Developmental roles of 21 Drosophila transcription factors are determined by quantitative differences in binding to an overlapping set of thousands of genomic regions

By Stewart MacArthur, Xiaoyong Li, Jingyi Li, James B. Brown, H. C. Chu, Lucy Zeng, Brandi P Grondona, A. Hechmer, L. Simirenko, Soile V. E. Keränen and 5 more. 2009

375 citations recorded by the source corpus.

BackgroundWe previously established that six sequence-specific transcription factors that initiate anterior/posterior patterning in Drosophila bind to overlapping sets of thousands of genomic regions in blastoderm embryos. While regions bound at high levels include known and probable functional targets, more poorly bound regions are preferentially associated with housekeeping genes and/or genes not transcribed in the blastoderm, and are frequently found in protein coding sequences or in less conserved non-coding DNA, suggesting that many are likely non-functional.ResultsHere we show that an additional 15 transcription factors that regulate other aspects of embryo patterning show a similar quantitative continuum of function and binding to thousands of genomic regions in vivo. Collectively, the 21 regulators show a surprisingly high overlap in the regions they bind given that they belong to 11 DNA binding domain families, specify distinct developmental fates, and can act via different cis-regulatory modules. We demonstrate, however, that quantitative differences in relative levels of binding to shared targets correlate with the known biological and transcriptional regulatory specificities of these factors.ConclusionsIt is likely that the overlap in binding of biochemically and functionally unrelated transcription factors arises from the high concentrations of these proteins in nuclei, which, coupled with their broad DNA binding specificities, directs them to regions of open chromatin. We suggest that most animal transcription factors will be found to show a similar broad overlapping pattern of binding in vivo, with specificity achieved by modulating the amount, rather than the identity, of bound factor.

Subfields: Molecular Biology

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

Citations in the corpus

Iterative random forests to discover predictive and stable high-order interactions (2017, positive): “To identify interactions that form the basis of chromatin-mediated splicing, we used iRF to predict thresholded splicing rates for 23 , 823 exons [RNA-seq percent-spliced-in (PSI) values (https://github.com/guigolab/ipsa-nf); 11 , 911 training, 11 , 912 test], from ChIP-seq assays measuring enrichme”
Dynamic reprogramming of chromatin accessibility during Drosophila embryo development (2011, methodology): “To map the occupancy patterns of specific regulators, chromatin immunoprecipitation (ChIP) has been applied to over 20 developmental transcription factors and RNA polymerase in the blastoderm embryo and, for several factors, at later stages of embryogenesis [30-36].”
Temporal Coordination of Gene Networks by Zelda in the Early Drosophila Embryo (2011, background): “Our genome-wide binding data indicated that Zld behaves similarly to other transcription factors in early Drosophila embryos binding thousands of genomic regions [13,14], but showing a stronger tendency to bind close to the TSS.”
Zelda Binding in the Early Drosophila melanogaster Embryo Marks Regions Subsequently Activated at the Maternal-to-Zygotic Transition (2011, methodology): “We therefore compared ZLD binding at cycle 8 to genome-wide binding measurements of 21 transcription factors involved in A-P and D-V patterning [12,18].”
Impacts of the ubiquitous factor Zelda on Bicoid-dependent DNA binding and transcription in Drosophila (2014, background): “Third, since Zld sites are present at hot spots where multiple TFs bind (Li et al. 2008, 2011; MacArthur et al. 2009; Satija and Bradley 2012), it may facilitate the binding of multiple activators and repressors to regions that function as enhancers.”
Zelda is differentially required for chromatin accessibility, transcription factor binding, and gene expression in the early Drosophila embryo (2015, background): “…are bound by a large number of different transcription factors, have been identified in multiple organisms, including worms, flies, and humans (Moorman et al. 2006; The ENCODE Project Consortium 2007; Li et al. 2008; MacArthur et al. 2009; Gerstein et al. 2010; Roy et al. 2010; Negre et al. 2011).”
Pioneer transcription factors: establishing competence for gene expression. (2011, background): “This passive mode is supported by the observation that the vast majority of promoters and enhancers, particularly those involved in tissue-specific expression, require binding by a combination of transcription factors for activity (Boyer et al. 2005; MacArthur et al. 2009; Levine 2010).”
Incremental causal effects (2019, methodology): “More specificaly, we consider the activity of p = 36 transcription factors in Drosophila embryos on n = 7809 segments of the genome (Li et al., 2008; MacArthur et al., 2009).”
Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities (2010, background): “This model offers an explanation for the extensive genome-wide and cell typespecific colocalization of transcription factors observed in various previous studies (Chen et al., 2008; MacArthur et al., 2009) and provides insights into how simple combinations of lineage-restricted transcription factors”