Biology subjects

Konovalov, D.

Publications and source records attributed to Konovalov, D..

4 recordsLinked to original sources

bioRxiv2024

Analysis of live cell data with G-DNABERT supports a role for G-quadruplexes in chromatin looping

Alternative DNA conformation formed by sequences called flipons potentially alter the readout of genetic information by directing the shape-specific assembly of complexes on DNA The biological roles of G-quadruplexes formed by motifs rich in guanosine repeats have been investigated experimentally using many different methodologies including G4-seq, G4 ChIP-seq, permanganate nuclease footprinting (KEx), KAS-seq, CUT&Tag with varying degrees of overlap between the results. Here we trained large language model DNABERT on existing data generated by KEx, a rapid chemical footprinting technique performed on live, intact cells using potassium permanganate. The snapshot of flipon state when combined with results from other in vitro methods that are performed on permeabilized cells, allows a high confidence mapping of G-flipons to proximal enhancer and promoter sequences. Using G4-DNABERT predictions,with data from ENdb, Zoonomia cCREs and single cell G4 CUT&Tag experiments, we found support for a model where G4-quadruplexes regulate gene expression through chromatin loop formation.

bioinformatics↗

bioRxiv2023

Z-Flipons conserved between human and mouse are associated with increased transcription initiation rates

A long-standing question concerns the role of Z-DNA in transcription. Here we use a deep learning approach based on the published DeepZ algorithm that predicts Z-flipons based on DNA sequence, structural properties of nucleotides and omics data. We examined Z-flipons that are conserved between human and mouse genomes after generating whole-genome Z-flipons maps by training DeepZ on ChIP-seq Z-DNA data, then overlapping the results with a common set of omics data features. We revealed similar pattern of transcription factors and histone marks associated with conserved Z-flipons, showing enrichment for transcription regulation coupled with chromatin organization. 15% and 7% of conserved Z-flipons fell in alternative and bidirectional promoters. We found that conserved Z-flipons in CpG-promoters are associated with increased transcription initiation rates. Our findings empower further experimental explorations to examine how the flip to Z-DNA alters the readout of genetic information by facilitating the transition of one epigenetic state to another.

bioinformatics↗

bioRxiv2023

Z-Flipon Variants reveal the many roles of Z-DNA and Z-RNA in health and disease

Identifying roles for Z-flipons remains challenging given their dynamic nature. Here we perform genome-wide interrogation with the DNABERT transformer algorithm trained on experimentally identified Z-DNA sequences. We show Z-flipons are enriched in promoters and telomeres and overlap quantitative trait loci for RNA expression, RNA editing, splicing and disease associated variants. Surprisingly, many effects are mediated through Z-RNA formation. We describe Z-RNA motifs present in SCARF2, SMAD1 and CACNA1 transcripts and others in non-coding RNAs. We also provide evidence for another Z-RNA motif that likely enables an adaptive anti-viral intracellular defense through alternative splicing of KRAB domain zinc finger proteins. An analysis of OMIM and gnomAD predicted loss-of-function datasets reveals an overlap of predicted and experimentally validated Z-flipons with disease causing variants in 8.6% and 2.9% of mendelian disease genes respectively, with frameshift variants present in 22% of cases. The work greatly extends the number of phenotypes mapped to Z-flipon variants.

genomics↗

bioRxiv2022

A role for Flipons and miRNAs in Promoter Specification during Development?

The classical view of gene regulation is based on prokaryotic models and the operon concept with protein-based transcription factors controlling the expression of metabolic pathways essential for bacterial adaptations in response to environmental changes. A new view for establishing cell identity is emerging in eukaryotes where RNA-based pathways provide the framework for the readout of genomic information. Another perspective poses that alternative DNA structures encoded by flipons enable switching of cellular responses from one state to another. Here we provide evidence that these RNA and DNA mechanisms are deeply connected. We present data supporting a model where flipons open up binding sites for microRNAs (miRNAs), leading to the establishment of bivalent promoters early in development whose location structures lineage-specific events. These outcomes are potentially influenced by ovarian and spermatozoan miRNAs, transmissions with evident evolutionary ramifications. The data supports a new perspective on genetic regulation, one in which the genome provides a canvas framed by flipons, sketched with miRNAs and embellished by proteins.

genetics↗