Using a structural and logics systems approach to infer bHLH–DNA binding specificity determinants

Masi, Federico De; Grove, Christian A.; Vedenko, Anastasia; Alibés, Andreu; Gisselbrecht, Stephen S.; Serrano, Luís; Bulyk, Martha L.; Walhout, Albertha J.M.

doi:10.1093/nar/gkr070

Cited by 73 publications

(96 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1), and there is a corresponding paucity in the diversity of preferred recognition sequences observed for the characterized HD population (Berger et al 2008;Noyes et al 2008a). This focused sequence preference is similar to many other families of DNA-binding domains (Deppmann et al 2006;Wei et al 2010;De Masi et al 2011) and could be the result of a general constraint of the domain architecture on its recognition potential. Consistent with this conjecture, previous attempts to select HDs with novel specificity have not succeeded in achieving dramatic alterations in recognition potential (Pomerantz and Sharp 1994;Connolly et al 1999).…”

supporting

confidence: 54%

“…The diversity in zinc finger protein (ZFP) recognition potential is even manifest within the human population, where differences in the fingers present in PRDM9 and their resulting specificity lead to differences in the location of meiotic recombination hotspots in individuals (Baudat et al 2010). In this regard, ZFPs appear to be an outlier, as most other well-characterized families of DNA-binding domains-like HDs-display limited diversity in their core recognition motifs and the recognition residues that they employ (Deppmann et al 2006;Wei et al 2010;De Masi et al 2011). It is possible that the recognition potential of these other families of DNA-binding domains are similarly constrained.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Exploring the DNA-recognition potential of homeodomains

et al. 2012

View full text Add to dashboard Cite

The recognition potential of most families of DNA-binding domains (DBDs) remains relatively unexplored. Homeodomains (HDs), like many other families of DBDs, display limited diversity in their preferred recognition sequences. To explore the recognition potential of HDs, we utilized a bacterial selection system to isolate HD variants, from a randomized library, that are compatible with each of the 64 possible 39 triplet sites (i.e., TAANNN). The majority of these selections yielded sets of HDs with overrepresented residues at specific recognition positions, implying the selection of specific binders. The DNA-binding specificity of 151 representative HD variants was subsequently characterized, identifying HDs that preferentially recognize 44 of these target sites. Many of these variants contain novel combinations of specificity determinants that are uncommon or absent in extant HDs. These novel determinants, when grafted into different HD backbones, produce a corresponding alteration in specificity. This information was used to create more explicit HD recognition models, which can inform the prediction of transcriptional regulatory networks for extant HDs or the engineering of HDs with novel DNA-recognition potential. The diversity of recovered HD recognition sequences raises important questions about the fitness barrier that restricts the evolution of alternate recognition modalities in natural systems.

show abstract

supporting

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Exploring the DNA-recognition potential of homeodomains

et al. 2012

View full text Add to dashboard Cite

show abstract

“…For structural reasons, individual bHLH proteins display a preference towards particular E-box half-sites, which however, does not necessarily predict the exact binding site of a given hetero-dimer that can even vary at different sites of the genome [9]. Class II bHLH factors cannot form homo-dimers and exert their transcriptional function only in concert with a class I or E-protein such as TCF4 [1].…”

Section: The Basic-helix-loop-helix Protein Tcf4mentioning

confidence: 99%

Transcription factor 4 (TCF4) and schizophrenia: integrating the animal and the human perspective

Quednow

Brzózka

Rossner

2014

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

Schizophrenia is a genetically complex disease considered to have a neurodevelopmental pathogenesis and defined by a broad spectrum of positive and negative symptoms as well as cognitive deficits. Recently, large genome-wide association studies have identified common alleles slightly increasing the risk for schizophrenia. Among the few schizophrenia-risk genes that have been consistently replicated is the basic Helix-Loop-Helix (bHLH) transcription factor 4 (TCF4). Haploinsufficiency of the TCF4 (formatting follows IUPAC nomenclature: TCF4 protein/protein function, Tcf4 rodent gene cDNA mRNA, TCF4 human gene cDNA mRNA) gene causes the Pitt-Hopkins syndrome-a neurodevelopmental disease characterized by severe mental retardation. Accordingly, Tcf4 null-mutant mice display developmental brain defects. TCF4-associated risk alleles are located in putative coding and non-coding regions of the gene. Hence, subtle changes at the level of gene expression might be relevant for the etiopathology of schizophrenia. Behavioural phenotypes obtained with a mouse model of slightly increased gene dosage and electrophysiological investigations with human risk-allele carriers revealed an overlapping spectrum of schizophrenia-relevant endophenotypes. Most prominently, early information processing and higher cognitive functions appear to be associated with TCF4 risk genotypes. Moreover, a recent human study unravelled gene × environment interactions between TCF4 risk alleles and smoking behaviour that were specifically associated with disrupted early information processing. Taken together, TCF4 is considered as an integrator ('hub') of several bHLH networks controlling critical steps of various developmental, and, possibly, plasticity-related transcriptional programs in the CNS and changes of TCF4 expression also appear to affect brain networks important for information processing. Consequently, these findings support the neurodevelopmental hypothesis of schizophrenia and provide a basis for identifying the underlying molecular mechanisms. AbstractSchizophrenia is a genetically complex disease considered to have a neurodevelopmental pathogenesis and defined by a broad spectrum of positive and negative symptoms as well as cognitive deficits.Recently, large genome-wide association studies have identified common alleles slightly increasing the risk for schizophrenia. Among the few schizophrenia-risk genes that have been consistently replicated is the basic Helix-Loop-Helix (bHLH) transcription factor 4 (TCF4 behaviour that were specifically associated with disrupted early information processing. Taken together, TCF4 is considered as an integrator ('hub') of several bHLH networks controlling critical steps of various developmental and possibly also plasticity related transcriptional programs in the CNS and changes of TCF4 expression appear to affect brain networks important for information processing.Consequently, these findings support the neurodevelopmental hypothesis of schizophrenia and provide a basis to identify the und...

show abstract

“…Our comparative DNA retardation assay showed that VP80 efficiently binds DNA in an E-box-independent manner, at least under in vitro conditions. Recently, it was shown for some other bHLH proteins, for instance, Drosophila melanogaster HLH-27 and HLH-29, that they recognize different, E-boxunrelated DNA sequence motifs (4).…”

Section: Discussionmentioning

confidence: 99%

Essential C-Terminal Region of the Baculovirus Minor Capsid Protein VP80 Binds DNA

Marek

Merten

Francis-Devaraj

et al. 2012

J Virol

View full text Add to dashboard Cite

The essential Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV) minor capsid protein VP80 has been recently shown to interact with the virus-triggered, nuclear F-actin cytoskeleton. A role for VP80 in virus morphogenesis has been proposed in the maturation of progeny nucleocapsids and in their egress from the virogenic stroma toward the nuclear periphery by a mechanism, which also includes F-actin filaments. We performed functional mapping of VP80 demonstrating that its highly conserved C-terminal region plays a crucial role in virion morphogenesis. Protein database mining identified a putative basic helix-loop-helix (bHLH) domain, a DNA-binding module typical for eukaryotic transcription factors, in the essential C-terminal region of VP80. Using a molecular modeling approach, we predicted the three-dimensional structure of this domain, revealing some unique properties. Biochemical assays proved that VP80 can form homodimers, a critical prerequisite of DNAbinding bHLH proteins. The ability of VP80 to bind DNA was subsequently confirmed by an electrophoretic mobility shift assay. We further show that AcMNPV DNA replication occurs in the absence of VP80. Immunolabeling of VP80 in baculovirusinfected cells rather points toward its involvement in nucleocapsid maturation. The competence of VP80 to interact with both F-actin and DNA provides novel insight into baculovirus morphogenesis.

show abstract

Using a structural and logics systems approach to infer bHLH–DNA binding specificity determinants

Cited by 73 publications

References 51 publications

Exploring the DNA-recognition potential of homeodomains

Exploring the DNA-recognition potential of homeodomains

Transcription factor 4 (TCF4) and schizophrenia: integrating the animal and the human perspective

Essential C-Terminal Region of the Baculovirus Minor Capsid Protein VP80 Binds DNA

Contact Info

Product

Resources

About