3D chromatin hubs as regulatory units of identity and survival in human acute leukemia

Molecular Cell, Год журнала: 2024, Номер 85(1), С. 42 - 60.e7

Опубликована: Дек. 24, 2024

Язык: Английский

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Boosting the detection of enhancer-promoter loops via novel normalization methods for chromatin interaction data

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Abstract Accurately detecting enhancer-promoter loops from genome-wide interaction data, such as Hi-C, is crucial for understanding gene regulation. Current normalization methods, Iterative Correction and Eigenvector decomposition (ICE), are commonly used to remove biases in Hi-C data prior chromatin loop detection. However, while structural or CTCF-associated signals retained, often greatly diminished after ICE similar making these regulatory harder detect. To address this limitation, we developed Raichu, a novel method normalizing contact data. Raichu identifies nearly twice many ICE, recovering almost all detected by revealing thousands of additional missed ICE. With its enhanced sensitivity loops, detects more biologically meaningful differential between conditions the same cell type. Furthermore, performs consistently across different sequencing depths platforms, including HiChIP, single-cell it versatile tool uncovering new insights into three- dimensional (3D) genomic organization transcriptional

Язык: Английский

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Long non-coding RNAs direct the SWI/SNF complex to cell type-specific enhancers

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Янв. 2, 2025

Abstract The coordination of chromatin remodeling is essential for DNA accessibility and gene expression control. highly conserved ubiquitously expressed SWItch/Sucrose Non-Fermentable (SWI/SNF) complex plays a central role in cell type- context-dependent expression. Despite the absence defined recognition motif, SWI/SNF binds lineage specific enhancers genome-wide where it actively maintains open state. It does so while retaining ability to respond dynamically cellular signals. However, mechanisms that guide genomic targets have remained elusive. Here we demonstrate trans -acting long non-coding RNAs (lncRNAs) direct type-specific enhancers. preferentially lncRNAs these predominantly bind . Together they localize enhancers, many which are type-specific. Knockdown SWI/SNF- enhancer-bound causes redistribution away from concomitant differential spatially connected target genes. These lncRNA-SWI/SNF-enhancer networks support an enhancer hub model targeting. Our findings reveal competitively recruit SWI/SNF, providing dynamic layer control over accessibility, reinforcing their mediating activity

Язык: Английский

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Gene Doping Detection From the Perspective of 3D Genome

Drug Testing and Analysis, Год журнала: 2025, Номер unknown

Опубликована: Янв. 5, 2025

ABSTRACT Since the early 20th century, concept of doping was first introduced. To achieve better athletic performance, chemical substances were used. By mid‐20th it became gradually recognized that illegal use can seriously endangered athletes' health and compromised fairness sports competitions. Over past 30 years, World Anti‐Doping Agency (WADA) has established corresponding rules regulations to prohibit athletes from using or restrict certain drugs, isotope, chromatography, mass spectrometry techniques accredited detect substances. With development gene editing technology, many genetic diseases have been effectively treated, but enabled by same also potential pose a threat in form doping. WADA explicitly indicated Prohibited List as prohibited method (M3) approved qPCR detection. However, easily evade detection, if target genes' upstream regulatory elements are considered, task more challenging. Hi‐C experiment driven 3D genome through perspectives such topologically associating domain (TAD) chromatin loop, provides comprehensive in‐depth understanding regulation expression, thereby preventing level In this work, we will explore different perspective analyzing recent studies on related genes under genome.

Язык: Английский

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Post-mitotic transcriptional activation and 3D regulatory interactions show locus- and differentiation-specific sensitivity to cohesin depletion

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 14, 2025

Abstract Prior studies showed that structural loops collapse upon acute cohesin depletion, while regulatory enhancer-promoter (E-P) largely persist, consistent with minimal transcriptional changes. However, these studies, conducted in asynchronous cells, could not resolve whether is required for the establishment of interactions and activation during cell division or state transitions. To address this gap, we degraded RAD21, a core subunit, naïve mouse embryonic stem cells (ESCs) transitioning from mitosis to G1 either self-renewal condition differentiation toward formative pluripotency. Although most failed be re-established without cohesin, about 35% reformed at normal higher frequencies. Cohesin-independent characteristics strong active enhancers promoters significant association H3K27ac mitotic bookmarks. inhibition CBP/p300 exit did impact cohesin-independent interactions, suggesting presence complex compensatory mechanisms. At level, depletion induced only minor changes, supporting post-mitotic reactivation independent cohesin. The few genes impaired were directly bound by RAD21 their promoters, engaged many loops, located within strongly insulated TADs low gene density. Importantly, degrading M-to-G1 transition EpiLC signals revealed larger group susceptible genes, including key signature transcription factors. Impaired was partly due failure establish de novo EpiLC-specific absence These experiments locus-specific context-specific dependencies between E-P transcription.

Язык: Английский

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Synergistic and antagonistic activities of IRF8 and FOS enhancer pairs during an immune-cell fate switch

The EMBO Journal, Год журнала: 2025, Номер unknown

Опубликована: Фев. 19, 2025

Язык: Английский

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Enhancer reprogramming: critical roles in cancer and promising therapeutic strategies

Cell Death Discovery, Год журнала: 2025, Номер 11(1)

Опубликована: Март 3, 2025

Abstract Transcriptional dysregulation is a hallmark of cancer initiation and progression, driven by genetic epigenetic alterations. Enhancer reprogramming has emerged as pivotal driver carcinogenesis, with cells often relying on aberrant transcriptional programs. The advent high-throughput sequencing technologies provided critical insights into enhancer events their role in malignancy. While targeting enhancers presents promising therapeutic strategy, significant challenges remain. These include the off-target effects enhancer-targeting technologies, complexity redundancy networks, dynamic nature reprogramming, which may contribute to resistance. This review comprehensively encapsulates structural attributes enhancers, delineates mechanisms underlying malignant transformation, evaluates opportunities limitations associated cancer.

Язык: Английский

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Acute Activation of Genes Through Transcriptional Condensates Impact Non-target Genes in a Chromatin Domain

Опубликована: Март 19, 2025

Transcription activation of genes by estrogen is driven enhancers, which are often located within the same Topologically Associating Domain (TAD) as non-targeted promoters. We investigated how acute enhancer-driven affects neighbouring non-target TAD. Using single-molecule RNA FISH (smFISH), we tracked transcription TFF1 (enhancer-targeted) and TFF3 (non-targeted) during stimulation. observed mutually exclusive expression patterns: peaked at 1 hour, while reached its peak 3 hours, after ’s had diminished. Chromatin looping data indicated that enhancer loops with but not , suggesting upregulation due to direct enhancer-promoter interactions. CRISPR deletion 1,6-hexanediol (HD) exposure revealed enhancer:promoter undergo Liquid-Liquid Phase Separation (LLPS), sequesters transcriptional machinery inhibits expression. As signalling wanes or LLPS disrupted, declines increases. Our findings reveal can indirectly influence genes, highlighting a dynamic shift in gene progresses.

Язык: Английский

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Three-dimensional regulatory hubs support oncogenic programs in glioblastoma

Molecular Cell, Год журнала: 2025, Номер unknown

Опубликована: Март 1, 2025

Язык: Английский

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Ultrastable and versatile multimeric ensembles of FoxP3 on microsatellites

Molecular Cell, Год журнала: 2025, Номер unknown

Опубликована: Апрель 1, 2025

Язык: Английский

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