Biology subjects

Osato, N.

Publications and source records attributed to Osato, N..

5 recordsLinked to original sources

bioRxiv2025

Functional prediction of DNA/RNA-binding proteins by deep learning from gene expression correlations

Understanding how regulatory architectures are reorganized during biological state transitions remains a central challenge in functional genomics. Here, we integrate co-expression-derived regulatory interactions with interpretable deep learning to compute gene-level contribution scores and introduce {Delta}NES (normalized enrichment score difference) to quantify pathway redistribution across biological states. Applying this framework to neural progenitor and leukemia-associated cellular states, we identify systematic redistribution of functional modules across RNA-binding proteins, including PKM, HNRNPK, and NELFE. Neural System- and Immune System-associated modules are differentially positioned along contribution-ranked regulatory landscapes, while Signal Transduction consistently forms a conserved signaling backbone. These findings suggest that pathway redistribution reflects regulatory reorganization across biological states and provides a framework for interpreting large-scale regulatory coordination beyond expression-centric analyses.

bioinformatics↗

bioRxiv2024

Discovery of regulatory motifs associated with human insulator sites reveals the role of directional bias in insulator function

Insulator proteins function as barriers to enhancer-promoter interactions (EPIs), thereby regulating gene expression. The primary insulator protein in vertebrates is CTCF, a DNA-binding protein (DBP); however, the roles of other DBPs in EPI insulation are not fully understood. To address this, we developed a systematic and comprehensive deep learning-based approach to identify DNA motifs of DBPs associated with insulator function. Applying this method to human fibroblast cells, we identified 97 directional motifs and a smaller number of non-directional motifs. These motifs were mapped to 23 DBPs previously linked to insulator activity, CTCF, and/or other forms of chromosomal transcriptional regulation. We found that the estimated orientation bias of CTCF was consistently proportional to the orientation bias observed in chromatin interaction data. Furthermore, these motifs showed significant enrichment at insulator sites that separate repressive and active chromatin regions, at chromatin interaction-defined boundaries, and at splice sites, compared to motifs of other DBPs. For instance, we observed that the key regulator MyoD-binding site is located at an insulator site near a gene involved in skeletal muscle differentiation and function. Importantly, our findings support the previously proposed insulator-pairing model, which suggests that insulator-insulator interactions are orientation-dependent, and highlight the involvement of multiple DNA-binding proteins beyond CTCF. Together, these results provide new insights into transcriptional regulatory mechanisms mediated by insulator-associated DBPs.

bioinformatics↗

bioRxiv2019

Comprehensive epigenome characterization reveals diverse transcriptional regulation across human vascular endothelial cells

BackgroundEndothelial cells (ECs) make up the innermost layer throughout the entire vasculature. Their phenotypes and physiological functions are initially regulated by developmental signals and extracellular stimuli. The underlying molecular mechanisms responsible for the diverse phenotypes of ECs from different organs are not well understood.\n\nResultsTo characterize the transcriptomic and epigenomic landscape in the vascular system, we cataloged gene expression and active histone marks in nine types of human ECs (generating 148 genome-wide datasets) and carried out a comprehensive analysis with chromatin interaction data. We identified 3,765 EC-specific enhancers, some of which were associated with disease-associated genetic variations. We also identified various candidate marker genes for each EC type. Notably, reflecting the developmental origins of ECs and their roles in angiogenesis, vasculogenesis and wound healing.\n\nConclusionsWhile the importance of several HOX genes for early vascular development and adult angiogenesis in pathological conditions has been reported, a systematic analysis of the regulation and roles of HOX genes in mature tissue cells has been lacking. These datasets provide a valuable resource for understanding the vascular system and associated diseases.

genomics↗

bioRxiv2018

Discovery of biased orientation of human DNA motif sequences affecting enhancer-promoter interactions and transcription of genes

BackgroundChromatin interactions are essential in enhancer-promoter interactions (EPIs) and transcriptional regulation. CTCF and cohesin proteins located at chromatin interaction anchors and other DNA-binding proteins such as YY1, ZNF143, and SMARCA4 are involved in chromatin interactions. However, there is still no good overall understanding of proteins associated with chromatin interactions and insulator functions. ResultsHere, I describe a systematic and comprehensive approach for discovering DNA-binding motifs of transcription factors (TFs) that affect EPIs and gene expression. This analysis identified 96 biased orientations [64 forward-reverse (FR) and 52 reverse-forward (RF)] of motifs that significantly affected the expression level of putative transcriptional target genes in monocytes, T cells, HMEC, and NPC and included CTCF, cohesin (RAD21 and SMC3), YY1, and ZNF143; some TFs have more than one motif in databases; thus, the total number is smaller than the sum of FRs and RFs. KLF4, ERG, RFX, RFX2, HIF1, SP1, STAT3, and AP1 were associated with chromatin interactions. Many other TFs were also known to have chromatin-associated functions. The predicted biased orientations of motifs were compared with chromatin interaction data. Correlations in expression level of nearby genes separated by the motif sites were then examined among 53 tissues. ConclusionOne hundred FR and RF orientations associated with chromatin interactions and functions were discovered. Most TFs showed weak directional biases at chromatin interaction anchors and were difficult to identify using enrichment analysis of motifs. These findings contribute to the understanding of chromatin-associated motifs involved in transcriptional regulation, chromatin interactions/regulation, and histone modifications.

bioinformatics↗

bioRxiv2016

Genome-wide analysis of human putative transcriptional target genes reveals significant functional enrichments

BackgroundTranscriptional target genes show functional enrichment of genes. However, how many and how significantly transcriptional target genes include functional enrichments are still unclear. To address these issues, I predicted human transcriptional target genes using open chromatin regions, ChIP-seq data and DNA binding sequences of transcription factors in databases, and examined functional enrichment and gene expression level of putative transcriptional target genes.\n\nResultsGene Ontology annotations showed four times larger numbers of functional enrichments in putative transcriptional target genes than gene expression information alone, independent of transcriptional target genes. To compare the number of functional enrichments of putative transcriptional target genes between cells or search conditions, I normalized the number of functional enrichment by calculating its ratios in the total number of transcriptional target genes. With this analysis, native putative transcriptional target genes showed the largest normalized number of functional enrichments, compared with target genes including 5 - 60% of randomly selected genes. The normalized number of functional enrichments was changed according to the criteria of enhancer-promoter interactions such as distance from transcriptional start sites and orientation of CTCF-binding sites. Forward-reverse orientation of CTCF-binding sites showed significantly higher normalized number of functional enrichments than the other orientations. Journal papers showed that the top five frequent functional enrichments were related to the cellular functions in the three cell types. The median expression level of transcriptional target genes changed according to the criteria of enhancer-promoter assignments (i.e. interactions) and was correlated with the changes of the normalized number of functional enrichments of transcriptional target genes.\n\nConclusionsHuman putative transcriptional target genes showed significant functional enrichments. Functional enrichments were related to the cellular functions. The normalized number of functional enrichments of human putative transcriptional target genes changed according to the criteria of enhancer-promoter assignments and correlated with the median expression level of the target genes. These analyses and characters of human putative transcriptional target genes would be useful to examine the criteria of enhancer-promoter assignments and to predict the novel mechanisms and factors such as DNA binding proteins and DNA sequences of enhancer-promoter interactions.

bioinformatics↗