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The heterochronic LIN-14 protein is a BEN domain transcription factor.

ABSTRACT: Heterochrony is a foundational concept in animal development and evolution, first introduced by Ernst Haeckel in 1875 and later popularized by Stephen J. Gould¹. A molecular understanding of heterochrony was first established by genetic mutant analysis in the nematode C. elegans, revealing a genetic pathway that controls the proper timing of cellular patterning events executed during distinct postembryonic juvenile and adult stages². This genetic pathway is composed of a complex temporal cascade of multiple regulatory factors, including the first-ever discovered miRNA, lin-4, and its target gene, lin-14, which encodes a nuclear, DNA-binding protein²^,³^,⁴. While all core members of the pathway have homologs based on primary sequences in other organisms, homologs for LIN-14 have never been identified by sequence homology. We report that the AlphaFold-predicted structure of the LIN-14 DNA binding domain is homologous to the BEN domain, found in a family of DNA binding proteins previously thought to have no nematode homologs⁵. We confirmed this prediction through targeted mutations of predicted DNA-contacting residues, which disrupt in vitro DNA binding and in vivo function. Our findings shed new light on potential mechanisms of LIN-14 function and suggest that BEN domain-containing proteins may have a conserved role in developmental timing.

SUBMITTER: Greene S

PROVIDER: S-EPMC10080584 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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The heterochronic LIN-14 protein is a BEN domain transcription factor.

Greene Sharrell S Huang Ji J Hamilton Keith K Tong Liang L Hobert Oliver O Sun HaoSheng H

Current biology : CB 20230301 6

Heterochrony is a foundational concept in animal development and evolution, first introduced by Ernst Haeckel in 1875 and later popularized by Stephen J. Gould<sup>1</sup>. A molecular understanding of heterochrony was first established by genetic mutant analysis in the nematode C. elegans, revealing a genetic pathway that controls the proper timing of cellular patterning events executed during distinct postembryonic juvenile and adult stages<sup>2</sup>. This genetic pathway is composed of a co ...[more]

PMID: 36977380

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Project description:BackgroundBoundaries in the Drosophila bithorax complex delimit autonomous regulatory domains that activate the parasegment (PS)-specific expression of homeotic genes. The Fab-7 boundary separates the iab-6 and iab-7 regulatory domains that control Abd-B expression in PS11 and PS12. This boundary is composed of multiple functionally redundant elements and has two key activities: it blocks crosstalk between iab-6 and iab-7 and facilitates boundary bypass.ResultsHere, we have used a structure-function approach to elucidate the biochemical properties and the in vivo activities of a conserved BEN domain protein, Insensitive, that is associated with Fab-7. Our biochemical studies indicate that in addition to the C-terminal BEN DNA-binding domain, Insv has two domains that mediate multimerization: one is a coiled-coil domain in the N-terminus, and the other is next to the BEN domain. These multimerization domains enable Insv to bind simultaneously to two canonical 8-bp recognition motifs, as well as to a ~ 100-bp non-canonical recognition sequence. They also mediate the assembly of higher-order multimers in the presence of DNA. Transgenic proteins lacking the N-terminal coiled-coil domain are compromised for boundary function in vivo. We also show that Insv interacts directly with CP190, a protein previously implicated in the boundary functions of several DNA-binding proteins, including Su(Hw) and dCTCF. While CP190 interaction is required for Insv binding to a subset of sites on polytene chromosomes, it has only a minor role in the boundary activity of Insv in the context of Fab-7.ConclusionsThe subdivision of eukaryotic chromosomes into discrete topological domains depends upon the pairing of boundary elements. In flies, pairing interactions are specific and typically orientation dependent. They occur in cis between neighboring heterologous boundaries, and in trans between homologous boundaries. One potential mechanism for ensuring pairing-interaction specificity is the use of sequence-specific DNA-binding proteins that can bind simultaneously with two or more recognition sequences. Our studies indicate that Insv can assemble into a multivalent DNA-binding complex and that the N-terminal Insv multimerization domain is critical for boundary function.

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The heterochronic LIN-14 protein is a BEN domain transcription factor.

Publications

The heterochronic LIN-14 protein is a BEN domain transcription factor.

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