Structure of the Forkhead Domain of FOXA2 Bound to a Complete DNA Consensus Site

Li, Jun; Machado, Ana Carolina Dantas; Guo, Ming; Sagendorf, Jared M.; Zhou, Zhan; Jiang, Longying; Chen, Xiaojuan; Wu, Daichao; Qu, Lingzhi; Chen, Zhuchu; Chen, Lin; Rohs, Remo; Chen, Yongheng

doi:10.1021/acs.biochem.7b00211

Cited by 41 publications

(50 citation statements)

References 48 publications

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“…1e). Therefore, and since crystallographic studies have demonstrated that actual DNA shape varies across Forkhead members 5,21 we decided to focus the analyses in the following sections on the DNA shape features, considering only the 1mer + shape models.…”

Section: Resultsmentioning

confidence: 99%

Mechanistic insights into transcription factor cooperativity and its impact on protein-phenotype interactions

et al. 2020

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Recent high-throughput transcription factor (TF) binding assays revealed that TF cooperativity is a widespread phenomenon. However, a global mechanistic and functional understanding of TF cooperativity is still lacking. To address this, here we introduce a statistical learning framework that provides structural insight into TF cooperativity and its functional consequences based on next generation sequencing data. We identify DNA shape as driver for cooperativity, with a particularly strong effect for Forkhead-Ets pairs. Follow-up experiments reveal a local shape preference at the Ets-DNA-Forkhead interface and decreased cooperativity upon loss of the interaction. Additionally, we discover many functional associations for cooperatively bound TFs. Examination of the link between FOXO1:ETV6 and lymphomas reveals that their joint expression levels improve patient clinical outcome stratification. Altogether, our results demonstrate that inter-family cooperative TF binding is driven by position-specific DNA readout mechanisms, which provides an additional regulatory layer for downstream biological functions.

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Section: Resultsmentioning

confidence: 99%

Mechanistic insights into transcription factor cooperativity and its impact on protein-phenotype interactions

et al. 2020

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“…Tridimensional modeling of the wild‐type and mutant FOXA2 DNA‐binding domains predicted conformational changes. These changes were predicted to modify the interaction between FOXA2 and DNA (Figure ) …”

Section: Resultsmentioning

confidence: 99%

“…The crystal structure of the FOXA2 DNA‐binding domain (PDB ID 5X07) was obtained from the RCSB protein databank . The FOXA2 3D model was generated with Discovery Studio Visualizer software (Dassault Systemes BIOVIA, San Diego).…”

Section: Methodsmentioning

confidence: 99%

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Exome sequencing identifies a de novo FOXA2 variant in a patient with syndromic diabetes

et al. 2019

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Objective When diabetes is associated with congenital malformations, without autoimmune antibodies, a genetic cause is suspected. Here, we aimed to identify a defective gene that led to diabetes. Research Design and Methods We performed an exome analysis of an index case and his healthy parents. Results The child presented with childhood‐onset diabetes, congenital hypopituitarism, cardiac malformation, and anal atresia. A DNA analysis revealed a heterozygous de novo pathogenic variant in the developmental transcription factor, forkhead box A2 (FOXA2). The mutation resided in the DNA‐binding domain, which is highly conserved among species. Tridimensional molecular dynamics simulation modeling predicted an altered interaction between the mutated protein and DNA. Conclusions A defect in the FOXA2 DNA‐binding domain was associated with childhood‐onset diabetes and multiple congenital anomalies, which reflected the pleiotropic nature of the gene. This report extends the recently described phenotype of neonatal hypoglycemia to later‐onset diabetes. We suggest to include FOXA2 analysis for neonatal hypoglycemia and to implement a long‐term follow‐up, particularly for the risk of diabetes.

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“…Based on protein structural predictions, all three variants are involved with DNA binding ability of FOXA2 (Boda et al, ). The p.R256S variant in our patient also occurs within the DNA‐binding domain (residues 157–258, [Li et al, ]); however, further functional studies are needed to determine whether the variant seen in this patient causes a dominant‐negative effect or haploinsufficiency.…”

Section: Discussionmentioning

confidence: 99%

Expanding phenotype with severe midline brain anomalies and missense variant supports a causal role for FOXA2 in 20p11.2 deletion syndrome

Dines

Liu

Neufeld-Kaiser

et al. 2019

American J of Med Genetics Pt A

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Rare individuals with 20p11.2 proximal deletions have been previously reported, with a variable phenotype that includes heterotaxy, biliary atresia, midline brain defects associated with panhypopituitarism, intellectual disability, scoliosis, and seizures. Deletions have ranged in size from 277 kb to 11.96 Mb. We describe a newborn with a de novo 2.7 Mb deletion of 20p11.22p11.21 that partially overlaps previously reported deletions and encompasses FOXA2. Her clinical findings further expand the 20p11.2 deletion phenotype to include severe midline cranial and intracranial defects such as aqueductal stenosis with hydrocephalus, mesencephalosynapsis with diencephalic‐mesencephalic junction dysplasia, and pyriform aperture stenosis. We also report one individual with a missense variant in FOXA2 who had abnormal glucose homeostasis, panhypopituitarism, and endodermal organ dysfunction. Together, these findings support the critical role of FOXA2 in panhypopituitarism and midline defects.

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Structure of the Forkhead Domain of FOXA2 Bound to a Complete DNA Consensus Site

Cited by 41 publications

References 48 publications

Mechanistic insights into transcription factor cooperativity and its impact on protein-phenotype interactions

Mechanistic insights into transcription factor cooperativity and its impact on protein-phenotype interactions

Exome sequencing identifies a de novo FOXA2 variant in a patient with syndromic diabetes

Expanding phenotype with severe midline brain anomalies and missense variant supports a causal role for FOXA2 in 20p11.2 deletion syndrome

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