To Be Specific or Not: The Critical Relationship Between Hox And TALE Proteins

Merabet, Samir; Mann, Richard S.

doi:10.1016/j.tig.2016.03.004

Cited by 129 publications

(157 citation statements)

References 77 publications

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“…In most Hox proteins, the W motif is related to the sequence YPWM (Merabet and Mann, 2016). In contrast, AbdB and its vertebrate orthologs rely on a distinct W-containing motif, which in AbdB is HEWT.…”

Section: Resultsmentioning

confidence: 99%

“…This problem is particularly striking for the Hox TFs, which all bind closely related TAAT-containing DNA motifs as monomers. However, upon heterodimerization with the Hox cofactor Extradenticle (Exd in Drosophila ; Pbx in vertebrates) distinct DNA binding preferences between different Hox-Exd heterodimers emerge (Merabet and Mann, 2016; Slattery et al, 2011). This phenomenon has been termed “latent specificity,” and depends on cofactor-mediated conformational stabilization of the N-terminal arms (NTAs) of Hox homeodomains.…”

Section: Introductionmentioning

confidence: 99%

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Intrinsic DNA Shape Accounts for Affinity Differences between Hox-Cofactor Binding Sites

et al. 2018

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SUMMARY Transcription factors bind to their binding sites over a wide range of affinities, yet how differences in affinity are encoded in DNA sequences is not well understood. Here, we report X-ray crystal structures of four heterodimers of the Hox protein AbdominalB bound with its cofactor Extradenticle to four target DNA molecules that differ in affinity by up to ~20-fold. Remarkably, despite large differences in affinity, the overall structures are very similar in all four complexes. In contrast, the predicted shapes of the DNA binding sites (i.e., the intrinsic DNA shape) in the absence of bound protein are strikingly different from each other and correlate with affinity: binding sites that must change conformations upon protein binding have lower affinities than binding sites that have more optimal conformations prior to binding. Together, these observations suggest that intrinsic differences in DNA shape provide a robust mechanism for modulating affinity without affecting other protein-DNA interactions.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Intrinsic DNA Shape Accounts for Affinity Differences between Hox-Cofactor Binding Sites

et al. 2018

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“…1 B and C). This finding is illustrated by enrichment at 12 h compared with 2 h for bipartite Hox-Pbx motifs, which serve as elements that integrate combinatorial binding of Hox, Pbx, and Meis (40). It is worth noting that Pbx1 is expressed at low levels in uninduced ES cells but Pbx, Meis, and other TALE (three amino acid loop extension proteins) transcription activator-like effector cofactors, known to partner with Hox proteins, are not generally available early in the differentiation process.…”

Section: Resultsmentioning

confidence: 99%

“…This finding suggests that there are likely to be temporal differences in the utilization of cofactors that impact site selection and binding specificity/affinity. Therefore, the shifts in binding profiles and sequence preferences may be mediated through temporal differences in the levels of expression or activity of Hoxa1 itself, and through variation of Hox cofactors, such as TALE proteins, chromatin modifiers, or other TFs that modulate Hoxa1 binding (40).…”

Section: Resultsmentioning

confidence: 99%

Dynamic regulation of Nanog and stem cell-signaling pathways by Hoxa1 during early neuro-ectodermal differentiation of ES cells

Kumar

Parker

Parrish

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Homeobox a1 (Hoxa1) is one of the most rapidly induced genes in ES cell differentiation and it is the earliest expressed Hox gene in the mouse embryo. In this study, we used genomic approaches to identify Hoxa1-bound regions during early stages of ES cell differentiation into the neuro-ectoderm. Within 2 h of retinoic acid treatment, Hoxa1 is rapidly recruited to target sites that are associated with genes involved in regulation of pluripotency, and these genes display early changes in expression. The pattern of occupancy of Hoxa1 is dynamic and changes over time. At 12 h of differentiation, many sites bound at 2 h are lost and a new cohort of bound regions appears. At both time points the genome-wide mapping reveals that there is significant co-occupancy of Nanog (Nanog homeobox) and Hoxa1 on many common target sites, and these are linked to genes in the pluripotential regulatory network. In addition to shared target genes, Hoxa1 binds to regulatory regions of Nanog, and conversely Nanog binds to a 3′ enhancer of Hoxa1. This finding provides evidence for direct cross-regulatory feedback between Hoxa1 and Nanog through a mechanism of mutual repression. Hoxa1 also binds to regulatory regions of Sox2 (sex-determining region Y box 2), Esrrb (estrogen-related receptor beta), and Myc, which underscores its key input into core components of the pluripotential regulatory network. We propose a model whereby direct inputs of Nanog and Hoxa1 on shared targets and mutual repression between Hoxa1 and the core pluripotency network provides a molecular mechanism that modulates the fine balance between the alternate states of pluripotency and differentiation.

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“…This suggests that all PLT/AIL members can bind to the same sequence motif, which is in agreement with the large overlap in regulated genes, their ability to (partially) complement plt1 plt2 double mutants and the similar root phenotypes upon overexpression. In animal systems, the limited binding specificity of homeodomain transcription factors is known to be increased by their interaction with transcription factors of the TALE superfamily (Merabet and Mann, 2016). In a similar way, yet to be identified coregulators of PLT proteins may refine target specificity.…”

Section: Discussionmentioning

confidence: 99%

The PLETHORA Gene Regulatory Network Guides Growth and Cell Differentiation in Arabidopsis Roots

et al. 2016

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Organ formation in animals and plants relies on precise control of cell state transitions to turn stem cell daughters into fully differentiated cells. In plants, cells cannot rearrange due to shared cell walls. Thus, differentiation progression and the accompanying cell expansion must be tightly coordinated across tissues. PLETHORA (PLT) transcription factor gradients are unique in their ability to guide the progression of cell differentiation at different positions in the growing Arabidopsis thaliana root, which contrasts with well-described transcription factor gradients in animals specifying distinct cell fates within an essentially static context. To understand the output of the PLT gradient, we studied the gene set transcriptionally controlled by PLTs. Our work reveals how the PLT gradient can regulate cell state by region-specific induction of cell proliferation genes and repression of differentiation. Moreover, PLT targets include major patterning genes and autoregulatory feedback components, enforcing their role as master regulators of organ development.

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To Be Specific or Not: The Critical Relationship Between Hox And TALE Proteins

Cited by 129 publications

References 77 publications

Intrinsic DNA Shape Accounts for Affinity Differences between Hox-Cofactor Binding Sites

Intrinsic DNA Shape Accounts for Affinity Differences between Hox-Cofactor Binding Sites

Dynamic regulation of Nanog and stem cell-signaling pathways by Hoxa1 during early neuro-ectodermal differentiation of ES cells

The PLETHORA Gene Regulatory Network Guides Growth and Cell Differentiation in Arabidopsis Roots

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