecificity. Variation in non-DNA-contacting amino acid residues of TFs is associated with human traits and may play a role in the evolution of TF DNA binding activities and gene regulatory networks.

Source: Cell Reports

DOI: 10.1016/j.celrep.2025.116427

Authors: Jessica King, Stephen S. Gisselbrecht, Julie-Alexia Dias, Raehoon Jeong, Elisabeth Rothman, Martha L. Bulyk

Institutions: Brigham and Women's Hospital, Harvard University

Language: English

Topic: Genomics and Chromatin Dynamics

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: gold

Estimated APC paid: $5,620

Funders: National Institutes of Health, National Human Genome Research Institute