CTCF/RAD21 organize the ground state of chromatin–nuclear speckle association
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The DEAD-box helicase eIF4A1/2 acts as RNA chaperone during mitotic exit enabling chromatin decondensation
During mitosis, chromosomes condense and decondense to segregate faithfully and undamaged. The exact molecular mechanisms are not well understood. We identify the DEAD-box helicase eIF4A1/2 as a critical factor in this process. In a cell-free condensation assay eIF4A1/2 is crucial for this process, relying on its RNA-binding ability but not its ATPase activity. Reducing eIF4A1/2 levels in cells consistently slows down chromatin decondensation during nuclear reformation. Conversely, increasing eIF4A1/2 concentration on mitotic chromosomes accelerates their decondensation. The absence of eIF4A1/2 affects the perichromatin layer, which surrounds the chromosomes during mitosis and consists of RNA and mainly nucleolar proteins. In vitro, eIF4A1/2 acts as an RNA chaperone, dissociating biomolecular condensates of RNA and perichromatin proteins. During mitosis, the chaperone activity of eIF4A1/2 is required to regulate the composition and fluidity of the perichromatin layer, which is crucial for the dynamic reorganization of chromatin as cells exit mitosis.
Enhancer reprogramming: critical roles in cancer and promising therapeutic strategies
Transcriptional dysregulation is a hallmark of cancer initiation and progression, driven by genetic and epigenetic alterations. Enhancer reprogramming has emerged as a pivotal driver of carcinogenesis, with cancer cells often relying on aberrant transcriptional programs. The advent of high-throughput sequencing technologies has provided critical insights into enhancer reprogramming events and their role in malignancy. While targeting enhancers presents a promising therapeutic strategy, significant challenges remain. These include the off-target effects of enhancer-targeting technologies, the complexity and redundancy of enhancer networks, and the dynamic nature of enhancer reprogramming, which may contribute to therapeutic resistance. This review comprehensively encapsulates the structural attributes of enhancers, delineates the mechanisms underlying their dysregulation in malignant transformation, and evaluates the therapeutic opportunities and limitations associated with targeting enhancers in cancer.
Coherence synthesis in nonlinear optics
It is commonly assumed that nonlinear frequency conversion requires lasers with high coherence; however, this assumption has constrained our broader understanding of coherence and overlooked the potential role of incoherence in nonlinear interactions. In this work, we study the synthesis of optical spatial coherence in second harmonic generation using quadratic nonlinear photonic crystals. We demonstrate a method where the second harmonic coherence is customized by employing quantitative phase retrieval and a complex square-root filter sequentially on fundamental frequency speckles. As a proof-of-concept, we experimentally show incoherent imaging of a smiley face transitioning from infrared to visible light. Moreover, we apply this method to produce two representative types of structured light beams in second harmonic generation: incoherent vortex and Airy beams. During the nonlinear synthesis of incoherent vortex beams, we have, for the first time, experimentally verified the conservation of orbital angular momentum in the nonlinear frequency conversion process of a low-coherence source. Furthermore, the generated second-harmonic incoherent Airy beam preserves the self-acceleration characteristics of its fundamental frequency counterpart, remaining unaffected by reductions in coherence. Our results not only deepen the fundamental understanding of optical coherence but also unlock exciting possibilities for applications in infrared imaging and fluorescence microscopy where optical nonlinear interactions play an important role.
ZBTB16/PLZF regulates juvenile spermatogonial stem cell development through an extensive transcription factor poising network
Spermatogonial stem cells balance self-renewal with differentiation and spermatogenesis to ensure continuous sperm production. Here, we identify roles for the transcription factor zinc finger and BTB domain-containing protein 16 (ZBTB16; also known as promyelocytic leukemia zinc finger (PLZF)) in juvenile mouse undifferentiated spermatogonia (uSPG) in promoting self-renewal and cell-cycle progression to maintain uSPG and transit-amplifying states. Notably, ZBTB16, Spalt-like transcription factor 4 (SALL4) and SRY-box transcription factor 3 (SOX3) colocalize at over 12,000 promoters regulating uSPG and meiosis. These regions largely share broad histone 3 methylation and acetylation (H3K4me3 and H3K27ac), DNA hypomethylation, RNA polymerase II (RNAPol2) and often CCCTC-binding factor (CTCF). Hi-C analyses show robust three-dimensional physical interactions among these cobound promoters, suggesting the existence of a transcription factor and higher-order active chromatin interaction network within uSPG that poises meiotic promoters for subsequent activation. Conversely, these factors do not notably occupy germline-specific promoters driving spermiogenesis, which instead lack promoter–promoter physical interactions and bear DNA hypermethylation, even when active. Overall, ZBTB16 promotes uSPG cell-cycle progression and colocalizes with SALL4, SOX3, CTCF and RNAPol2 to help establish an extensive and interactive chromatin poising network.
Hypoxia-induced ATF3 escalates breast cancer invasion by increasing collagen deposition via P4HA1
Activating transcription factors (ATFs), members of the adaptive-response gene family, participate in cellular processes to aid adaptations in response to extra and/or intracellular changes. In this study, we observed that one of the ATFs, Activating transcription factor 3 (ATF3), is upregulated under hypoxia via alterations in the epigenetic landscape of its promoter, followed by transcriptional upregulation. Under hypoxic conditions, Hypoxia-inducible factor 1-alpha (HIF1ɑ) alleviates methylation at the ATF3 promoter by recruiting TET1 and induces ATF3 transcription. In addition, our RNA-seq analysis showed that ATF3 globally affects transcription under hypoxia and controls the processes of EMT and cancer invasion by stimulating the transcription of Prolyl 4-Hydroxylase Subunit Alpha 1 (P4HA1), an enzyme which enhances invasion-conducive extracellular matrix (ECM) under hypoxic conditions. Prolyl hydroxylases play a critical role in the hydroxylation and deposition of collagen in the extracellular matrix (ECM) during the evolution of cancer, which is necessary for metastasis. Importantly, P4HA1 undergoes alternative splicing under hypoxia, where the inclusion of exon 9a is increased. Interestingly, involvement of ATF3 in P4HA1 splicing was also evident, as binding of ATF3 at intron 9a led to demethylation of this DNA region via recruitment of TET1. Furthermore, we also show that the demethylated DNA region of intron 9a then becomes accessible to CCCTC-binding factor (CTCF). Thus, a cascade of demethylation via ATF3 recruited TET1, followed by increased RNA Pol II pause at intron 9a via CTCF, leads to inclusion of exon 9a. The P4HA1 9a isoform leads to enhanced invasion under hypoxic conditions by increasing deposition of collagen in the ECM. These results reveal a novel hypoxia-induced HIF1ɑ-ATF3-P4HA1 axis which can potentially be exploited as a therapeutic target to impede EMT and ultimately breast cancer invasion.
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