Biology subjects

Ichikawa, Y.

Publications and source records attributed to Ichikawa, Y..

6 recordsLinked to original sources

bioRxiv2026

The human RNA-DNA interactome is cell type-specific and dynamic

More than twenty years ago, the FANTOM consortium uncovered that mammalian genomes are pervasively transcribed, revealing multitudes of RNAs with unknown functions. A subset of these transcripts has since then been linked to transcriptional control and to chromatin organization via their ability to interact with DNA, suggesting that chromatin-associated RNAs could be key players in genome regulation. Although recent technological advances now enable the mapping of genome-wide RNA-DNA contacts, a lack of analyses integrating these methods with other genomic features and across multiple cellular contexts hinders our comprehensive understanding of the principles underlying RNA-DNA interactions and of their biological importance. As part of the FANTOM6 project, we thus generated RNA-DNA interaction maps in 16 different human cell types, then combined these contacts with multiple layers of other genomic data to investigate how patterns of interaction between RNA and DNA relate to chromatin organization and function. We show that the RNA-DNA interactome is highly dynamic yet reproducibly organized in cell-type specific networks, constituted of a great diversity of interactions that vary in function of their distance, the nature of their sources and the chromatin state of their targets. In particular, we detected numerous regulatory elements that exhibit marked changes in activity when differentially bound by transcripts, implying that thousands of RNA-DNA interactions can play a mechanistic role in gene expression. This regulatory function correlates with RNA-protein interactions and significantly associates with cell type-relevant and disorder-related traits. In addition to providing essential resources for future research in RNA-mediated chromatin regulation, cellular biology and human diseases, our study thus establishes the RNA-DNA interactome as a new genome regulatory layer that defines and maintains cellular identity and behavior.

genomics↗

bioRxiv2026

Why linkage disequilibrium measures disagree: Fisher geometry of rare common haplotype structure

Conventional LD measures such as r2 perform poorly in the rare-common regime, particularly in asymmetric configurations such as nested haplotype structure. Because r2 is symmetric and quadratic, it removes directional structure in two ways: squaring discards the sign, or phase, retained by the signed LD coefficient D, while symmetric normalization hides the asymmetry between the conditional probabilities P(A|B) and P(B|A). Although D recovers the phase, it is locus-symmetric and unnormalized; its magnitude is hard to compare across frequency regimes and it does not by itself express which way the asymmetry runs. We therefore analyze the conditional-probability asymmetry {Delta} = P(A|B) - P(B|A), together with r2 and D, as distinct scalar functions on the haplotype simplex under the Fisher information metric. The conditional probabilities P(A|B) and P(B|A) are bounded in [0, 1], directly express carrier-set inclusion, and are more readily visualized than D. Moreover, their difference admits the exact decomposition {Delta} = M + C into a marginal-frequency term M and an LD-coupled term C. Prior work has characterized either the mathematical behavior of LD normalizations across allele-frequency space or the Fisher geometry of the haplotype simplex, but not their connection. We bridge this gap by showing that the geometric structure of the simplex explains why LD measures disagree in the rare-common regime and why symmetric normalizations such as r2 lose directional information. We show that the fixed-frequency leaf is intrinsically anisotropic, positively curved, and frequency-dependent under the Fisher metric. These geometric predictions are tested empirically -- in phased 1000 Genomes data1 and a two-locus Wright-Fisher model -- in a companion paper (Ichikawa, preprint2); the present note develops the geometry itself.

genetics↗

bioRxiv2026

Formation, persistence, and breakdown of carrier-set topology in linkage disequilibrium: empirical structure in 1000 Genomes and a two locus Wright Fisher model

Linkage disequilibrium between two biallelic loci is usually summarized by scalar association measures such as r2 and D'. These measures quantify how visible an allelic association is to a symmetric LD scan, but they do not directly represent the topology of carrier sets: whether the carriers of one variant are contained within, partially overlap with, or are disjoint from the carriers of the other. This distinction is structural. On the haplotype-frequency simplex, carrier-set inclusion corresponds to a boundary face where one haplotype class is absent. In the rare-common regime, a nested rare variant is further constrained by the ceiling r2 [≤] pA/pB, so that complete carrier-set inclusion can remain nearly invisible to r2. Here, as a companion to the Fisher-geometry preprint 1, we examine the empirical and dynamic behavior of this carrier-set topology. In 1000 Genomes Phase 3, across 156,604,320 SNP pairs from the MHC and NEGR1 regions, pairs on the | D' |= 1 boundary span a wide range of r2 and | C |. Within fixed r2 strata, r2 poorly distinguishes nested from non-nested carrier-set configurations, with AUROC values of approximately 0.54-0.62, whereas the boundary-sensitive normalization | D' | separates them much more effectively, with AUROC values of approximately 0.90-0.92. The empirical data also obey the predicted r2 [≤] pA/pB ceiling. We then introduce a temporal axis using a two-locus Wright-Fisher model on the same simplex. Carrier-set topology evolves through three motions relative to the | D' |= 1 boundary: formation or persistence, in which recombination suppression establishes and maintains inclusion without requiring selection; visibility change, in which selection or drift moves r2 along the boundary while preserving the inclusion relation; and breaking, in which a recombination pulse introduces the previously absent haplotype and dissolves inclusion. A fourth mode, specificity erosion, expands the partner carrier set while preserving inclusion, thereby lowering P(A | B) while keeping P(B | A) and | D' | equal to one. This mode shows that asymmetric conditional probabilities are best understood as diagnostic coordinates for carrier-set topology, not as the primary object itself. Together, these results show that topology and visibility are separable axes of LD structure. Conventional r2-based scans and carrier-set topology scans therefore answer complementary, not interchangeable, questions.

genetics↗

bioRxiv2026

The MICA rs2596542 locus is not an island: component-aware haplotype decomposition reveals a composite MHC tag with distinct regulatory axes

Cross-population reversal of signed linkage disequilibrium (LD), or the "flip-flop" phenomenon, can arise when a tag SNP captures different extended haplotype backgrounds across populations. The MICA hepatocellular carcinoma susceptibility variant rs2596542 exemplifies this problem in the MHC, where signed LD reverses between Japanese and European populations but the relevant regulatory backgrounds are obscured by haplotypic complexity. We analyzed 7,303 biallelic SNVs surrounding rs2596542 across 26 populations using carrier-set topology classification followed by non-negative matrix factorization of carrier haplotypes. This identified two regulatory axes. Axis I, represented by components c4/c6, was population-stable and MICA-regulatory, with coherent MICA cis-eQTL enrichment and depletion for signed-LD reversal. Axis II, represented by component c5, was enriched for signed-LD reversal and showed an HLA-B{uparrow}/HLA-C{downarrow} expression signature with no MICA overlap across six GTEx tissues. The previously proposed cross-population tag rs2244546 mapped to a population-stable component rather than Axis II. Together, these findings indicate that rs2596542-T is not a single MICA-regulatory proxy but a composite MHC tag that captures separable MICA- and HLA-B/HLA-C-regulatory haplotypic backgrounds. Carrier-set topology combined with NMF provides a practical approach for resolving such composite tag signals and for interpreting cross-population signed-LD reversal in complex MHC loci.

genomics↗

bioRxiv2020

Potential silencing of gene expression by PIWI-interacting RNAs (piRNAs) in somatic tissues in mollusk

PIWI/piRNA suppress transposon activity in animals, thereby safeguarding the genome from detrimental insertion mutagenesis. Recently, evidence revealed additional piRNA targets and functions in various animals. Although piRNAs are ubiquitously expressed in somatic tissues of the pearl oyster Pinctada fucata, their role is not well-characterized. Here, we report a PIWI/piRNA pathway, including piRNA biogenesis and piRNA-mediated gene regulation in P. fucata. A locked-nucleic-acid modified oligonucleotide (LNA-antagonist) was used to silence a single piRNA (piRNA0001) expression in P. fucata, which resulted in the differential expression of hundreds of endogenous genes. Target prediction analysis revealed that, following silencing, tens of endogenous genes were targeted by piRNA0001, including twelve up-regulated and nine down-regulated genes. Bioinformatic analyses suggested that different piRNA populations participate in the ping-pong amplification loop in a tissue-specific manner. These findings have improved our knowledge of the role of piRNA in mollusks, and provided evidence to understand the regulatory function of the PIWI/piRNA pathway on protein-coding genes outside of germline cells.

molecular biology↗

bioRxiv2017

A synthetic biology approach to probing nucleosome symmetry

The repeating subunit of chromatin, the nucleosome, includes two copies of each of the four core histones, and several recent studies have reported that asymmetrically-modified nucleosomes occur at regulatory elements in vivo. To probe the mechanisms by which histone modifications are read out, we designed an obligate pair of H3 heterodimers, termed H3X and H3Y, which we extensively validated genetically and biochemically. Comparing the effects of asymmetric histone tail point mutants with those of symmetric double mutants revealed that a single methylated H3K36 per nucleosome was sufficient to silence cryptic transcription in vivo. We also demonstrate the utility of this system for analysis of histone modification crosstalk, using mass spectrometry to separately identify modifications on each H3 molecule within asymmetric nucleosomes. The ability to generate asymmetric nucleosomes in vivo and in vitro provides a powerful and generalizable tool to probe the mechanisms by which H3 tails are read out by effector proteins in the cell.

molecular biology↗