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SUMMARY: Strigolactones (SL) function as plant hormones in control of multiple aspects of plant development, mostly via the regulation of gene expression. Immediate early‐gene regulation by SL remains unexplored due to difficulty in dissecting early from late gene expression responses to SL. We used synthetic SL, rac‐GR24 treatment of protoplasts and RNA‐seq to explore early SL‐induced changes in gene expression over time (5–180 minutes) and discovered rapid, dynamic and SL receptor D14‐dependent regulation of gene expression in response to rac‐GR24. Importantly, we discovered a significant dependence of SL signalling on chromatin remodelling processes, as the induction of a key SL‐induced transcription factor BRANCHED1 requires the SWI/SNF chromatin remodelling ATPase SPLAYED (SYD) and leads to upregulation of a homologue SWI/SNF ATPase BRAHMA. ATAC‐seq profiling of genome‐wide changes in chromatin accessibility in response to rac‐GR24 identified large‐scale changes, with over 1400 differentially accessible regions. These changes in chromatin accessibility often precede transcriptional changes and are likely to harbour SL cis‐regulatory elements. Importantly, we discovered that this early and extensive modification of the chromatin landscape also requires SYD. This study, therefore, provides evidence that SL signalling requires regulation of chromatin accessibility, and it identifies genomic locations harbouring likely SL cis‐regulatory sequences. Significance Statement: We have identified that the significant transcriptomic reprogramming by rac‐GR24 requires extensive changes to chromatin accessibility at over a thousand locations throughout the genome. We showed that two chromatin remodellers, SPLAYED and BRAHMA, are involved in this response. Our findings discovered a new component of gene regulation by the plant hormone strigolactone. [ABSTRACT FROM AUTHOR]

The switch/sucrose non-fermentable (SWI/SNF) subfamily are evolutionarily conserved, ATP-dependent chromatin-remodelling complexes that alter nucleosome position and regulate a spectrum of nuclear processes, including gene expression, DNA replication, DNA damage repair, genome stability and tumour suppression. These complexes, through their ATP-dependent chromatin remodelling, contribute to the dynamic regulation of genetic information and the maintenance of cellular processes essential for normal cellular function and overall genomic integrity. Mutations in SWI/SNF subunits are detected in 25% of human malignancies, indicating that efficient functioning of this complex is required to prevent tumourigenesis in diverse tissues. During development, SWI/SNF subunits help establish and maintain gene expression patterns essential for proper cellular identity and function, including maintenance of lineage-specific enhancers. Moreover, specific molecular signatures associated with SWI/SNF mutations, including disruption of SWI/SNF activity at enhancers, evasion of G0 cell cycle arrest, induction of cellular plasticity through pro-oncogene activation and Polycomb group (PcG) complex antagonism, are linked to the initiation and progression of carcinogenesis. Here, we review the molecular insights into the aetiology of human malignancies driven by disruption of the SWI/SNF complex and correlate these mechanisms to their developmental functions. Finally, we discuss the therapeutic potential of targeting SWI/SNF subunits in cancer.

Cholangiocarcinoma is a devastating liver cancer characterized by high aggressiveness and therapy resistance, resulting in poor prognosis. Long non-coding RNAs and signals imposed by oncogenic pathways, such as transforming growth factor β (TGFβ), frequently contribute to cholangiocarcinogenesis. Here, we explore novel effectors of TGFβ signalling in cholangiocarcinoma. LINC00313 is identified as a novel TGFβ target gene. Gene expression and genome-wide chromatin accessibility profiling reveal that nuclear LINC00313 transcriptionally regulates genes involved in Wnt signalling, such as the transcriptional activator TCF7. LINC00313 gain-of-function enhances TCF/LEF-dependent transcription, promotes colony formation in vitro and accelerates tumour growth in vivo. Genes affected by LINC00313 over-expression in CCA tumours are associated with KRAS and TP53 mutations and reduce overall patient survival. Mechanistically, ACTL6A and BRG1, subunits of the SWI/SNF chromatin remodelling complex, interact with LINC00313 and affect TCF7 and SULF2 transcription. We propose a model whereby TGFβ induces LINC00313 in order to regulate the expression of hallmark Wnt pathway genes, in co-operation with SWI/SNF. By modulating key genes of the Wnt pathway, LINC00313 fine-tunes Wnt/TCF/LEF-dependent transcriptional responses and promotes cholangiocarcinogenesis. Synopsis: LINC00313 produces a TGFβ-regulated long non-coding RNA in cholangiocarcinoma cells. By modulating key genes of the Wnt pathway, LINC00313 transcripts fine-tune Wnt/TCF/LEF-dependent transcriptional responses and promote cholangiocarcinogenesis. LINC00313 is a TGFβ-induced non-coding gene in cholangiocarcinoma. LINC00313 enhances TCF/LEF-dependent transcriptional responses and the expression of Wnt pathway genes. Core and accessory subunits of the SWI/SNF complex interact with LINC00313 transcripts. LINC00313 expression promotes chromatin accessibility, transcription and recruitment of BRG1 to TCF7 and SULF2. LINC00313 produces a TGFβ-regulated long non-coding RNA in cholangiocarcinoma cells. By modulating key genes of the Wnt pathway, LINC00313 transcripts fine-tune Wnt/TCF/LEF-dependent transcriptional responses and promote cholangiocarcinogenesis. [ABSTRACT FROM AUTHOR]

Nowadays, it is an established concept that the capability to reach a specialised cell identity via differentiation, as in the case of multi- and pluripotent stem cells, is not only determined by biochemical factors, but that also physical aspects of the microenvironment play a key role; interpreted by the cell through a force-based signalling pathway called mechanotransduction. However, the intricate ties between the elements involved in mechanotransduction, such as the extracellular matrix, the glycocalyx, the cell membrane, Integrin adhesion complexes, Cadherin-mediated cell/cell adhesion, the cytoskeleton, and the nucleus, are still far from being understood in detail. Here we report what is currently known about these elements in general and their specific interplay in the context of multi- and pluripotent stem cells. We furthermore merge this overview to a more comprehensive picture, that aims to cover the whole mechanotransductive pathway from the cell/microenvironment interface to the regulation of the chromatin structure in the nucleus. Ultimately, with this review we outline the current picture of the interplay between mechanotransductive cues and epigenetic regulation and how these processes might contribute to stem cell dynamics and fate.

Plants grown at different latitudes perceive and interpret seasonal variations in day length (photoperiod) and exposure to cold winter temperatures (vernalization). These factors control the expression of various genes involved in flowering, depending on the variations in photoperiod and vernalization. Epigenetic regulatory systems have evolved in plants to process environmental signals. Gene expression is modified through chromatin remodelling and small RNAs in response to seasonal changes in both annual and perennial plants. Key regulators of flowering, such as FLOWERING LOCUS C (FLC) and FLOWERING LOCUS T (FT), interact with other floral regulatory factors and undergo chromatin remodelling in response to seasonal cues. The Polycomb repressive complex (PRC) controls the expression of flowering‐related genes in photoperiodic flowering regulation. FLC acts as a potent suppressor by down‐regulating the expression of genes that promote flowering. Methylation, particularly in the context of CHG, CG and CHH, plays a critical role in embryogenesis. This review briefly explores and describes the regulation of flowering mechanisms in response to day‐length variations, cold exposure (vernalization) and seed development in plants. [ABSTRACT FROM AUTHOR]

To find nucleosomes, chromatin remodelers slide and hop along DNA, and their direction of approach affects the direction that nucleosomes slide in.

The MYC proto‐oncogene and BRD4, a BET family protein, are two cardinal proteins that have a broad influence in cell biology and disease. Both proteins are expressed ubiquitously in mammalian cells and play central roles in controlling growth, development, stress responses and metabolic function. As chromatin and transcriptional regulators, they play a critical role in regulating the expression of a burgeoning array of genes, maintaining chromatin architecture and genome stability. Consequently, impairment of their function or regulation leads to many diseases, with cancer being the most predominant. Interestingly, accumulating evidence indicates that regulation of the expression and functions of MYC are tightly intertwined with BRD4 at both transcriptional and post‐transcriptional levels. Here, we review the mechanisms by which MYC and BRD4 are regulated, their functions in governing various molecular mechanisms and the consequences of their dysregulation that lead to disease. We present a perspective of how the regulatory mechanisms for the two proteins could be entwined at multiple points in a BRD4‐MYC nexus that leads to the modulation of their functions and disease upon dysregulation. [ABSTRACT FROM AUTHOR]

Background: Heavy ion irradiation (IR) with high-linear energy transfer (LET) is characterized by a unique depth dose distribution and increased biological effectiveness. Following high-LET IR, localized energy deposition along the particle trajectories induces clustered DNA lesions, leading to low electron density domains (LEDDs). To investigate the spatiotemporal dynamics of DNA repair and chromatin remodeling, we established the automated image analysis of transmission electron micrographs. Methods: Human fibroblasts were irradiated with high-LET carbon ions or low-LET photons. At 0.1 h, 0.5 h, 5 h, and 24 h post-IR, nanoparticle-labeled repair factors (53BP1, pKu70, pKu80, DNA-PKcs) were visualized using transmission electron microscopy in interphase nuclei to monitor the formation and repair of DNA damage in the chromatin ultrastructure. Using AI-based software tools, advanced image analysis techniques were established to assess the DNA damage pattern following low-LET versus high-LET IR. Results: Low-LET IR induced single DNA lesions throughout the nucleus, and most DNA double-strand breaks (DSBs) were efficiently rejoined with no visible chromatin decondensation. High-LET IR induced clustered DNA damage concentrated along the particle trajectories, resulting in circumscribed LEDDs. Automated image analysis was used to determine the exact number of differently sized nanoparticles, their distance from one another, and their precise location within the micrographs (based on size, shape, and density). Chromatin densities were determined from grayscale features, and nanoparticles were automatically assigned to euchromatin or heterochromatin. High-LET IR-induced LEDDs were delineated using automated segmentation, and the spatial distribution of nanoparticles in relation to segmented LEDDs was determined. Conclusions: The results of our image analysis suggest that high-LET IR induces chromatin relaxation along particle trajectories, enabling the critical repair of successive DNA damage. Following exposure to different radiation qualities, automated image analysis of nanoparticle-labeled DNA repair proteins in the chromatin ultrastructure enables precise characterization of specific DNA damage patterns. [ABSTRACT FROM AUTHOR]

Background: Climate change has had a tremendous impact on the environment in general as well as agricultural crops grown in these situations as time passed. Agricultural production of crops is less suited and of lower quality due to disturbances in plant metabolism brought on by sensitivity to environmental stresses, which are brought on by climate change. Abiotic stressors that are specific to climate change, including as drought, extremes in temperature, increasing CO2, waterlogging from heavy rain, metal toxicity, and pH changes, are known to negatively affect an array of species. Plants adapt to these challenges by undergoing genome-wide epigenetic changes, which are frequently accompanied by differences in transcriptional gene expression. The sum of a cell's biochemical modifications to its nuclear DNA, post-translational modifications to histones, and variations in the synthesis of non-coding RNAs is called an epigenome. These modifications frequently lead to variations in gene expression that occur without any alteration in the underlying base sequence. Epigenetic mechanisms and marks: The methylation of homologous loci by three different modifications—genomic (DNA methylation), chromatin (histone modifications), and RNA-directed DNA methylation (RdDM)-could be regarded as epigenetic mechanisms that control the regulation of differential gene expression. Stresses from the environment cause chromatin remodelling, which enables plant cells to adjust their expression patterns temporarily or permanently. Epigenomics' consequences for genome stability and gene expression: DNA methylation affects gene expression in response to abiotic stressors by blocking or suppressing transcription. Environmental stimuli cause changes in DNA methylation levels, either upward in the case of hypermethylation or downward in the case of hypomethylation. The type of stress response that occurs as a result also affects the degree of DNA methylation alterations. Stress is also influenced by DRM2 and CMT3 methylating CNN, CNG, and CG. Both plant development and stress reactions depend on histone changes. Gene up-regulation is associated with histone tail phosphorylation, ubiquitination, and acetylation, while gene down-regulation is associated with de-acetylation and biotinylation. Plants undergo a variety of dynamic changes to histone tails in response to abiotic stressors. The relevance of these transcripts against stress is highlighted by the accumulation of numerous additional antisense transcripts, a source of siRNAs, caused by abiotic stresses. The study highlights the finding that plants can be protected from a range of abiotic stresses by epigenetic mechanisms such DNA methylation, histone modification, and RNA-directed DNA methylation. Transgenerational inheritance and sources of epigenetic variation: Stress results in the formation of epialleles, which are either transient or enduring epigenetic stress memory in plants. After the stress is gone, the stable memory is kept for the duration of the plant's remaining developmental cycles or passed on to the next generations, leading to plant evolution and adaptability. The bulk of epigenetic changes brought on by stress are temporary and return to normal after the stress has passed. Some of the modifications, however, might be long-lasting and transmitted across mitotic or even meiotic cell divisions. Epialleles often have genetic or non-genetic causes. Epialleles can arise spontaneously due to improper methylation state maintenance, short RNA off-target effects, or other non-genetic causes. Developmental or environmental variables that influence the stability of epigenetic states or direct chromatin modifications may also be non-genetic drivers of epigenetic variation. Transposon insertions that change local chromatin and structural rearrangements, such copy number changes that are genetically related or unrelated, are two genetic sources of epialleles. Epigenomics in crop improvement: To include epigenetics into crop breeding, it is necessary to create epigenetic variation as well as to identify and evaluate epialleles. Epigenome editing or epi-genomic selection may be required for epiallele creation and identification. In order to combat the challenges given by changing environments, these epigenetic mechanisms have generated novel epialleles that can be exploited to develop new crop types that are more climate-resilient. Numerous techniques can be used to alter the epigenome generally or at specific target loci in order to induce the epigenetic alterations necessary for crop development. Technologies like CRISPR/Cas9 and dCas, which have recently advanced, have opened up new avenues for the study of epigenetics. Epialleles could be employed in epigenomics-assisted breeding in addition to sequence-based markers for crop breeding. Conclusions and future prospectus: A few of the exciting questions that still need to be resolved in the area of heritable epigenetic variation include a better understanding of the epigenetic foundation of characteristics, the stability and heritability of epialleles, and the sources of epigenetic variation in crops. Investigating long intergenic non-coding RNAs (lincRNAs) as an epigenetic process might open up a new path to understanding crop plant's ability to withstand abiotic stress. For many of these technologies and approaches to be more applicable and deployable at a lower cost, technological breakthroughs will also be necessary. Breeders will probably need to pay closer attention to crop epialleles and how they can affect future responses to climate changes. The development of epialleles suitable for particular environmental circumstances may be made possible by creating targeted epigenetic changes in pertinent genes and by comprehending the molecular underpinnings of trans generational epigenetic inheritance. More research on a wider variety of plant species is required in order to fully comprehend the mechanisms that produce and stabilise epigenetic variation in crops. In addition to a collaborative and multidisciplinary effort by researchers in many fields of plant science, this will require a greater integration of the epigenomic data gathered in many crops. Before it may be applied generally, more study is required. [ABSTRACT FROM AUTHOR]

Cellular quiescence is an important physiological state both in unicellular and multicellular eukaryotes. Quiescent cells are halted for proliferation and stop the cell cycle at the G0 stage. Using fission yeast as a model organism, we have previously found that several subunits of a conserved chromatin remodeling complex, Ino80C (INOsitol requiring nucleosome remodeling factor), are required for survival in quiescence. Here, we demonstrate that Ino80C has a key function in the regulation of gene expression in G0 cells. We show that null mutants for two Ino80C subunits, Iec1 and Ies2, a putative subunit Arp42, a null mutant for the histone variant H2A.Z, and a null mutant for the Inositol kinase Asp1 have very similar phenotypes in quiescence. These mutants show reduced transcription genome-wide and specifically fail to activate 149 quiescence genes, of which many are localized to the subtelomeric regions. Using spike in normalized ChIP-seq experiments, we show that there is a global reduction of H2A.Z levels in quiescent wild-type cells but not in iec1∆ cells and that a subtelomeric chromosome boundary element is strongly affected by Ino80C. Based on these observations, we propose a model in which Ino80C is evicting H2A.Z from chromatin in quiescent cells, thereby inactivating the subtelomeric boundary element, leading to a reorganization of the chromosome structure and activation of genes required to survive in quiescence. [ABSTRACT FROM AUTHOR]

Abstract Background Epigenetic programming during development is essential for determining cell lineages, and alterations in this programming contribute to the initiation of embryonal tumour development. In neuroblastoma, neural crest progenitors block their course of natural differentiation into sympathoadrenergic cells, leading to the development of aggressive and metastatic paediatric cancer. Research of the epigenetic regulators responsible for oncogenic epigenomic networks is crucial for developing new epigenetic-based therapies against these tumours. Mammalian switch/sucrose non-fermenting (mSWI/SNF) ATP-dependent chromatin remodelling complexes act genome-wide translating epigenetic signals into open chromatin states. The present study aimed to understand the contribution of mSWI/SNF to the oncogenic epigenomes of neuroblastoma and its potential as a therapeutic target. Methods Functional characterisation of the mSWI/SNF complexes was performed in neuroblastoma cells using proteomic approaches, loss-of-function experiments, transcriptome and chromatin accessibility analyses, and in vitro and in vivo assays. Results Neuroblastoma cells contain three main mSWI/SNF subtypes, but only BRG1-associated factor (BAF) complex disruption through silencing of its key structural subunits, ARID1A and ARID1B, impairs cell proliferation by promoting cell cycle blockade. Genome-wide chromatin remodelling and transcriptomic analyses revealed that BAF disruption results in the epigenetic repression of an extensive invasiveness-related expression program involving integrins, cadherins, and key mesenchymal regulators, thereby reducing adhesion to the extracellular matrix and the subsequent invasion in vitro and drastically inhibiting the initiation and growth of neuroblastoma metastasis in vivo. Conclusions We report a novel ATPase-independent role for the BAF complex in maintaining an epigenomic program that allows neuroblastoma invasiveness and metastasis, urging for the development of new BAF pharmacological structural disruptors for therapeutic exploitation in metastatic neuroblastoma.

Wound healing and function recovery of injured tendons are still a big challenge for orthopaedic surgery. Evidence in clinic shows that early controlled motion has significant favourable effects on tendon healing; however, the mechanisms involved in are not fully understood. In the present study, it was shown that an appropriate mechanical stretch (10% strain, 0.5 Hz for 1 h) evidently promotes rat tenocyte migration and nuclear morphology changes. The farther research discovered that mechanical stretch had no effect on Lamin A/C expression, but it could promote chromatin decondensation. Moreover, the histone modification plays an important role in mechanical stretch‐mediated chromatin decondensation. Inhibition histone modification could inhibit mechanical stretch‐promoted nuclear morphology changes and tenocyte migration. These results indicating that mechanical stretch may promote tenocyte migration via chromatin remodelling‐mediated nuclear morphology changes, which contribute to a better understanding of the role of mechanical stretch on tenocyte migration and repair of injured tendon. [ABSTRACT FROM AUTHOR]

The Nucleosome Remodelling and Deacetylase (NuRD) complex represents one of the major chromatin remodelling complexes in mammalian cells, uniquely coupling the ability to "open" the chromatin by inducing nucleosome sliding with histone deacetylase activity. At the core of the NuRD complex are a family of ATPases named CHDs that utilise the energy produced by the hydrolysis of the ATP to induce chromatin structural changes. Recent studies have highlighted the prominent role played by the NuRD in regulating gene expression during brain development and in maintaining neuronal circuitry in the adult cerebellum. Importantly, components of the NuRD complex have been found to carry mutations that profoundly affect neurological and cognitive development in humans. Here, we discuss recent literature concerning the molecular structure of NuRD complexes and how the subunit composition and numerous permutations greatly determine their functions in the nervous system. We will also discuss the role of the CHD family members in an array of neurodevelopmental disorders. Special emphasis will be given to the mechanisms that regulate the NuRD complex composition and assembly in the cortex and how subtle mutations may result in profound defects of brain development and the adult nervous system. [ABSTRACT FROM AUTHOR]

Several amino acids can stimulate milk synthesis in mammary epithelial cells (MEC); however, the regulatory role of isoleucine (Ile) and underlying molecular mechanism remain poorly understood. In this study, we aimed to evaluate the regulatory effects of Ile on milk protein and fat synthesis in MEC and reveal the mediation mechanism of Brahma-related gene 1 (BRG1) on this regulation. Ile dose dependently affected milk protein and fat synthesis, mechanistic target of rapamycin (mTOR) phosphorylation, sterol regulatory element binding protein 1c (SREBP-1c) expression and maturation, and BRG1 protein expression in bovine MEC. Phosphatidylinositol 3 kinase (PI3K) inhibition by LY294002 treatment blocked the stimulation of Ile on BRG1 expression. BRG1 knockdown and gene activation experiments showed that it mediated the stimulation of Ile on milk protein and fat synthesis, mTOR phosphorylation, and SREBP-1c expression and maturation in MEC. ChIP-PCR analysis detected that BRG1 bound to the promoters of mTOR and SREBP-1c , and ChIP-qPCR further detected that these bindings were increased by Ile stimulation. In addition, BRG1 positively regulated the binding of H3K27ac to these two promoters, while it negatively affected the binding of H3K27me3 to these promoters. BRG1 knockdown blocked the stimulation of Ile on these two gene expressions. The expression of BRG1 was higher in mouse mammary gland in the lactating period, compared with that in the puberty or dry period. Taken together, these experimental data reveal that Ile stimulates milk protein and fat synthesis in MEC via the PI3K-BRG1-mTOR/SREBP-1c pathway. [ABSTRACT FROM AUTHOR]

Understanding plant stress memory under extreme temperatures such as cold and heat could contribute to plant development. Plants employ different types of stress memories, such as somatic, intergenerational and transgenerational, regulated by epigenetic changes such as DNA and histone modifications and microRNAs (miRNA), playing a key role in gene regulation from early development to maturity. In most cases, cold and heat stresses result in short-term epigenetic modifications that can return to baseline modification levels after stress cessation. Nevertheless, some of the modifications may be stable and passed on as stress memory, potentially allowing them to be inherited across generations, whereas some of the modifications are reactivated during sexual reproduction or embryogenesis. Several stressrelated genes are involved in stress memory inheritance by turning on and off transcription profiles and epigenetic changes. Vernalization is the best example of somatic stress memory. Changes in the chromatin structure of the Flowering Locus C (FLC) gene, a MADS-box transcription factor (TF), maintain cold stress memory during mitosis. FLC expression suppresses flowering at high levels during winter; and during vernalization, B3 TFs, cold memory cis-acting element and polycomb repressive complex 1 and 2 (PRC1 and 2) silence FLC activation. In contrast, the repression of SQUAMOSA promoter-binding protein-like (SPL) TF and the activation of Heat Shock TF (HSFA2) are required for heat stress memory. However, it is still unclear how stress memory is inherited by offspring, and the integrated view of the regulatory mechanisms of stress memory and mitotic and meiotic heritable changes in plants is still scarce. Thus, in this review, we focus on the epigenetic regulation of stress memory and discuss the application of new technologies in developing epigenetic modifications to improve stress memory. [ABSTRACT FROM AUTHOR]

Abstract Background Jasmonates (JAs) mediate trade-off between responses to both biotic and abiotic stress and growth in plants. The Arabidopsis thaliana HISTONE DEACETYLASE 6 is part of the CORONATINE INSENSITIVE1 receptor complex, co-repressing the HDA6/COI1-dependent acetic acid-JA pathway that confers plant drought tolerance. The decrease in HDA6 binding to target DNA mirrors histone H4 acetylation (H4Ac) changes during JA-mediated drought response, and mutations in HDA6 also cause depletion in the constitutive repressive marker H3 lysine 27 trimethylation (H3K27me3). However, the genome-wide effect of HDA6 on H4Ac and much of the impact of JAs on histone modifications and chromatin remodelling remain elusive. Results We performed high-throughput ChIP-Seq on the HDA6 mutant, axe1-5, and wild-type plants with or without methyl jasmonate (MeJA) treatment to assess changes in active H4ac and repressive H3K27me3 histone markers. Transcriptional regulation was investigated in parallel by microarray analysis in the same conditions. MeJA- and HDA6-dependent histone modifications on genes for specialized metabolism; linolenic acid and phenylpropanoid pathways; and abiotic and biotic stress responses were identified. H4ac and H3K27me3 enrichment also differentially affects JAs and HDA6-mediated genome integrity and gene regulatory networks, substantiating the role of HDA6 interacting with specific families of transposable elements in planta and highlighting further specificity of action as well as novel targets of HDA6 in the context of JA signalling for abiotic and biotic stress responses. Conclusions The findings demonstrate functional overlap for MeJA and HDA6 in tuning plant developmental plasticity and response to stress at the histone modification level. MeJA and HDA6, nonetheless, maintain distinct activities on histone modifications to modulate genetic variability and to allow adaptation to environmental challenges.

Germline or somatic variation in the family of KMT2 lysine methyltransferases have been associated with a variety of congenital disorders and cancers. Notably, KMT2A-fusions are prevalent in 70% of infant leukaemias but fail to phenocopy short latency leukaemogenesis in mammalian models, suggesting additional factors are necessary for transformation. Given the lack of additional somatic mutation, the role of epigenetic regulation in cell specification, and our prior results of germline KMT2C variation in infant leukaemia patients, we hypothesized that germline dysfunction of KMT2C altered haematopoietic specification. In isogenic KMT2C KO hPSCs, we found genome-wide differences in histone modifications at active and poised enhancers, leading to gene expression profiles akin to mesendoderm rather than mesoderm highlighted by a significant increase in NODAL expression and WNT inhibition, ultimately resulting in a lack of in vitro hemogenic endothelium specification. These unbiased multi-omic results provide new evidence for germline mechanisms increasing risk of early leukaemogenesis.

Understanding plant stress memory under extreme temperatures such as cold and heat could contribute to plant development. Plants employ different types of stress memories, such as somatic, intergenerational and transgenerational, regulated by epigenetic changes such as DNA and histone modifications and microRNAs (miRNA), playing a key role in gene regulation from early development to maturity. In most cases, cold and heat stresses result in short-term epigenetic modifications that can return to baseline modification levels after stress cessation. Nevertheless, some of the modifications may be stable and passed on as stress memory, potentially allowing them to be inherited across generations, whereas some of the modifications are reactivated during sexual reproduction or embryogenesis. Several stress-related genes are involved in stress memory inheritance by turning on and off transcription profiles and epigenetic changes. Vernalization is the best example of somatic stress memory. Changes in the chromatin structure of the Flowering Locus C (FLC) gene, a MADS-box transcription factor (TF), maintain cold stress memory during mitosis. FLC expression suppresses flowering at high levels during winter; and during vernalization, B3 TFs, cold memory cis-acting element and polycomb repressive complex 1 and 2 (PRC1 and 2) silence FLC activation. In contrast, the repression of SQUAMOSA promoter-binding protein-like (SPL) TF and the activation of Heat Shock TF (HSFA2) are required for heat stress memory. However, it is still unclear how stress memory is inherited by offspring, and the integrated view of the regulatory mechanisms of stress memory and mitotic and meiotic heritable changes in plants is still scarce. Thus, in this review, we focus on the epigenetic regulation of stress memory and discuss the application of new technologies in developing epigenetic modifications to improve stress memory.

Round spermatid injection (ROSI) results in a lower birth rate than intracytoplasmic sperm injection, which has hampered its clinical application. Inefficient development of ROSI embryos has been attributed to epigenetic abnormalities. However, the chromatin-based mechanism that underpins the low birth rate in ROSI remains to be determined. Here, we show that a repressive histone mark, H3K27me3, persists from mouse round spermatids into zygotes in ROSI and that round spermatid-derived H3K27me3 is associated with less accessible chromatin and impaired gene expression in ROSI embryos. These loci are initially marked by H3K27me3 but undergo histone modification remodelling in spermiogenesis, resulting in reduced H3K27me3 in normal spermatozoa. Therefore, the absence of epigenetic remodelling, presumably mediated by histone turnover during spermiogenesis, leads to dysregulation of chromatin accessibility and transcription in ROSI embryos. Thus, our results unveil a molecular logic, in which chromatin states in round spermatids impinge on chromatin accessibility and transcription in ROSI embryos, highlighting the importance of epigenetic remodelling during spermiogenesis in successful reproduction. [ABSTRACT FROM AUTHOR]

Packaging of eukaryotic genome into chromatin is a major obstacle to cells encountering DNA damage caused by external or internal agents. For maintaining genomic integrity, the double-strand breaks (DSB) must be efficiently repaired, as these are the most deleterious type of DNA damage. The DNA breaks have to be detected in chromatin context, the DNA damage response (DDR) pathways have to be activated to repair breaks either by nonhomologous end joining and homologous recombination repair. It is becoming clearer now that chromatin is not a mere hindrance to DDR, it plays active role in sensing, detection and repair of DNA damage. The repair of DSB is governed by the reorganization of the pre-existing chromatin, leading to recruitment of specific machineries, chromatin remodelling complexes, histone modifiers to bring about dynamic alterations in histone composition, nucleosome positioning, histone modifications. In response to DNA break, modulation of chromatin occurs via various mechanisms including post-translational modification of histones. DNA breaks induce many types of histone modifications, such as phosphorylation, acetylation, methylation and ubiquitylation on specific histone residues which are signal and context dependent. DNA break induced histone modifications have been reported to function in sensing the breaks, activating processing of breaks by specific pathways, and repairing damaged DNA to ensure integrity of the genome. Favourable environment for DSB repair is created by generating open and relaxed chromatin structure. Histone acetylation mediate de-condensation of chromatin and recruitment of DSB repair proteins to their site of action at the DSB to facilitate repair. In this review, we will discuss the current understanding on the critical role of histone acetylation in inducing changes both in chromatin organization and promoting recruitment of DSB repair proteins to sites of DNA damage. It consists of an overview of function and regulation of the deacetylase enzymes which remove these marks and the function of histone acetylation and regulators of acetylation in genome surveillance. [ABSTRACT FROM AUTHOR]

Background: Epigenetic programming during development is essential for determining cell lineages, and alterations in this programming contribute to the initiation of embryonal tumour development. In neuroblastoma, neural crest progenitors block their course of natural differentiation into sympathoadrenergic cells, leading to the development of aggressive and metastatic paediatric cancer. Research of the epigenetic regulators responsible for oncogenic epigenomic networks is crucial for developing new epigenetic-based therapies against these tumours. Mammalian switch/sucrose non-fermenting (mSWI/SNF) ATP-dependent chromatin remodelling complexes act genome-wide translating epigenetic signals into open chromatin states. The present study aimed to understand the contribution of mSWI/SNF to the oncogenic epigenomes of neuroblastoma and its potential as a therapeutic target. Methods: Functional characterisation of the mSWI/SNF complexes was performed in neuroblastoma cells using proteomic approaches, loss-of-function experiments, transcriptome and chromatin accessibility analyses, and in vitro and in vivo assays. Results: Neuroblastoma cells contain three main mSWI/SNF subtypes, but only BRG1-associated factor (BAF) complex disruption through silencing of its key structural subunits, ARID1A and ARID1B, impairs cell proliferation by promoting cell cycle blockade. Genome-wide chromatin remodelling and transcriptomic analyses revealed that BAF disruption results in the epigenetic repression of an extensive invasiveness-related expression program involving integrins, cadherins, and key mesenchymal regulators, thereby reducing adhesion to the extracellular matrix and the subsequent invasion in vitro and drastically inhibiting the initiation and growth of neuroblastoma metastasis in vivo. Conclusions: We report a novel ATPase-independent role for the BAF complex in maintaining an epigenomic program that allows neuroblastoma invasiveness and metastasis, urging for the development of new BAF pharmacological structural disruptors for therapeutic exploitation in metastatic neuroblastoma. [ABSTRACT FROM AUTHOR]

Testicular development and spermatogenesis in mice involve complex and dynamic gene regulation and chromatin remodelling. In this study, Real-time fluorescence quantitative PCR (RT-qPCR), Western Blot (WB), Immunofluorescence (IF), transfection and other techniques were used to analyse the expression of Ino80d mRNA and its encoded proteins in mouse testicular tissue and mouse spermatogonial cells, and to further analyse the possible target-regulatory relationship and function of miR-92a-3p and Ino80d. We found that Ino80d mRNA and protein expression was up-regulated in adult mouse testis tissue relative to juvenile mouse testis tissue, whereas miR-92a-3p expression was down-regulated in adult mouse testis tissue. Immunofluorescence results showed that the Ino80d protein was mainly localized in the nucleus of male germ cells. Ino80d protein expression is higher in spermatogonia, spermatid and lower in primary spermatocytes, secondary spermatocytes and sperm. There is a decreasing trend in development from spermatogonia to secondary spermatocytes. The transfection results showed that the expression levels of Ino80d mRNA and protein were down-regulated after overexpression of miR-92a-3p in mouse spermatogonia. Increased miR-92a-3p may be a key factor in inhibiting the expression of Ino80d mRNA and proteins in the miR-92a-3p mimics group of mouse spermatogonial cells, whereas differential expression may be a result of the negative regulation of miR-92a-3p, which regulates testicular development and spermatogenesis in mice., Competing Interests: Declaration of Competing Interest All authors disclosed no relevant relationships., (Copyright © 2024 Society for Biology of Reproduction & the Institute of Animal Reproduction and Food Research of Polish Academy of Sciences in Olsztyn. Published by Elsevier B.V. All rights reserved.)

The switch/sucrose non-fermentable (SWI/SNF) subfamily are evolutionarily conserved, ATP-dependent chromatin-remodelling complexes that alter nucleosome position and regulate a spectrum of nuclear processes, including gene expression, DNA replication, DNA damage repair, genome stability and tumour suppression. These complexes, through their ATP-dependent chromatin remodelling, contribute to the dynamic regulation of genetic information and the maintenance of cellular processes essential for normal cellular function and overall genomic integrity. Mutations in SWI/SNF subunits are detected in 25% of human malignancies, indicating that efficient functioning of this complex is required to prevent tumourigenesis in diverse tissues. During development, SWI/SNF subunits help establish and maintain gene expression patterns essential for proper cellular identity and function, including maintenance of lineage-specific enhancers. Moreover, specific molecular signatures associated with SWI/SNF mutations, including disruption of SWI/SNF activity at enhancers, evasion of G0 cell cycle arrest, induction of cellular plasticity through pro-oncogene activation and Polycomb group (PcG) complex antagonism, are linked to the initiation and progression of carcinogenesis. Here, we review the molecular insights into the aetiology of human malignancies driven by disruption of the SWI/SNF complex and correlate these mechanisms to their developmental functions. Finally, we discuss the therapeutic potential of targeting SWI/SNF subunits in cancer.

Despite mitochondria being key for the control of cell homeostasis and fate, their role in DNA damage response is usually just regarded as an apoptotic trigger. However, growing evidence points to mitochondrial factors modulating nuclear functions. Remarkably, after DNA damage, cytochrome c (Cc) interacts in the cell nucleus with a variety of well‐known histone chaperones, whose activity is competitively inhibited by the haem protein. As nuclear Cc inhibits the nucleosome assembly/disassembly activity of histone chaperones, it might indeed affect chromatin dynamics and histone deposition on DNA. Several histone chaperones actually interact with Cc Lys residues through their acidic regions, which are also involved in heterotypic interactions leading to liquid–liquid phase transitions responsible for the assembly of nuclear condensates, including heterochromatin. This relies on dynamic histone–DNA interactions that can be modulated by acetylation of specific histone Lys residues. Thus, Cc may have a major regulatory role in DNA repair by fine‐tuning nucleosome assembly activity and likely nuclear condensate formation.

Packaging of eukaryotic genome into chromatin is a major obstacle to cells encountering DNA damage caused by external or internal agents. For maintaining genomic integrity, the double-strand breaks (DSB) must be efficiently repaired, as these are the most deleterious type of DNA damage. The DNA breaks have to be detected in chromatin context, the DNA damage response (DDR) pathways have to be activated to repair breaks either by non‐ homologous end joining and homologous recombination repair. It is becoming clearer now that chromatin is not a mere hindrance to DDR, it plays active role in sensing, detection and repair of DNA damage. The repair of DSB is governed by the reorganization of the pre-existing chromatin, leading to recruitment of specific machineries, chromatin remodelling complexes, histone modifiers to bring about dynamic alterations in histone composition, nucleosome positioning, histone modifications. In response to DNA break, modulation of chromatin occurs via various mechanisms including post-translational modification of histones. DNA breaks induce many types of histone modifications, such as phosphorylation, acetylation, methylation and ubiquitylation on specific histone residues which are signal and context dependent. DNA break induced histone modifications have been reported to function in sensing the breaks, activating processing of breaks by specific pathways, and repairing damaged DNA to ensure integrity of the genome. Favourable environment for DSB repair is created by generating open and relaxed chromatin structure. Histone acetylation mediate de-condensation of chromatin and recruitment of DSB repair proteins to their site of action at the DSB to facilitate repair. In this review, we will discuss the current understanding on the critical role of histone acetylation in inducing changes both in chromatin organization and promoting recruitment of DSB repair proteins to sites of DNA damage. It consists of an overview of function and regulation of the deacetylase enzymes which remove these marks and the function of histone acetylation and regulators of acetylation in genome surveillance.

The global cancer cases and mortality rates are increasing and demand efficient biomarkers for accurate screening, detection, diagnosis, and prognosis. Recent studies have demonstrated that variations in epigenetic mechanisms like aberrant promoter methylation, altered histone modification and mutations in ATP-dependent chromatin remodelling complexes play an important role in the development of carcinogenic events. However, the influence of other epigenetic alterations in various cancers was confirmed with evolving research and the emergence of high throughput technologies. Therefore, alterations in epigenetic marks may have clinical utility as potential biomarkers for early cancer detection and diagnosis. In this review, an outline of the key epigenetic mechanism(s), and their deregulation in cancer etiology have been discussed to decipher the future prospects in cancer therapeutics including precision medicine. Also, this review attempts to highlight the gaps in epigenetic drug development with emphasis on integrative analysis of epigenetic biomarkers to establish minimally noninvasive biomarkers with clinical applications. [ABSTRACT FROM AUTHOR]

The long interspersed nuclear elements 1 (LINE-1/L1s) are the only active autonomous retrotransposons found in humans which can integrate anywhere in the human genome. They can expand the genome and thus bring good or bad effects to the host cells which really depends on their integration site and associated polymorphism. LINE-1 retrotransposition has been found participating in various neurological disorders such as autism spectrum disorder, Alzheimer's disease, major depression disorder, post-traumatic stress disorder and schizophrenia. Despite the recent progress, the roles and pathological mechanism of LINE-1 retrotransposition in schizophrenia and its heritable risks, particularly, contribution to "missing heritability" are yet to be determined. Therefore, this review focuses on the potentially etiological roles of L1s in the development of schizophrenia, possible therapeutic choices and unaddressed questions in order to shed lights on the future research. [ABSTRACT FROM AUTHOR]

The global cancer cases and mortality rates are increasing and demand efficient biomarkers for accurate screening, detection, diagnosis, and prognosis. Recent studies have demonstrated that variations in epigenetic mechanisms like aberrant promoter methylation, altered histone modification and mutations in ATP-dependent chromatin remodelling complexes play an important role in the development of carcinogenic events. However, the influence of other epigenetic alterations in various cancers was confirmed with evolving research and the emergence of high throughput technologies. Therefore, alterations in epigenetic marks may have clinical utility as potential biomarkers for early cancer detection and diagnosis. In this review, an outline of the key epigenetic mechanism(s), and their deregulation in cancer etiology have been discussed to decipher the future prospects in cancer therapeutics including precision medicine. Also, this review attempts to highlight the gaps in epigenetic drug development with emphasis on integrative analysis of epigenetic biomarkers to establish minimally non-invasive biomarkers with clinical applications.

The long interspersed nuclear elements 1 (LINE-1/L1s) are the only active autonomous retrotransposons found in humans which can integrate anywhere in the human genome. They can expand the genome and thus bring good or bad effects to the host cells which really depends on their integration site and associated polymorphism. LINE-1 retrotransposition has been found participating in various neurological disorders such as autism spectrum disorder, Alzheimer’s disease, major depression disorder, post-traumatic stress disorder and schizophrenia. Despite the recent progress, the roles and pathological mechanism of LINE-1 retrotransposition in schizophrenia and its heritable risks, particularly, contribution to “missing heritability” are yet to be determined. Therefore, this review focuses on the potentially etiological roles of L1s in the development of schizophrenia, possible therapeutic choices and unaddressed questions in order to shed lights on the future research.

Nowadays, it is an established concept that the capability to reach a specialised cell identity via differentiation, as in the case of multi- and pluripotent stem cells, is not only determined by biochemical factors, but that also physical aspects of the microenvironment play a key role; interpreted by the cell through a force-based signalling pathway called mechanotransduction. However, the intricate ties between the elements involved in mechanotransduction, such as the extracellular matrix, the glycocalyx, the cell membrane, Integrin adhesion complexes, Cadherin-mediated cell/cell adhesion, the cytoskeleton, and the nucleus, are still far from being understood in detail. Here we report what is currently known about these elements in general and their specific interplay in the context of multi- and pluripotent stem cells. We furthermore merge this overview to a more comprehensive picture, that aims to cover the whole mechanotransductive pathway from the cell/microenvironment interface to the regulation of the chromatin structure in the nucleus. Ultimately, with this review we outline the current picture of the interplay between mechanotransductive cues and epigenetic regulation and how these processes might contribute to stem cell dynamics and fate. • Mechanotransductive stimuli play a crucial role in stem cell homeostasis. • Membrane tension and actin cortex are important factors for pluripotency exit. • Mechanotransductive cues affect structural chromatin conformation in stem cells. [ABSTRACT FROM AUTHOR]

The Nucleosome Remodelling and Deacetylase (NuRD) complex represents one of the major chromatin remodelling complexes in mammalian cells, uniquely coupling the ability to “open” the chromatin by inducing nucleosome sliding with histone deacetylase activity. At the core of the NuRD complex are a family of ATPases named CHDs that utilise the energy produced by the hydrolysis of the ATP to induce chromatin structural changes. Recent studies have highlighted the prominent role played by the NuRD in regulating gene expression during brain development and in maintaining neuronal circuitry in the adult cerebellum. Importantly, components of the NuRD complex have been found to carry mutations that profoundly affect neurological and cognitive development in humans. Here, we discuss recent literature concerning the molecular structure of NuRD complexes and how the subunit composition and numerous permutations greatly determine their functions in the nervous system. We will also discuss the role of the CHD family members in an array of neurodevelopmental disorders. Special emphasis will be given to the mechanisms that regulate the NuRD complex composition and assembly in the cortex and how subtle mutations may result in profound defects of brain development and the adult nervous system.

Summary: Many environmental conditions fluctuate and organisms need to respond effectively. This is especially true for temperature cues that can change in minutes to seasons and often follow a diurnal rhythm. Plants cannot migrate and most cannot regulate their temperature. Therefore, a broad array of responses have evolved to deal with temperature cues from freezing to heat stress. A particular response to mildly elevated temperatures is called thermomorphogenesis, a suite of morphological adaptations that includes thermonasty, formation of thin leaves and elongation growth of petioles and hypocotyl. Thermomorphogenesis allows for optimal performance in suboptimal temperature conditions by enhancing the cooling capacity. When temperatures rise further, heat stress tolerance mechanisms can be induced that enable the plant to survive the stressful temperature, which typically comprises cellular protection mechanisms and memory thereof. Induction of thermomorphogenesis, heat stress tolerance and stress memory depend on gene expression regulation, governed by diverse epigenetic processes. In this Tansley review we update on the current knowledge of epigenetic regulation of heat stress tolerance and elevated temperature signalling and response, with a focus on thermomorphogenesis regulation and heat stress memory. In particular we highlight the emerging role of H3K4 methylation marks in diverse temperature signalling pathways. [ABSTRACT FROM AUTHOR]

The murine esBAF complex plays a major role in the regulation of gene expression during stem cell development and differentiation. As one of its core subunits, Smarcb1 is indispensable for its function and its loss is connected to neurodevelopmental disorders and participates in the carcinogenesis of entities such as rhabdoid tumours. We explored how Smarcb1 regulates gene programs in murine embryonic stem cells (mESC) and in this way orchestrates differentiation. Our data underline the importance of Smarcb1 expression and function for the development of the nervous system along with basic cellular functions, such as cell adhesion and cell organisation. Using ChIP-seq, we were able to portray the consequences of Smarcb1 knockdown (kd) for the binding of esBAF and PRC2 as well as its influence on histone marks H3K27me3, H3K4me3 and H3K27ac. Their signals are changed in gene and enhancer regions of genes connected to nervous system development and offers a plausible explanation for changes in gene expression. Further, we describe a group of genes that are, despite increased BAF binding, suppressed after Smarcb1 kd by mechanisms independent of PRC2 function. [ABSTRACT FROM AUTHOR]

Background: Jasmonates (JAs) mediate trade-off between responses to both biotic and abiotic stress and growth in plants. The Arabidopsis thaliana HISTONE DEACETYLASE 6 is part of the CORONATINE INSENSITIVE1 receptor complex, co-repressing the HDA6/COI1-dependent acetic acid-JA pathway that confers plant drought tolerance. The decrease in HDA6 binding to target DNA mirrors histone H4 acetylation (H4Ac) changes during JA-mediated drought response, and mutations in HDA6 also cause depletion in the constitutive repressive marker H3 lysine 27 trimethylation (H3K27me3). However, the genome-wide effect of HDA6 on H4Ac and much of the impact of JAs on histone modifications and chromatin remodelling remain elusive. Results: We performed high-throughput ChIP-Seq on the HDA6 mutant, axe1-5, and wild-type plants with or without methyl jasmonate (MeJA) treatment to assess changes in active H4ac and repressive H3K27me3 histone markers. Transcriptional regulation was investigated in parallel by microarray analysis in the same conditions. MeJA- and HDA6-dependent histone modifications on genes for specialized metabolism; linolenic acid and phenylpropanoid pathways; and abiotic and biotic stress responses were identified. H4ac and H3K27me3 enrichment also differentially affects JAs and HDA6-mediated genome integrity and gene regulatory networks, substantiating the role of HDA6 interacting with specific families of transposable elements in planta and highlighting further specificity of action as well as novel targets of HDA6 in the context of JA signalling for abiotic and biotic stress responses. Conclusions: The findings demonstrate functional overlap for MeJA and HDA6 in tuning plant developmental plasticity and response to stress at the histone modification level. MeJA and HDA6, nonetheless, maintain distinct activities on histone modifications to modulate genetic variability and to allow adaptation to environmental challenges. [ABSTRACT FROM AUTHOR]

BRG1 and BRM are ATPase core subunits of the human SWI/SNF chromatin remodelling complexes mainly associated with transcriptional initiation. They also have a role in alternative splicing, which has been shown for BRM-containing SWI/SNF complexes at a few genes. Here, we have identified a subset of genes which harbour alternative exons that are affected by SWI/SNF ATPases by expressing the ATPases BRG1 and BRM in C33A cells, a BRG1- and BRM-deficient cell line, and analysed the effect on splicing by RNA sequencing. BRG1- and BRM-affected sub-sets of genes favouring both exon inclusion and exon skipping, with only a minor overlap between the ATPase. Some of the changes in alternative splicing induced by BRG1 and BRM expression did not require the ATPase activity. The BRG1-ATPase independent included exons displayed an exon signature of a high GC content. By investigating three genes with exons affected by the BRG-ATPase-deficient variant, we show that these exons accumulated phosphorylated RNA pol II CTD, both serine 2 and serine 5 phosphorylation, without an enrichment of the RNA polymerase II. The ATPases were recruited to the alternative exons, together with both core and signature subunits of SWI/SNF complexes, and promoted the binding of RNA binding factors to chromatin and RNA at the alternative exons. The interaction with the nascent RNP, however, did not reflect the association to chromatin. The hnRNPL, hnRNPU and SAM68 proteins associated with chromatin in cells expressing BRG1 and BRM wild type, but the binding of hnRNPU to the nascent RNP was excluded. This suggests that SWI/SNF can regulate alternative splicing by interacting with splicing-RNA binding factor and influence their binding to the nascent pre-mRNA particle. [ABSTRACT FROM AUTHOR]

Chromatin remodelling is an important process in neural development and is related to autism spectrum disorder (ASD) and schizophrenia (SCZ) aetiology. To further elucidate the involvement of chromatin remodelling genes in the genetic aetiology of ASD and SCZ in the Japanese population, we performed a case–control study. Targeted sequencing was conducted on coding regions of four BAF chromatin remodelling complex genes: SMARCA2, SMARCA4, SMARCC2, and ARID1B in 185 ASD, 432 SCZ patients, and 517 controls. 27 rare non-synonymous variants were identified in ASD and SCZ patients, including 25 missense, one in-frame deletion in SMRACA4, and one frame-shift variant in SMARCC2. Association analysis was conducted to investigate the burden of rare variants in BAF genes in ASD and SCZ patients. Significant enrichment of rare missense variants in BAF genes, but not synonymous variants, was found in ASD compared to controls. Rare pathogenic variants indicated by in silico tools were significantly enriched in ASD, but not statistically significant in SCZ. Pathogenic-predicted variants were located in disordered binding regions and may confer risk for ASD and SCZ by disrupting protein–protein interactions. Our study supports the involvement of rare missense variants of BAF genes in ASD and SCZ susceptibility. [ABSTRACT FROM AUTHOR]

Alterations in chromatin remodelling genes are increasingly recognised as drivers of undifferentiated malignancies. In atypical teratoid/rhabdoid tumours (ATRTs) and extracranial rhabdoid tumours (ECRTs), inactivation of SMARCB1 underlies >95% of cases. In the remainder, the culprit is another SWI/SNF family member, SMARCA4. By contrast, in small cell carcinoma of the ovary hypercalcaemic type (SCCOHT), SMARCA4 deficiency is by far the most common driver mechanism, while SMARCB1 alterations are rarely seen. It is unclear why alterations are so heavily weighted towards one or another subunit based on site alone, but both have become essential markers for the diagnosis and management of these undifferentiated lesions. Core SMARCA4‐deficient undifferentiated malignancies share an aggressive clinical course and show an overlapping morphologic phenotype. In their study, Andrianteranagna, Cyrta and colleagues used DNA methylation and gene expression profiling to compare two subsets of SMARCA4‐deficient malignancies diagnosed as SCCOHT and ECRT. Their work gives further insight into the subtle molecular spectrum of SMARCA4‐deficient tumours, and their distinction from ATRT and ECRT with SMARCB1 inactivation. The characterisation of these molecular features is likely to play an important role in the future as we try to establish a clinically meaningful framework for the diagnosis and management of these lesions. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Regeneration is a response mechanism aiming to reconstruct lost or damaged structures. To achieve this, the cells repopulating the lost tissue often have to change their original identity, a process that involves chromatin remodelling.We have analysed the issue of chromatin remodelling during regeneration in the wing disc of Drosophila. In this disc the ablation of the central region (the pouch) induces the regenerative response of the cells from the lateral region (the hinge), which reconstitute the wing pouch. We have examined euchromatin and heterochromatin histone marks during the process and find that heterochromatin marks disappear but are recovered when regeneration is complete. Euchromatin marks are not modified. We also describe the transcription of two retrotransposons, Roo and F-element in the regenerating cells. We have established a temporal correlation between the alterations of heterochromatin marks and the levels of transcription of two retrotransposons, Roo and F-element, both during embryonic development and in the regeneration process. [Display omitted] • During regeneration of the wing disc there is chromatin remodelling, as indicated by histone modifications. • Heterochromatin histone marks are modified during the process but euchromatin marks are not. • The transcription of two retrotransposons, Roo and F-element, is blocked in regenerating cells but resumed at the end of the process. • The epigenetic modifications found during regeneration resemble those that occur during early development. [ABSTRACT FROM AUTHOR]

Germline or somatic variation in the family of KMT2 lysine methyltransferases have been associated with a variety of congenital disorders and cancers. Notably, KMT2A-fusions are prevalent in 70% of infant leukaemias but fail to phenocopy short latency leukaemogenesis in mammalian models, suggesting additional factors are necessary for transformation. Given the lack of additional somatic mutation, the role of epigenetic regulation in cell specification, and our prior results of germline KMT2C variation in infant leukaemia patients, we hypothesized that germline dysfunction of KMT2C altered haematopoietic specification. In isogenic KMT2C KO hPSCs, we found genome-wide differences in histone modifications at active and poised enhancers, leading to gene expression profiles akin to mesendoderm rather than mesoderm highlighted by a significant increase in NODAL expression and WNT inhibition, ultimately resulting in a lack of in vitro hemogenic endothelium specification. These unbiased multi-omic results provide new evidence for germline mechanisms increasing risk of early leukaemogenesis. [ABSTRACT FROM AUTHOR]