Biology subjects

Brovkina, M. V.

Publications and source records attributed to Brovkina, M. V..

3 recordsLinked to original sources

bioRxiv2026

Fruitless produces diverse neuronal sex differences by editing lineage-programmed chromatin landscapes

A major question in metazoan development is how a limited set of DNA-binding transcription factors generate the much larger number of cell fates and states in the organism. In vivo, individual transcription factors are joined by varied sets of collaborating or competing proteins across cellular contexts. Brains provide particularly diverse transcriptional milieus across thousands of neuron types, where each cell is a phenotypic readout of intrinsic transcriptional regulation over developmental time. Todays methods allow interrogation of individual cells, transforming the diversity of neurons in the brain from an experimental hindrance to a benefit in interrogation of combinatorial transcription factor action. Here, we use the BTB domain transcription factor Fruitless as a model to determine how a single factor produces cell-type specific regulatory effects, in this case sexual dimorphisms. In Drosophila melanogaster, Fruitless is transcribed in a precise neuronal repertoire (irrespective of sex) but translated into protein only in male cells. By performing joint scRNA/ATACseq on fruitless neurons from both sexes (i.e. with and without Fru protein) we determine the transcriptional mechanisms by which Fruitless produces cell-type specific regulatory effects. We demonstrate that Fruitlesss actions are constrained by the chromatin landscape produced by cell lineage. Within lineage-specific landscapes, type-specific transcriptional dimorphisms arise from varying "Fru power" across cell types, which emerges as a combination of Fruitless dose, DNA binding domain isoforms, and the motif repertoire of individual enhancers. Together, these mechanisms allow a single factor to produce multifaceted transcriptional effects that subtly alter individual neuron types and produce sex-specific circuit functions.

molecular biology↗

bioRxiv2022

A common genomic architecture for interacting with the external world

The radiation of mammals at the extinction of the dinosaurs produced a plethora of new forms--as diverse as bats, dolphins, and elephants--in only 10-20 million years. Behind the scenes, adaptation to new niches is accompanied by extensive innovation in large families of genes that allow animals to contact the environment, including chemosensors, xenobiotic enzymes, and immune and barrier proteins. Genes in these "outward-looking" families are allelically diverse among humans and exhibit tissue-specific and sometimes stochastic expression. Here, we show that outward-looking genes are clustered in tandem arrays, enriched in AT-biased isochores, and lack CpG islands in their promoters. Models of mammalian genome evolution have not incorporated the sharply different functions and transcriptional patterns of genes in AT-versus GC-biased regions. To examine the relationship between gene family expansion, sequence content, and functional diversification, we use population genetic data and comparative analysis. First, we find that AT bias can emerge with gene family expansion in cis. Second, human genes in AT-biased isochores or with GC-poor promoters experience relatively low rates of de novo point mutation today but are enriched for functional variants. Finally, we find that isochores containing gene clusters exhibit low rates of recombination. We hypothesize that the depletion of GC bases in outward-facing gene clusters results from tolerance of sequence variation and low recombination. In turn, high AT content exerts a profound effect on their chromatin organization and transcriptional regulation.

evolutionary biology↗

bioRxiv2020

Fruitless decommissions regulatory elements to implement cell-type-specific neuronal masculinization

In the fruit fly Drosophila melanogaster, male-specific splicing and translation of the Fruitless transcription factor (FruM) alters the presence, anatomy, and/or connectivity of >60 types of central brain neurons that interconnect to generate male-typical behaviors. While the indispensable function of FruM in sex-specific behavior has been understood for decades, the molecular mechanisms underlying its activity remain unknown. Here, we take a genome-wide, brain-wide approach to identifying regulatory elements whose activity depends on the presence of FruM. We identify 436 high-confidence genomic regions differentially accessible in male fruitless neurons, validate candidate regions as bona-fide, differentially regulated enhancers, and describe the particular cell types in which these enhancers are active. We find that individual enhancers are not activated universally but are dedicated to specific fru+ cell types. Aside from fru itself, genes are not dedicated to or common across the fru circuit; rather, FruM appears to masculinize each cell type differently, by tweaking expression of the same effector genes used in other circuits. Finally, we find FruM motifs enriched among regulatory elements that are open in the female but closed in the male. Together, these results suggest that FruM acts cell-type-specifically to decommission regulatory elements in male fruitless neurons.

neuroscience↗