Biology subjects

Matsushima, W.

Publications and source records attributed to Matsushima, W..

7 recordsLinked to original sources

bioRxiv2026

An overexpression platform reveals the functional diversity of human KRAB-Zinc Finger Proteins in maintaining cellular homeostasis

Kruppel associated box zinc finger proteins (KZFPs) form the largest family of transcriptional regulators in mammals, yet most remain uncharacterized. Here we established a scalable framework to probe KZFP function. An arrayed inducible overexpression screen of 366 human KZFPs in K562 cells identified factors that alter cellular proliferation, enabling functional prioritization. Integrative transcriptomic, chromatin and proteomic analyses revealed diverse mechanisms, including transposable element-linked repression (ZNF43), promoter proximal regulation (ZNF257), and SCAN domain dependent transcriptional activation (ZNF498/ZSCAN25 and ZNF18). These results highlight the functional diversity of KZFPs and provide a strategy for their annotation.

genetics↗

bioRxiv2025

Tissue-specific restriction of TE-derived regulatory elements safeguards cell-type identity

Transposable elements (TEs) have extensively reshaped the cis-regulatory landscape of mammalian genomes, yet the mechanisms that govern their context-specific activity remain incompletely understood. KRAB zinc finger proteins (KZFPs), a large family of transcription factors specialized in TE recognition, are known repressors of TE-derived regulatory activity through TRIM28-mediated H3K9me3 deposition. Here, we expand this paradigm by uncovering noncanonical relationships between TEs and KZFPs. By generating a comprehensive epigenomic map of KZFP-bound TEs, we find that the regulatory activity of ancient mammalian L2/MIR elements is broadly delineated by KZFP binding patterns, despite low H3K9me3 enrichment. We further dissect this relationship by investigating the function of ZNF436, a non-canonical KZFP, highly expressed during in vivo human fetal heart development. Using loss-of-function approaches, we show that ZNF436 preserves cardiomyocyte function by promoting cardiac gene expression while restricting the activation of alternative lineage programs. Mechanistically, ZNF436 recruits specialized SWI/SNF chromatin remodeling complexes to limit the accessibility of L2/MIR-derived enhancers, many of which are active in non-cardiac tissues. These findings reveal a noncanonical, TRIM28-independent role for KZFPs in shaping cell-type-specific regulatory landscapes and emphasize the importance of repressing alternative regulatory programs alongside activating lineage-specific ones to safeguard cell identity.

genomics↗

bioRxiv2025

Zinc-finger proteins with a co-opted capsid domain anchor nucleosomes over transposon sequences

Transposable elements (TEs) are frequently co-opted as cis-regulatory sequences that govern multiple aspects of host biology. The regulatory activity of these domesticated sequences are controlled by host factors, notably KRAB domain-containing zinc-finger proteins (KZFPs) in tetrapods. Here, we report that SCAN domain-containing zinc-finger proteins (SZFPs), which originally arose through capture of a retroviral capsid domain by a KZFP gene, have expanded and diversified their DNA recognition specificity to bind distinct TE subfamilies. We further demonstrate that SZFPs anchor nucleosomes at their target sites, and that their depletion leads to global shifts of nucleosomes away from underlying TE-derived sequences, occasionally accompanied by a gain of enhancer-associated chromatin states. Thus, SZFPs represent a novel layer of chromatin regulation centered on rapidly evolving TE-derived regulatory sequences.

genetics↗

bioRxiv2023

Ancestral genome reconstruction enhances transposable element annotation by identifying degenerate integrants

Growing evidence indicates that transposable elements (TEs) play important roles in evolution by providing genomes with coding and non-coding elements. Identification of TE-derived functional elements, however, has relied on TE annotations in individual species, which limits its scope to relatively intact TE sequences and misses elements derived from evolutionarily old TEs. Here, we report a novel approach to uncover previously unannotated degenerate TEs (degTEs) by probing multiple ancestral genomes reconstructed from hundreds of species. We applied this method to the human genome and discovered 1,452,810 degTEs, representing a 10.8% increase over the most recent human TE coverage. Further, we discovered that degTEs contribute to various cis-regulatory elements as well as transcription factor binding sites, including those of a known TE-controlling family, the KRAB zinc-finger proteins. We also report unannotated chimeric transcripts between degTEs and human genes expressed in embryos. This study provides a novel methodology and a freely available resource that will facilitate the investigation of TE co-option events on a full scale.

genomics↗

bioRxiv2019

Mature sperm small RNA profile in the sparrow: implications for transgenerational effects of age on fitness

Mammalian sperm RNA has recently received a lot of interest due to its involvement in epigenetic germline inheritance. Studies of epigenetic germline inheritance have shown that environmental exposures can induce effects in the offspring without altering the DNA sequence of germ cells. Most mechanistic studies were conducted in laboratory rodents and C.elegans while observational studies confirm the phenotypic phenomenon in wild populations of humans and other species including birds. Prominently, paternal age in house sparrows affects offspring fitness, yet the mechanism is unknown. This study provides a first reference of house sparrow sperm small RNA as an attempt to uncover their role in the transmission of the effects of paternal age on the offspring. In this small scale pilot, we found no statistically significant differences between miRNA and tRNA fragments in aged and prime sparrow sperm. These results indicate a role of other epigenetic information carriers, such as distinct RNA classes, RNA modifications, DNA methylation and retained histones, and a clear necessity of future studies in wild populations.

developmental biology↗

bioRxiv2018

Alterations in sperm long RNA contribute to the epigenetic inheritance of the effects of postnatal trauma

Psychiatric diseases have a strong heritable component known to not be restricted to DNA sequence-based genetic inheritance alone but to also involve epigenetic factors in germ cells 1,2. Initial evidence suggested that sperm RNA is causally linked 2,3 to the transmission of symptoms induced by traumatic experiences. Here we show that alterations in long RNA in sperm contribute to the inheritance of specific trauma symptoms. Injection of long RNA fraction from sperm of males exposed to postnatal trauma recapitulates the effects on food intake, glucose response to insulin and risk-taking in adulthood whereas the small RNA fraction alters body weight and behavioral despair. Alterations in long RNA are maintained after fertilization, suggesting a direct link between sperm and embryo RNA.

developmental biology↗

bioRxiv2017

SLAM-ITseq: Sequencing cell type-specific transcriptomes without cell sorting

Cell type-specific transcriptome analysis is an essential tool in understanding biological processes but can be challenging due to the limits of microdissection or fluorescence-activated cell sorting (FACS). Here, we report a novel in vivo sequencing method, which captures the transcriptome of a specific type of cells in a tissue without prior cellular or molecular sorting. SLAM-ITseq provides an accurate snapshot of the transcriptional state in vivo.

molecular biology↗