Stochastic Binary Modeling of Cells in Continuous Time as an Alternative to Biochemical Reaction Equations

We have developed a coarse-grained formulation for modeling the dynamic behavior of cells quantitatively, based on stochasticity and heterogeneity, rather than on biochemical reactions. We treat each reaction as a continuous-time stochastic process, while reducing each biochemical quantity to a binary value at the level of individual cells. The system can be analytically represented by a finite set of ordinary linear differential equations, which provides a continuous time course prediction of each molecular state. In this letter, we introduce our formalism and demonstrate it with several examples.Comment: 10pages, 3 figure

Malt1-Induced Cleavage of Regnase-1 in CD4+ Helper T Cells Regulates Immune Activation

SummaryRegnase-1 (also known as Zc3h12a and MCPIP1) is an RNase that destabilizes a set of mRNAs, including Il6 and Il12b, through cleavage of their 3′ UTRs. Although Regnase-1 inactivation leads to development of an autoimmune disease characterized by T cell activation and hyperimmunoglobulinemia in mice, the mechanism of Regnase-1-mediated immune regulation has remained unclear. We show that Regnase-1 is essential for preventing aberrant effector CD4+ T cell generation cell autonomously. Moreover, in T cells, Regnase-1 regulates the mRNAs of a set of genes, including c-Rel, Ox40, and Il2, through cleavage of their 3′ UTRs. Interestingly, T cell receptor (TCR) stimulation leads to cleavage of Regnase-1 at R111 by Malt1/paracaspase, freeing T cells from Regnase-1-mediated suppression. Furthermore, Malt1 protease activity is critical for controlling the mRNA stability of T cell effector genes. Collectively, these results indicate that dynamic control of Regnase-1 expression in T cells is critical for controlling T cell activation

The N⁶-methyladenosine methyltransferase METTL16 enables erythropoiesis through safeguarding genome integrity

RNA修飾による赤血球造血制御機構を解明 --RNAのメチル化がDNA修復に必要--. 京都大学プレスリリース. 2022-11-10.Mice show METTL in DNA blood repair: RNA methylation shows important role in erythropoiesis. 京都大学プレスリリース. 2022-11-25.During erythroid differentiation, the maintenance of genome integrity is key for the success of multiple rounds of cell division. However, molecular mechanisms coordinating the expression of DNA repair machinery in erythroid progenitors are poorly understood. Here, we discover that an RNA N⁶-methyladenosine (m⁶A) methyltransferase, METTL16, plays an essential role in proper erythropoiesis by safeguarding genome integrity via the control of DNA-repair-related genes. METTL16-deficient erythroblasts exhibit defective differentiation capacity, DNA damage and activation of the apoptotic program. Mechanistically, METTL16 controls m⁶A deposition at the structured motifs in DNA-repair-related transcripts including Brca2 and Fancm mRNAs, thereby upregulating their expression. Furthermore, a pairwise CRISPRi screen revealed that the MTR4-nuclear RNA exosome complex is involved in the regulation of METTL16 substrate mRNAs in erythroblasts. Collectively, our study uncovers that METTL16 and the MTR4-nuclear RNA exosome act as essential regulatory machinery to maintain genome integrity and erythropoiesis

Hematopoietic cell-derived IL-15 supports NK cell development in scattered and clustered localization within the bone marrow

骨髄のNK細胞の分化に造血細胞が産生するIL-15が必須である --2種類の局在を示すNK細胞の新規分化モデル--. 京都大学プレスリリース. 2023-09-20.Natural killer (NK) cells are innate immune cells critical for protective immune responses against infection and cancer. Although NK cells differentiate in the bone marrow (BM) in an interleukin-15 (IL-15)-dependent manner, the cellular source of IL-15 remains elusive. Using NK cell reporter mice, we show that NK cells are localized in the BM in scattered and clustered manners. NK cell clusters overlap with monocyte and dendritic cell accumulations, whereas scattered NK cells require CXCR4 signaling. Using cell-specific IL-15-deficient mice, we show that hematopoietic cells, but not stromal cells, support NK cell development in the BM through IL-15. In particular, IL-15 produced by monocytes and dendritic cells appears to contribute to NK cell development. These results demonstrate that hematopoietic cells are the IL-15 niche for NK cell development in the BM and that BM NK cells are present in scattered and clustered compartments by different mechanisms, suggesting their distinct functions in the immune response

Delamination of trophoblast-like syncytia from the amniotic ectodermal analogue in human primed embryonic stem cell-based differentiation model

Human primed embryonic stem cells (ESCs) are known to be converted to cells with several trophoblast properties, but it has remained controversial whether this phenomenon represents the inherent differentiation competence of human primed ESCs to trophoblast lineages. In this study, we report that chemical blockage of ACTIVIN/NODAL and FGF signals is sufficient to steer human primed ESCs into GATA3-expressing cells that give rise to placental hormone-producing syncytia analogous to syncytiotrophoblasts of the post-implantation stage of the human embryo. Despite their cytological similarity to syncytiotrophoblasts, these syncytia arise from the non-trophoblastic differentiation trajectory that recapitulates amniogenesis. These results provide insights into the possible extraembryonic differentiation pathway that is unique in primate embryogenesis

A clustering-independent method for finding differentially expressed genes in single-cell transcriptome data

How cell clusters are defined in single-cell sequencing data has important consequences for downstream analyses and the interpretation of results, but is often not straightforward. Here, the authors present a new approach that enables the prediction of differentially expressed genes without relying on explicit clustering of cells

Modeling the cis-regulatory modules of genes expressed in developmental stages of Drosophila melanogaster

Because transcription is the first step in the regulation of gene expression, understanding how transcription factors bind to their DNA binding motifs has become absolutely necessary. It has been shown that the promoters of genes with similar expression profiles share common structural patterns. This paper presents an extensive study of the regulatory regions of genes expressed in 24 developmental stages of Drosophila melanogaster. It proposes the use of a combination of structural features, such as positioning of individual motifs relative to the transcription start site, orientation, pairwise distance between motifs, and presence of motifs anywhere in the promoter for predicting gene expression from structural features of promoter sequences. RNA-sequencing data was utilized to create and validate the 24 models. When genes with high-scoring promoters were compared to those identified by RNA-seq samples, 19 (79.2%) statistically significant models, a number that exceeds previous studies, were obtained. Each model yielded a set of highly informative features, which were used to search for genes with similar biological functions

A Set of Structural Features Defines the <i>Cis</i>-Regulatory Modules of Antenna-Expressed Genes in <i>Drosophila melanogaster</i>

<div><p>Unraveling the biological information within the regulatory region (RR) of genes has become one of the major focuses of current genomic research. It has been hypothesized that RRs of co-expressed genes share similar architecture, but to the best of our knowledge, no studies have simultaneously examined multiple structural features, such as positioning of <i>cis</i>-regulatory elements relative to transcription start sites and to each other, and the order and orientation of regulatory motifs, to accurately describe overall <i>cis</i>-regulatory structure. In our work we present an improved computational method that builds a feature collection based on all of these structural features. We demonstrate the utility of this approach by modeling the <i>cis</i>-regulatory modules of antenna-expressed genes in <i>Drosophila melanogaster</i>. Six potential antenna-related motifs were predicted initially, including three that appeared to be novel. A feature set was created with the predicted motifs, where a correlation-based filter was used to remove irrelevant features, and a genetic algorithm was designed to optimize the feature set. Finally, a set of eight highly informative structural features was obtained for the RRs of antenna-expressed genes, achieving an area under the curve of 0.841. We used these features to score all <i>D. melanogaster</i> RRs for potentially unknown antenna-expressed genes sharing a similar regulatory structure. Validation of our predictions with an independent RNA sequencing dataset showed that 76.7% of genes with high scoring RRs were expressed in antenna. In addition, we found that the structural features we identified are highly conserved in RRs of orthologs in other <i>Drosophila</i> sibling species. This approach to identify tissue-specific regulatory structures showed comparable performance to previous approaches, but also uncovered additional interesting features because it also considered the order and orientation of motifs.</p></div

Conservation of SFs between the RR of <i>D. melanogaster ac</i> and the RRs of orthologs across the <i>Drosophila</i> lineage.

<p>The colored squares represent the antenna-related motifs. Squares on or under the black line indicate motifs on the plus or minus strand, respectively. The red cross means either that the respective region does not contain conserved features or that there is no such ortholog. The phylogenetic tree is based on the tree reported in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0104342#pone.0104342-Stark1" target="_blank">[46]</a>.</p