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The cis-regulatory logic underlying abdominal Hox-mediated repression versus activation of regulatory elements in Drosophila.

ABSTRACT: During development diverse transcription factor inputs are integrated by cis-regulatory modules (CRMs) to yield cell-specific gene expression. Defining how CRMs recruit the appropriate combinations of factors to either activate or repress gene expression remains a challenge. In this study, we compare and contrast the ability of two CRMs within the Drosophila embryo to recruit functional Hox transcription factor complexes. The DCRE CRM recruits Ultrabithorax (Ubx) and Abdominal-A (Abd-A) Hox complexes that include the Extradenticle (Exd) and Homothorax (Hth) transcription factors to repress the Distal-less leg selector gene, whereas the RhoA CRM selectively recruits Abd-A/Exd/Hth complexes to activate rhomboid and stimulate Epidermal Growth Factor secretion in sensory cell precursors. By swapping binding sites between these elements, we found that the RhoA Exd/Hth/Hox site configuration that mediates Abd-A specific activation can convey transcriptional repression by both Ubx and Abd-A when placed into the DCRE. We further show that the orientation and spacing of Hox sites relative to additional binding sites within the RhoA and DCRE is critical to mediate cell- and segment-specific output. These results indicate that the configuration of Exd, Hth, and Hox site within RhoA is neither Abd-A specific nor activation specific. Instead Hox specific output is largely dependent upon the presence of appropriately spaced and oriented binding sites for additional TF inputs. Taken together, these studies provide insight into the cis-regulatory logic used to generate cell-specific outputs via recruiting Hox transcription factor complexes.

SUBMITTER: Zandvakili A

PROVIDER: S-EPMC6333500 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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The cis-regulatory logic underlying abdominal Hox-mediated repression versus activation of regulatory elements in Drosophila.

Zandvakili Arya A Uhl Juli D JD Campbell Ian I Salomone Joseph J Song Yuntao Charlie YC Gebelein Brian B

Developmental biology 20181120 2

During development diverse transcription factor inputs are integrated by cis-regulatory modules (CRMs) to yield cell-specific gene expression. Defining how CRMs recruit the appropriate combinations of factors to either activate or repress gene expression remains a challenge. In this study, we compare and contrast the ability of two CRMs within the Drosophila embryo to recruit functional Hox transcription factor complexes. The DCRE CRM recruits Ultrabithorax (Ubx) and Abdominal-A (Abd-A) Hox comp ...[more]

PMID: 30468713

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Project description:BackgroundA major goal of computational studies of gene regulation is to accurately predict the expression of genes based on the cis-regulatory content of their promoters. The development of computational methods to decode the interactions among cis-regulatory elements has been slow, in part, because it is difficult to know, without extensive experimental validation, whether a particular method identifies the correct cis-regulatory interactions that underlie a given set of expression data. There is an urgent need for test expression data in which the interactions among cis-regulatory sites that produce the data are known. The ability to rapidly generate such data sets would facilitate the development and comparison of computational methods that predict gene expression patterns from promoter sequence.ResultsWe developed a gene expression simulator which generates expression data using user-defined interactions between cis-regulatory sites. The simulator can incorporate additive, cooperative, competitive, and synergistic interactions between regulatory elements. Constraints on the spacing, distance, and orientation of regulatory elements and their interactions may also be defined and Gaussian noise can be added to the expression values. The simulator allows for a data transformation that simulates the sigmoid shape of expression levels from real promoters. We found good agreement between sets of simulated promoters and predicted regulatory modules from real expression data. We present several data sets that may be useful for testing new methodologies for predicting gene expression from promoter sequence.ConclusionWe developed a flexible gene expression simulator that rapidly generates large numbers of simulated promoters and their corresponding transcriptional output based on specified interactions between cis-regulatory sites. When appropriate rule sets are used, the data generated by our simulator faithfully reproduces experimentally derived data sets. We anticipate that using simulated gene expression data sets will facilitate the direct comparison of computational strategies to predict gene expression from promoter sequence. The source code is available online and as additional material. The test sets are available as additional material.

Dataset Information

The cis-regulatory logic underlying abdominal Hox-mediated repression versus activation of regulatory elements in Drosophila.

Publications

The cis-regulatory logic underlying abdominal Hox-mediated repression versus activation of regulatory elements in Drosophila.

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