Biology subjects

Suzuki, H. I.

Publications and source records attributed to Suzuki, H. I..

3 recordsLinked to original sources

bioRxiv2026

Chromatin landscape and epigenetic heterogeneity of acute myeloid leukemia

Acute myeloid leukemia (AML) is an aggressive hematologic cancer characterized by proliferation of immature myeloblasts. It shows profound molecular heterogeneity, which has been primarily studied through genetic abnormalities, providing the basis for disease classification, prognostication, and therapeutic choice. However, genetic factors alone may not fully explain AML pathogenesis and diversity, while leaving the role of abnormal epigenome, particularly chromatin state, largely unexplored in a large cohort of patients. Here we show that AML is classified into 16 subgroups with distinct chromatin accessibility profiles based on ATAC-seq in 1,563 AML cases, including novel AML subgroups not previously recognized in conventional genomic classifications. By integrating multi-omics analyses of genome, transcriptome, and major histone marks, we show that these epigenetic subgroups exhibit unique features in clinical presentation, gene mutations, differentiation states, gene expression, and super-enhancer profiles, which are validated across independent cohorts. Single-cell sequencing demonstrates the presence of subgroup-specific ATAC signatures that are shared by all leukemic cells, confirming the definitive role of the epigenome in the ATAC-based classification. Mechanistically, each subgroup is associated with a distinct gene regulatory network centered on key transcription factors, where subgroup-specific super-enhancers play a pivotal role. These ATAC subgroups also have prognostic significance independent of genomic classification, and help reveal unexpected drug sensitivities. In summary, ATAC-based chromatin profiling in this large sample set, combined with multi-omics data, provides new insights into AML pathogenesis beyond genomic profiling and also serves as an invaluable resource for AML research.

cancer biology↗

bioRxiv2025

RNA Dynamics Regulate Transcriptional Condensate Vivacity to Drive Gene Coordination

Transcriptional condensates (TCs), enriched with Mediator, orchestrate super-enhancer (SE)-driven gene expression critical for cell identity. However, how their dynamic physical properties shape transcriptional activities remains unclear. Here, we reveal a previously unknown regulatory axis wherein dynamic features of enhancer RNA (eRNA), transcribed but rapidly degraded by the RNA exosome, maintain optimal TC fluidity and stability. Depletion of RNA exosome disrupts TC integrity, altering Mediator and Pol II colocalization, in embryonic stem cells. This TC perturbation attenuates proper transcriptional regulator loading and pause-release regulation, enhances transcriptional noise, and diminishes coordinated eRNA-mRNA expression for SE-associated genes. Multi-omics analyses, live-cell imaging, and computational modeling collectively demonstrate that RNA turnover modulates TC vivacity, facilitating widespread chromatin contacts between SE-containing active A compartments and coordinated transcriptional bursts across SE-associated genes. Our findings establish RNA-dependent condensate dynamics as an essential quality-control mechanism that fine-tunes global transcriptional coordination, maintaining cellular homeostasis and cell identity. HighlightsO_LIRNA exosome is required for the homeostasis of transcriptional condensates (TCs) C_LIO_LIRNA synthesis and decay optimize the fluidity and dynamic properties of TCs C_LIO_LITCs maintain the transcriptional consistency of super-enhancer (SE) genes C_LIO_LITCs support contacts of SE-containing A compartments for coordinated transcription C_LI

molecular biology↗

bioRxiv2020

Programmable downsizing of CRISPR-Cas9 activity for precise and safe genome editing

CRSIPR-Cas9 system has opened up the avenue to efficient genome editing1-4. However, together with known off-target effects, several concerns of current CRISPR-Cas9 platform, including severe DNA damage, cytotoxicity, and large genomic alteration, have emerged in recent reports5-7 and establish a formidable obstacle to precisely model allele dosage effects of disease mutations and risk variants, especially mono-allelic effects, and correct them. Here, by developing an allele-specific indel monitor system (AIMS), we demonstrate that small and simple modification of conventional single-guide RNAs (sgRNAs) enable programmable tuning of CRISPR-Cas9 activities and alleviate such adverse effects. AIMS, which visualizes various indel events in two alleles separately in living cells, is convenient and accurate to determine the in vitro editing efficiency and revealed frequent mosaicism during genome editing. Using AIMS, we show that adding cytosine stretches to the 5 end of conventional sgRNA efficiently reduced Cas9 activity in a length dependent manner. By combining systematic experiments and computational modeling, we established the quantitative relationships between the length of cytosine extension and multiple aspects of CRISPR-Cas9 system. In general, short cytosine extension dramatically relieves p53-dependent cytotoxicity and suppression of homology-directed repair (HDR) while relatively maintaining on-target activity. Long cytosine extension further decreases on-target activity, thereby maximizing mono-allelic editing, while conventional system typically induces bi-allelic editing. Furthermore, such downregulation of on-target activity contributes to downregulation of relative off-target activity and protection of HDR-allele from second off-target editing. Therefore, cytosine extension method finally enables both single-step generation of heterozygous single-nucleotide disease mutations from homozygous states in mouse ES cells and correction of heterozygous disease mutations in human iPS cells. Taken together, our study proposes updates of standard CRISPR-Cas9 platform in mammalian cells toward precise and safe genome editing in diverse applications.

molecular biology↗