Divergent expression of paralogous genes by modification of shared enhancer activity through a promoter-proximal silencer.

The duplication of genes and their associated cis-regulatory elements, or enhancers, is a key contributor to genome evolution and biological complexity. Moreover, many paralogs, particularly tandem duplicates, are fixed for long periods of time under the control of shared enhancers. However, in most cases, the mechanism by which gene expression and function diverge following duplication is not known.

Transcription factor paralogs orchestrate alternative gene regulatory networks by context-dependent cooperation with multiple cofactors.

In eukaryotes, members of transcription factor families often exhibit similar DNA binding properties in vitro, yet orchestrate paralog-specific gene regulatory networks in vivo. The serially homologous first (T1) and third (T3) thoracic legs of Drosophila, which are specified by the Hox proteins Scr and Ubx, respectively, offer a unique opportunity to address this paradox in vivo. Genome-wide analyses using epitope-tagged alleles of both Hox loci in the T1 and T3 leg imaginal discs, the precursors to the adult legs and ventral body regions, show that ~8% of Hox binding is paralog-specific.

Cell-type-specific Hox regulatory strategies orchestrate tissue identity.

Hox proteins are homeodomain transcription factors that diversify serially homologous segments along the animal body axis, as revealed by the classic bithorax phenotype of Drosophila melanogaster, in which mutations in Ultrabithorax (Ubx) transform the third thoracic segment into the likeness of the second thoracic segment. To specify segment identity, we show that Ubx both increases and decreases chromatin accessibility, coinciding with its dual role as both an activator and repressor of transcription. However, the choice of transcriptional activity executed by Ubx is spatially regulated and depends on the availability of cofactors, with Ubx acting as a repressor in some populations and as an activator in others.

Control of tissue morphogenesis by the HOX gene .

Mutations in the () gene cause homeotic transformation of the normally two-winged into a four-winged mutant fly. encodes a HOX family transcription factor that specifies segment identity, including transformation of the second set of wings into rudimentary halteres. is known to control the expression of many genes that regulate tissue growth and patterning, but how it regulates tissue morphogenesis to reshape the wing into a haltere is still unclear.

Context-Dependent Gene Regulation by Homeodomain Transcription Factor Complexes Revealed by Shape-Readout Deficient Proteins.

Eukaryotic transcription factors (TFs) form complexes with various partner proteins to recognize their genomic target sites. Yet, how the DNA sequence determines which TF complex forms at any given site is poorly understood. Here, we demonstrate that high-throughput in vitro DNA binding assays coupled with unbiased computational analysis provide unprecedented insight into how different DNA sequences select distinct compositions and configurations of homeodomain TF complexes.

Low affinity binding sites in an activating CRM mediate negative autoregulation of the Drosophila Hox gene Ultrabithorax.

Specification of cell identity and the proper functioning of a mature cell depend on precise regulation of gene expression. Both binary ON/OFF regulation of transcription, as well as more fine-tuned control of transcription levels in the ON state, are required to define cell types. The Drosophila melanogaster Hox gene, Ultrabithorax (Ubx), exhibits both of these modes of control during development.

Community-acquired pneumonia in children: cell-free plasma sequencing for diagnosis and management.

Community-acquired pneumonia (CAP) is a common cause of pediatric hospital admission. Empiric antibiotic therapy for hospitalized children with serious CAP now targets the most likely pathogen(s), including those that may demonstrate significant antibiotic resistance. Cell-free plasma next-generation sequencing (CFPNGS) was first made available for Pediatric Infectious Diseases physicians in June 1, 2017, to supplement standard-of-care diagnostic techniques.

Accurate and sensitive quantification of protein-DNA binding affinity.

Transcription factors (TFs) control gene expression by binding to genomic DNA in a sequence-specific manner. Mutations in TF binding sites are increasingly found to be associated with human disease, yet we currently lack robust methods to predict these sites. Here, we developed a versatile maximum likelihood framework named No Read Left Behind (NRLB) that infers a biophysical model of protein-DNA recognition across the full affinity range from a library of in vitro selected DNA binding sites.

Origins and Specification of the Drosophila Wing.

The insect wing is a key evolutionary innovation that was essential for insect diversification. Yet despite its importance, there is still debate about its evolutionary origins. Two main hypotheses have been proposed: the paranotal hypothesis, which suggests that wings evolved as an extension of the dorsal thorax, and the gill-exite hypothesis, which proposes that wings were derived from a modification of a pre-existing branch at the dorsal base (subcoxa) of the leg.

Connectivity of vertebrate genomes: Paired-related homeobox (Prrx) genes in spotted gar, basal teleosts, and tetrapods.

Teleost fish are important models for human biology, health, and disease. Because genome duplication in a teleost ancestor (TGD) impacts the evolution of teleost genome structure and gene repertoires, we must discriminate gene functions that are shared and ancestral from those that are lineage-specific in teleosts or tetrapods to accurately apply inferences from teleost disease models to human health. Generalizations must account both for the TGD and for divergent evolution between teleosts and tetrapods after the likely two rounds of genome duplication shared by all vertebrates.