Structural Insight into the DNA Binding Function of Transcription Factor ERF

Abstract

ETS family transcription factors control development of different cell types in humans, whereas deregulation of these proteins leads to severe developmental syndromes and cancers. One of a few members of the ETS family that are known to act solely as repressors, ERF, is required for normal osteogenesis and hematopoiesis. Another important function of ERF is acting as a tumor suppressor by antagonizing oncogenic fusions involving other ETS family factors. The structure of ERF and the DNA binding properties specific to this protein have not been elucidated. In this study, we determined two crystal structures of the complexes of the DNA binding domain of ERF with DNA. In one, ERF is in a distinct dimeric form, with Cys72 in a reduced state. In the other, two dimers of ERF are assembled into a tetramer that is additionally locked by two Cys72–Cys72 disulfide bonds across the dimers. In the tetramer, the ERF molecules are bound to a pseudocontinuous DNA on the same DNA face at two GGAA binding sites on opposite strands. Sedimentation velocity analysis showed that this tetrameric assembly forms on continuous DNA containing such tandem sites spaced by 7 bp. Our bioinformatic analysis of three previously reported sets of ERF binding loci across entire genomes showed that these loci were enriched in such 7 bp spaced tandem sites. Taken together, these results strongly suggest that the observed tetrameric assembly is a functional state of ERF in the human cell.

The CIC-ERF co-deletion underlies fusion-independent activation of ETS family member, ETV1, to drive prostate cancer progression

“…CIC is located on chromosome 19q13.2, directly adjacent to another transcriptional repressor, namely the ERF ( Figure 1B ). ERF binds and competes for ETS TF-binding sites (GGAA-motifs) and is frequently altered in human PCa, predominantly through focal deletions ( Bose et al, 2017 ; Hou et al, 2020 ). We thus hypothesized that concurrent loss of CIC and ERF may de-repress an ETS-driven transcriptional program that drives PCa progression in a fusion-independent manner.…”

The CIC-ERF co-deletion underlies fusion independent activation of ETS family member, ETV1, to drive prostate cancer progression

“…CIC is located on chromosome 19q13.2, directly adjacent to another transcriptional repressor, namely the ETS2 repressor factor ( ERF ) (Fig 1b). ERF binds and competes for ETS TF binding sites (GGAA-motifs) and is frequently altered in human prostate cancer, predominantly through focal deletions 20,24 . We thus hypothesized that concurrent loss of CIC and ERF may de-repress an ETS driven transcriptional program that drives PCa progression in a fusion independent manner.…”

Intrafamilial variability in six family members with ERF‐related craniosynostosis syndrome type 4

“…Furthermore, depletion of ERF is associated with increased levels of fetal hemoglobin in beta-thalassemia (Bao et al, 2021). In contrast to most of the other members of the ETS transcription factor family, ERF acts as a repressor only (Hou et al, 2020). Impaired or loss of function of ERF promotes premature suture ossification, that is, craniosynostosis.…”

“…The ERF (ETS2 repressor factor, OMIM #611888, 19q13.2) gene codes for a member of the ETS transcription factor family, which controls regulation of cell proliferation and differentiation. ERF in particular plays an important role in osteogenesis, cranial development and tumor suppression, such as prostate cancers (Hou et al, 2020). Furthermore, depletion of ERF is associated with increased levels of fetal hemoglobin in beta‐thalassemia (Bao et al, 2021).…”