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Chromatin remodeling, carried out by four major subfamilies of ATP-dependent remodeler complexes across eukaryotes, alleviates the topological challenge posed by nucleosomes to regulate genome access. Recently, single-molecule and single-cell imaging techniques have been widely employed to probe this crucial process, both in vitro and in cellulo. Herein, we provide an integrated account of key recent efforts that leverage these approaches to visualize, quantify and map chromatin remodelers at work, elucidating diverse aspects of the remodeling process in both space and time, including molecular mechanisms of DNA wrapping/unwrapping, nucleosome translocation and histone exchange, dynamics of chromatin binding/target search and their intranuclear organization into hotspots or phase condensates, as well as functional coupling with transcription. The mechanistic insights and quantitative parameters revealed shed light on a multi-modal yet shared landscape for regulating remodeling across molecular and cellular scales, and pave the way for further interrogating the implications of its misregulation in disease contexts., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The substrate for the repair of DNA damage in living cells is not DNA but chromatin. Chromatin bears a range of modifications, which in turn bind ligands that compact or open chromatin structure, and determine its spatial organization within the nucleus. In some cases, RNA in the form of RNA:DNA hybrids or R-loops modulates DNA accessibility. Each of these parameters can favor particular pathways of repair. Chromatin or nucleosome remodelers are key regulators of chromatin structure, and a number of remodeling complexes are implicated in DNA repair. We cover novel insights into the impact of chromatin structure, nuclear organization, R-loop formation, nuclear actin, and nucleosome remodelers in DNA double-strand break repair, focusing on factors that alter repair functional upon ablation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Biologists have the capability to edit a genome at the nanometer scale and then observe whether or not the edit affects the structure of a developing organ or organism at the centimeter scale. Our understanding of the underlying mechanisms driving this emergent phenomenon from a multiscale perspective remains incomplete. This review focuses predominantly on recent experimental developments in uncovering the mechanical interplay between the chromatin and cell scale since mechanics plays a major role in determining nuclear, cellular, and tissue structure. Here, we discuss the generation and transmission of forces through the cytoskeleton, affecting chromatin diffusivity and organization. Decoding such pieces of these multiscale connections lays the groundwork for solving the genotype-to-phenotype puzzle in biology., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Eukaryotic genomes are organized into 3D structures, which range from small-scale nucleosome arrays to large-scale chromatin domains. These structures have an important role in the regulation of transcription and other nuclear processes. Despite advances in our understanding of the properties, functions, and underlying mechanisms of genome structures, there are many open questions about the interplay between these structures across scales. In particular, it is not well understood if and how 1D features of nucleosome arrays influence large-scale 3D genome folding patterns. In this review, we discuss recent studies that address these questions and summarize our current understanding of the relationship between nucleosome positioning and higher-order genome folding., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Cardiovascular diseases (CVD), including coronary heart disease and stroke, comprise the number one cause of mortality worldwide. A major contributor to CVD is atherosclerosis, which is a low-grade inflammatory disease of vasculature that involves a pathological build-up of plaque within the arterial walls. Studies have shown that regulation of gene expression via transcription factors and epigenetic mechanisms play a fundamental role in transcriptomic changes linked to the development of atherosclerosis. Chromatin remodeling is a reversible phenomenon and studies have supported the clinical application of chromatin-modifying agents for the prevention and treatment of CVD. In addition, pre-clinical studies have identified multiple transcription factors as potential therapeutic targets in combating atherosclerotic CVD. Although interaction between transcription factors and epigenetic mechanisms facilitate gene regulation, a limited number of studies appreciate this crosstalk in the context of CVD. Here, we reviewed this gene regulatory mechanism underappreciated in atherosclerosis, which will highlight the mechanisms underlying novel therapeutics targeting epigenetic modifiers and transcription factors in atherosclerosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Development of cancer therapies targeting chromatin modifiers and transcriptional regulatory factors is rapidly expanding to include new targets and novel targeting strategies. At the same time, basic molecular research continues to refine our understanding of the epigenetic mechanisms regulating transcription, gene expression, and oncogenesis. This mini-review focuses on cancer therapies targeting the chromatin-associated factors that recognize histone lysine acetylation. Recently reported safety and efficacy are discussed for inhibitors targeting the bromodomains of bromodomain and extraterminal domain (BET) family proteins. In light of recent results indicating that the transcriptional regulator BRD4-PTEFb can function independently of BRD4's bromodomains, the clinical trial performance of these BET inhibitors is placed in a broader context of existing and potential strategies for targeting BRD4-PTEFb. Recently developed therapies targeting bromodomain-containing factors within the SWI/SNF (BAF) family of chromatin remodeling complexes are discussed, as is the potential for targeting the bromodomain-containing transcription factor TAF1 and the YEATS acetylrecognition domain-containing factor GAS41. Recent findings regarding the selectivity and combinatorial specificity of acetylrecognition are highlighted. In conclusion, the potential for further development is discussed with a focus on proximity-based therapies targeting this class of epigenetic factors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Aberrant chromatin regulation can promote the initiation and progression of human cancer. An improved understanding of such mechanisms has resulted in the identification of cancers with an enhanced dependency on specific chromatin regulatory proteins relative to nonmalignant cell types. Hence, targeting of such complexes with small molecules has significant therapeutic potential in oncology. In recent years, several drugs have been developed and evaluated in human cancer patients, which can influence tumor biology by reprogramming of chromatin structure. In this review, we summarize several of the known mechanisms that endow cancer cells with a powerful dependency on chromatin regulation that exceeds the requirements for normal tissue homeostasis. We also summarize the remarkable small-molecule inhibitors that exploit chromatin regulator dependencies with a clear therapeutic benefit in human cancer patients., Competing Interests: Declaration of Competing Interest C.R.V. has received consulting fees from Flare Therapeutics, Roivant Sciences, and C4 Therapeutics; has served on the advisory boards of KSQ Therapeutics, Syros Pharmaceuticals, and Treeline Biosciences; and owns stock from Treeline Biosciences., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Aims: Renal fibrosis is an important pathophysiological process commonly observed in patients chronic kidney disease (CKD). Angiotensin II (Ang II) is a major risk factor for CKD in part by promoting renal fibrosis. In the present study we investigated Brahma-Related Gene 1 (BRG1, encoded by Smarca4) in Ang II induced pro-fibrogenic response in renal fibroblasts., Methods and Materials: CKD was induced by chronic angiotensin II infusion. Fibroblast- and myofibroblast-specific BRG1 deletion was achieved by crossing the BRG1 f/f mice to the Col1a1-Cre ERT2 mice and the Postn-Cre ERT2 mice, respectively., Key Findings: BRG1 expression was up-regulated when fibroblasts were exposed to Ang II in vitro and in vivo. BRG1 silencing in primary renal fibroblasts blocked transition to myofibroblasts as evidenced by down-regulation of myofibroblast marker genes and reduction in cell proliferation, migration, and contraction. Consistently, deletion of BRG1 from fibroblasts or from myofibroblasts significantly attenuated renal fibrosis in mice subjected to chronic Ang II infusion. Transcriptomic analysis indicated that BRG1 primarily regulated expression of genes involved in cell migroproliferative behavior and extracellular matrix remodeling. Importantly, administration of PFI-3, a small-molecule BRG1 inhibition, markedly ameliorated Ang II induced renal fibrosis in mice., Significance: Our data support a role for BRG1 in Ang II induced fibrogenic response in renal fibroblasts and suggest that targeting BRG1 could be considered as a reasonable approach for the intervention of CKD., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023. Published by Elsevier Inc.)

The mammalian SWI/SNF chromatin remodelling complexes are commonly dysregulated in cancer. These complexes contribute to maintaining genome stability through a variety of pathways. Recent research has highlighted an important interplay between genome instability and immune signalling, and evidence suggests that this interplay can modulate the response to immunotherapy. Here, we review emerging studies where direct evidence of this relationship has been uncovered in SWI/SNF deficient cells. We also highlight genome maintenance activities of SWI/SNF that could potentially shape immune responses and discuss potential therapeutic implications., Competing Interests: Declaration of Competing Interest The authors disclose no potential conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Aims: Hepatic ischemia-reperfusion injury (IRI) is a common complication secondary to liver transplantation. Extensive death of hepatocytes, typically in the form of apoptosis, is observed in and contributes to IRI. In the present study we investigated the role of BRG1 (encoded by Smarca4), a chromatin remodeling protein, in the pathogenesis of liver IRI focusing on the transcriptional mechanism and translational potential., Methods: Smarca4 f/f mice were crossed to Alb-Cre mice to generate hepatocytes-specific BRG1 knockout mice (CKO). Alterations in cellular transcriptome were evaluated by RNA-seq., Results: BRG1 expression was up-regulated in liver tissues of mice subjected to I/R and in hepatocytes exposed to hypoxia-reoxygenation (H/R). Compared to wild type (WT) littermates, the BRG1 CKO mice displayed significant amelioration of liver injury following ischemia-reperfusion as evidenced by decreased ALT/AST levels and cell apoptosis. Primary hepatocytes isolated from the CKO mice were protected from H/R-induced apoptosis compared to those from the WT mice. RNA-seq analysis revealed phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1, also known as NOXA) as a novel target for BRG1. Consistently, NOXA knockdown attenuated liver IRI in mice. More importantly, administration of a small-molecule BRG1 inhibitor (PFI-3) protected the mice from liver IRI., Conclusions: Our data uncover a pivotal role for BRG1 in liver IRI and suggest that targeting BRG1 with small-molecule inhibitors can be considered as a reasonable therapeutic strategy., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023. Published by Elsevier Inc.)

Bromodomain PHD finger transcription factor (BPTF), a core subunit of nucleosome-remodeling factor (NURF) complex, plays an important role in chromatin remodeling. However, few information of BPTF is available in pig, especially in mammalian follicular granulosa cells (GCs). The present study firstly confirmed that BPTF in porcine was relative close to human and mouse. The expression of BPTF could be detected in ovary, testes, lung, kidney, large intestine, and small intestine. And a relative high expression of BPTF was observed in ovarian follicles and GCs. When BPTF was knocked down (BPTF-siRNA), the viability of GCs was affected. And the expression level of CDK1, cyclin B1, CDK4 and CDK2 was higher than the control, which might indicate that the cell cycle of GCs was inhibited from S to G2/M phase. Although the apoptosis level was induced in the BPTF-siRNA GCs, the reduced level of H3K4 methylation was detected with the down regulation of SMYD3, EHMT2 and DPY30. Thereby, results in the present might provide the primary knowledge of BPTF in GCs and the follicular development in pig., Competing Interests: Declaration of competing interest the authors have declared no potential conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

This study investigates sex-associated systemic innate immune differences by examining bone marrow-derived dendritic cells (BMDCs). BMDC grown from 7-day-old mice show enhanced type-I interferon (IFN) signaling in female compared to male BMDC. Upon respiratory syncytial virus (RSV) infection of 7-day-old mice, a significantly altered phenotype of BMDC at 4 weeks post-infection is observed in a sex-dependent manner. The alterations include heightened Ifnb/ interleukin (Il12a) and enhanced IFNAR1+ expression in BMDC from early-life RSV-infected female mice that leads to increased IFN-γ production by T cells. Phenotypic differences were verified upon pulmonary sensitization whereby EL-RSV male-derived BMDC promoted enhanced T helper 2/17 responses and exacerbated disease upon RSV infection while EL-RSV/F BMDC sensitization was relatively protective. Assay for transposase-accessible chromatin using sequencing analysis (ATAC-seq) demonstrated that EL-RSV/F BMDC had enhanced chromatin accessibility near type-I immune genes with JUN, STAT1/2, and IRF1/8 transcription factors predicted to have binding sites in accessible regions. Importantly, ATAC-seq of human cord blood-derived monocytes displayed a similar sex-associated chromatin landscape with female-derived monocytes having more accessibility in type-I immune genes. These studies enhance our understanding of sex-associated differences in innate immunity by epigenetically controlled transcriptional programs amplified by early-life infection in females via type-I immunity., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

In the baker's yeast Saccharomyces cerevisiae, NuA4 and SWR1-C, two multisubunit complexes, are involved in histone acetylation and chromatin remodeling, respectively. Eaf1 is the assembly platform subunit of NuA4, Swr1 is the assembly platform and catalytic subunit of SWR1-C, while Swc4, Yaf9, Arp4 and Act1 form a functional module, and is present in both NuA4 and SWR1 complexes. ACT1 and ARP4 are essential for cell survival. Deletion of SWC4, but not YAF9, EAF1 or SWR1 results in a severe growth defect, but the underlying mechanism remains largely unknown. Here, we show that swc4Δ, but not yaf9Δ, eaf1Δ, or swr1Δ cells display defects in DNA ploidy and chromosome segregation, suggesting that the defects observed in swc4Δ cells are independent of NuA4 or SWR1-C integrity. Swc4 is enriched in the nucleosome-free regions (NFRs) of the genome, including characteristic regions of RDN5s, tDNAs and telomeres, independently of Yaf9, Eaf1 or Swr1. In particular, rDNA, tDNA and telomere loci are more unstable and prone to recombination in the swc4Δ cells than in wild-type cells. Taken together, we conclude that the chromatin associated Swc4 protects nucleosome-free chromatin of rDNA, tDNA and telomere loci to ensure genome integrity., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Chromatin remodeling regulates many basic cellular processes, such as gene transcription, DNA repair, and programmed cell death. As the largest member of nucleosome remodeling factor (NURF), BPTF plays a vital role in the occurrence and development of cancer. Currently, BPTF bromodomain inhibitors are still in development. In this study, by conducting homogenous time-resolved fluorescence resonance energy transfer (HTRF) assay, we identified a potential, novel BPTF inhibitor scaffold Sanguinarine chloride with the IC 50 value of 344.2 ± 25.1 nM. Biochemical analysis revealed that compound Sanguinarine chloride exhibited high binding affinity to the BPTF bromodomain. Molecular docking predicted the binding mode of Sanguinarine chloride and elucidated the activities of its derivatives. Moreover, Sanguinarine chloride showed a potent anti-proliferative effect in MIAPaCa-2 cells and inhibited the expression of BPTF target gene c-Myc. Taken together, Sanguinarine chloride provides a qualified chemical tool for developing potent BPTF bromodomain inhibitors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Gene expression patterns in complex multicellular organisms are regulated by enhancers, which communicate with their target gene promoters in three-dimensional (3D) chromatin structures. Despite advances in our understanding of the mechanisms that organize mammalian genomes into compartments and topologically associating domains (TADs), it is not well understood how specific interactions between enhancers and promoters are controlled in this 3D context. In this review, we give an overview of recent evidence that shows that a process of loop extrusion plays an important role in the regulation of enhancer-promoter communication and discuss recent insights into the molecular mechanism by which loop extrusion contributes to enhancer-mediated gene activation., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Most animal genomes fold in 3D chromatin domains called topologically associated domains (TADs) that facilitate interactions between cis-regulatory elements (CREs) and promoters. Owing to their critical role in the control of developmental gene expression, we explore how TADs have shaped animal evolution. In the light of recent studies that profile TADs in disparate animal lineages, we discuss their phylogenetic distribution and the mechanisms that underlie their formation. We present evidence indicating that TADs are plastic entities composed of genomic strata of different ages: ancient cores are combined with newer regions and brought into extant TADs through genomic rearrangements. We highlight that newly incorporated TAD strata enable the establishment of new CRE-promoter interactions and in turn new expression patterns that can drive phenotypical innovation. We further highlight how subtle changes in chromatin folding may fine-tune the expression levels of developmental genes and hold a potential for evolutionary significance., Competing Interests: Conflict of interest statement Nothing declared., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Epigenetic modifications to DNA are crucial for normal cellular and biological functioning. DNA methylation, histone modifications, and chromatin remodeling are the most common epigenetic mechanisms. These changes are heritable but still reversible. The aberrant epigenetic alterations, such as DNA methylation, histone modification, and non-coding RNA (ncRNA)-mediated gene regulation, play an essential role in developing various human diseases, including cancer. Recent studies show that synthetic and dietary epigenetic inhibitors attenuate the abnormal epigenetic modifications in cancer cells and therefore have strong potential for cancer treatment. In this chapter, we have highlighted various types of epigenetic modifications, their mechanism, and as drug targets for epigenetic therapy., (Copyright © 2023. Published by Elsevier Inc.)

The critical role of dysregulated epigenetic pathways in cancer genesis, development, and therapy has typically been established as a result of scientific and technical innovations in next generation sequencing. RNA interference, histone modification, DNA methylation and chromatin remodelling are epigenetic processes that control gene expression without causing mutations in the DNA. Although epigenetic abnormalities are thought to be a symptom of cell tumorigenesis and malignant events that impact tumor growth and drug resistance, physicians believe that related processes might be a key therapeutic target for cancer treatment and prevention due to the reversible nature of these processes. A plethora of novel strategies for addressing epigenetics in cancer therapy for immuno-oncological complications are currently available - ranging from basic treatment to epigenetic editing. - and they will be the subject of this comprehensive review. In this review, we cover most of the advancements made in the field of targeting epigenetics with special emphasis on microbiology, plasma science, biophysics, pharmacology, molecular biology, phytochemistry, and nanoscience., Competing Interests: Declaration of competing interest The manuscript is solely submitted to BBA Reviews on Cancer and authors have not conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Most eukaryotic DNA is packaged into chromatin, which is made up of tandemly repeating nucleosomes. This packaging of DNA poses a significant barrier to the various enzymes that must act on DNA, including DNA damage response enzymes that interact intimately with DNA to prevent mutations and cell death. To regulate access to certain DNA regions, chromatin remodeling, variant histone exchange, and histone post-translational modifications have been shown to assist several DNA repair pathways including nucleotide excision repair, single strand break repair, and double strand break repair. While these chromatin-level responses have been directly linked to various DNA repair pathways, how they modulate the base excision repair (BER) pathway remains elusive. This review highlights recent findings that demonstrate how BER is regulated by the packaging of DNA into nucleosome core particles (NCPs) and higher orders of chromatin structures. We also summarize the available data that indicate BER may be enabled by chromatin modifications and remodeling., (Copyright © 2022 Elsevier B.V. All rights reserved.)

ATP-dependent chromatin remodelers are essential enzymes that restructure eukaryotic genomes to enable all DNA-based processes. The diversity and complexity of these processes arethe complexity of the enzymes that carry them out, making remodelers a challenging class of molecular motors to study by conventional methods. Here we use a single molecule biophysical assay to overcome some of these challenges, enabling a detailed mechanistic dissection of a paradigmatic remodeler reaction, that of sliding a nucleosome towards the longer DNA linker. We focus on how two motors of a dimeric remodeler coordinate to accomplish such directional sliding. We find that ATP hydrolysis by both motors promotes coordination, suggesting a role for ATP in resolving the competition for directional commitment. Furthermore, we show an artificially constitutive dimer is no more or less coordinated, but is more processive, suggesting a cell could modulate a remodeler's oligomeric state to modulate local chromatin dynamics., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Chromatin remodelers affect the spatio-temporal dynamics of global gene-expression by structurally modulating and/or reorganizing the chromatin. Microrchidia (MORC) family is a relatively new addition to the four well studied families of chromatin remodeling proteins. In this review, we discuss the current understanding of the structural aspects of human MORCs as well as their epigenetic functions. From a molecular and systems-level perspective, we explore their participation in phase-separated structures, possible influence on various biological processes through protein-protein interactions, and potential extra-nuclear roles. We describe how dysregulation/dysfunction of MORCs can lead to various pathological conditions. We conclude by emphasizing the importance of undertaking integrated efforts to obtain a holistic understanding of the various biological roles of MORCs., Competing Interests: Competing Interests All authors declare they have no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The clinical use of androgen receptor (AR) antagonists has been successful in treating prostate cancer patients, inducing remission of androgen-dependent tumors. However, a couple of years after treatment, prostate tumors transition into an androgen-independent state with altered gene expression profiles, but the molecular basis is not understood. Since the AR antagonists trigger this transition, we assessed whether AR antagonists induce chromatin reorganization in an androgen-dependent prostate cancer cell line (LNCaP). Treatment of LNCaP cells with two clinically used AR antagonists (bicalutamide [Bic] and enzalutamide [Enz]) expectedly resulted in antagonistic effects on cell proliferation, AR transactivation, and dihydrotestosterone (DHT)-induced expression of AR target genes. Thus, the antagonists expectedly acted to antagonize the transactivation function of AR activated by androgen binding. By ChIP-qPCR assay, AR bound to Bic, but not Enz, was recruited to an endogenous consensus AR-binding site within the kallikrein-related peptidase 3 gene promoter after treatment with Bic, similar to the effect of DHT. By ATAC-seq analysis of the cells after long-term treatment for 5 days, Bic and dihydrotestosterone DHT induced different chromatin reorganization patterns and gene expression profiles, suggesting that Bic exhibited a distinct action from that by DHT. Thus, these results suggest that the action of a known AR antagonist is mediated by chromatin reorganization in a prostate cancer cell line., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

PTEN is a tumor suppressor protein frequently altered in various cancers. PTEN-null cells have a characteristic of rapid proliferation with an unstable genome. Replication stress is one of the causes of the accumulation of genomic instability if not sensed by the cellular signaling. Though PTEN-null cells have shown to be impaired in replication progression and stalled fork recovery, the association between the catalytic function of PTEN regulated by posttranslational modulation and cellular response to replication stress has not been studied explicitly. To understand molecular mechanism, we find that PTEN-null cells display unrestrained replication fork progression with accumulation of damaged DNA after treatment with aphidicolin which can be rescued by ectopic expression of full-length PTEN, as evident from DNA fiber assay. Moreover, the C-terminal phosphorylation (Ser 380, Thr 382/383) of PTEN is essential for its chromatin association and sensing replication stress that, in response, induce cell cycle arrest. Further, we observed that PTEN induces HP1α expression and H3K9me3 foci formation in a C-terminal phosphorylation-dependent manner. However, phosphatase dead PTEN cannot sense replication stress though it can be associated with chromatin. Together, our results suggest that DNA replication perturbation by aphidicolin enables chromatin association of PTEN through C-terminal phosphorylation, induces heterochromatin formation by stabilizing and up-regulating H3K9me3 foci and augments CHK1 activation. Thereby, PTEN prevents DNA replication fork elongation and simultaneously causes G1-S phase cell cycle arrest to limit cell proliferation in stress conditions. Thus PTEN act as stress sensing protein during replication arrest to maintain genomic stability., Competing Interests: Conflict of Interests All authors declare that there is no conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The Plant Homeodomain 6 gene (PHF6) encodes a nucleolar and chromatin-associated leukemia tumor suppressor with proposed roles in transcription regulation. However, specific molecular mechanisms controlled by PHF6 remain rudimentarily understood. Here we show that PHF6 engages multiple nucleosome remodeling protein complexes, including nucleosome remodeling and deacetylase, SWI/SNF and ISWI factors, the replication machinery and DNA repair proteins. Moreover, after DNA damage, PHF6 localizes to sites of DNA injury, and its loss impairs the resolution of DNA breaks, with consequent accumulation of single- and double-strand DNA lesions. Native chromatin immunoprecipitation sequencing analyses show that PHF6 specifically associates with difficult-to-replicate heterochromatin at satellite DNA regions enriched in histone H3 lysine 9 trimethyl marks, and single-molecule locus-specific analyses identify PHF6 as an important regulator of genomic stability at fragile sites. These results extend our understanding of the molecular mechanisms controlling hematopoietic stem cell homeostasis and leukemia transformation by placing PHF6 at the crossroads of chromatin remodeling, replicative fork dynamics, and DNA repair., (© 2022 by The American Society of Hematology.)

Background: Till now, no definite clinical or laboratory marker can predict the recurrence or progression of T1 G3 urothelial carcinoma (UC). Genetic aberrations of the chromatin remodeling genes and sister chromatid cohesion and segregation (SCCS) were identified in UC. Here we investigated the impact of novel miRNAs and their targeted expressed SCCS and chromatin remodeling genes on T1G3 UC response to Bacillus Calmette-Guérin (BCG) therapy., Methods: One hundred tissue samples were obtained from NMIBC patients. Gene expression and immunohistochemical assay of STAG2, ARID1A, NCOR1and UTX were assessed. MiRNA analysis for their targeting miRNAs (miR-21, miR-31, Let7a and miR-199a) was carried out. Assessed genes were compared between responders and no responders to BCG. Univariate and multivariate analysis of predictors of disease recurrence and progression were performed using cox regression analysis., Results: Thirty-two and 22 patients developed recurrence and progression to MIBC (BCG non-responders). BCG non-responders showed statistically significant higher expression of miR-21 and their targeted STAG2, miR-199a and NCOR1 gene (P < .001), and lower expression of miR-31, Let7a, ARID1A and UTX genes (P < .001). Higher miR-199a (P = .006) and lower miR-31 (P = .01), ARID1A (P = .008) and UTX (P = .03) were independent predictor of higher tumor recurrence. Recurrent disease (P = .003), higher expression of STAG2 (P = .01), NCOR1 (P = .01) and miR-21 (P = .03) genes and lower expression of miR-31 (P = .02), Let7a (P = .04) and ARID1A (P = .04) genes were the independent predictor of disease progression., Conclusion: Upregulation of STAG2 and NCOR1 and down regulation of ARID1A and UTX genes and their targeting miRNAs were associated with UC non-response to BCG., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Dynamic assembly and disassembly of actin proteins play a key role in the cytoskeleton, but the cellular functions of actin are not only restricted to the cytoplasmic compartment. Recent studies have shown that actin spatiotemporally changes its polymerized state in the nucleus as well and such dynamic nature of actin is relevant to key nuclear events including gene expression, DNA damage response and chromatin organization. In this review, we highlight emerging roles of actin in the nuclear compartment especially in the context of embryonic development and cellular differentiation. We first explain how the actin nucleoskeleton can be formed and function in cells. Notably, nuclear actin dynamics are greatly altered when cell fates change, such as after fertilization and T cell differentiation. We discuss how the dynamic actin nucleoskeleton contributes to accomplishing developmental programs., Competing Interests: Conflict of interest statement Nothing declared, (Copyright © 2022 Elsevier Ltd. All rights reserved.)