Chromatin Remodeling Mechanisms Research Articles

MALAT1: A Long Non-Coding RNA with Multiple Functions and Its Role in Processes Associated with Fat Deposition.

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) belongs to the lncRNA molecules, which are involved in transcriptional and epigenetic regulation and the control of gene expression, including the mechanism of chromatin remodeling. MALAT1 was first discovered during carcinogenesis in lung adenocarcinoma, hence its name. In humans, 66 of its isoforms have been identified, and in pigs, only 2 are predicted, for which information is available in Ensembl databases (Ensembl Release 111). MALAT1 is expressed in numerous tissues, including adipose, adrenal gland, heart, kidney, liver, ovary, pancreas, sigmoid colon, small intestine, spleen, and testis. MALAT1, as an lncRNA, shows a wide range of functions. It is involved in the regulation of the cell cycle, where it has pro-proliferative effects and high cellular levels during the G1/S and mitotic (M) phases. Moreover, it is involved in invasion, metastasis, and angiogenesis, and it has a crucial function in alternative splicing during carcinogenesis. In addition, MALAT1 plays a significant role in the processes of fat deposition and adipogenesis. The human adipose tissue stem cells, during differentiation into adipocytes, secrete MALAT1 as one the most abundant lncRNAs in the exosomes. MALAT1 expression in fat tissue is positively correlated with adipogenic FABP4 and LPL. This lncRNA is involved in the regulation of PPARγ at the transcription stage, fatty acid metabolism, and insulin signaling. The wide range of MALAT1 functions makes it an interesting target in studies searching for drugs to prevent obesity development in humans. In turn, in farm animals, it can be a source of selection markers to control the fat tissue content.

Chromatin remodeler CHD8 is required for spermatogonial proliferation and early meiotic progression.

Meiosis is a key step during germ cell differentiation, accompanied by the activation of thousands of genes through germline-specific chromatin reorganization. The chromatin remodeling mechanisms underpinning early meiotic stages remain poorly understood. Here we focus on the function of one of the major autism genes, CHD8, in spermatogenesis, based on the epidemiological association between autism and low fertility rates. Specific ablation of Chd8 in germ cells results in gradual depletion of undifferentiated spermatogonia and the failure of meiotic double-strand break (DSB) formation, leading to meiotic prophase I arrest and cell death. Transcriptional analyses demonstrate that CHD8 is required for extensive activation of spermatogenic genes in spermatogonia, necessary for spermatogonial proliferation and meiosis. CHD8 directly binds and regulates genes crucial for meiosis, including H3K4me3 histone methyltransferase genes, meiotic cohesin genes, HORMA domain-containing genes, synaptonemal complex genes, and DNA damage response genes. We infer that CHD8 contributes to meiotic DSB formation and subsequent meiotic progression through combined regulation of these meiosis-related genes. Our study uncovers an essential role of CHD8 in the proliferation of undifferentiated spermatogonia and the successful progression of meiotic prophase I.

Abstract P1133: Bmal1 Drives Postnatal Cardiac Hypertrophy Via Circadian Chromatin Remodeling Of The Pro-hypertrophic Gene Sik1

Background: Neonatal cardiomyocyte physiological hypertrophy is temporally encoded, yet the chromatin remodeling mechanisms driving this behavior are unclear. In other tissues, genes regulated by the master circadian rhythm factor BMAL1 display circadian oscillations in histone acetylation and nucleosome and RNAPII occupancy. Hypothesis: BMAL1 regulates temporal chromatin remodeling and expression of genes critical to neonatal cardiac hypertrophy. Methods: RNAPII and BMAL1 ChIP-seq and ATAC-seq data were analyzed to identify genes at which BMAL1 may drive chromatin remodeling. Bmal1 was knocked down in neonatal rat ventricular myocytes via siRNA and hypertrophy was assessed by measuring cell size and L-azidohomoalanine incorporation into total protein, and Nppa/Nppb RT-qPCR. Bmal1 target gene promoter accessibility was assessed via MNase-qPCR and levels of chromatin-associated nucleosome core histones H2A, H2B, H3 and H4 were measured by immunoblotting of acid soluble chromatin fractions. Results: RNAPII occupancy at Bmal1 target genes was increased in adult as compared to E12.5 hearts. BMAL1 ChIP-seq and ATAC-seq revealed cardiac-specific BMAL1 co-localization (other tissues served as controls) with accessibility at the pro-hypertrophic gene salt-inducible kinase 1 (Sik1). BMAL1 knockdown impaired serum-stimulated hypertrophy, indicated by 30% decrease in cell size, 50% decrease in L-azidohomoalanine incorporation into total protein, and 80% decrease in Nppa/Nppb mRNA. BMAL1 knockdown decreased mRNA and promoter accessibility of BMAL1 targets Per2 and Sik1 and decreased chromatin-associated histones by 50%. Finally, Sik1 knockdown decreased myocyte size and Nppb mRNA. Conclusion: These findings indicate that BMAL1 controls Sik1 expression—and possibly that of other growth inducing genes—in part by modulating nucleosome assembly at specific loci, thereby regulating neonatal myocyte physiological hypertrophy.

Recent insights into the SWI/SNF complex and the molecular mechanism of hSNF5 deficiency in rhabdoid tumors.

Genetic information encoded by DNA is packaged in the nucleus using the chromatin structure. The accessibility of transcriptional elements in DNA is controlled by the dynamic structural changes of chromatin for the appropriate regulation of gene transcription. Chromatin structure is regulated by two general mechanisms, one is histone modification and the other is chromatin remodeling in an ATP-dependent manner. Switch/sucrose nonfermentable (SWI/SNF) complexes utilize the energy from ATP hydrolysis to mobilize nucleosomes and remodel the chromatin structure, contributing to conformational changes in chromatin. Recently, the inactivation of encoding genes for subunits of the SWI/SNF complexes has been documented in a series of human cancers, accounting for up to almost 20% of all human cancers. For example, human SNF5 (hSNF5), the gene that encodes a subunit of the SWI/SNF complexes, is the sole mutation target that drives malignant rhabdoid tumors (MRT). Despite remarkably simple genomes, the MRT has highly malignant characteristics. As a key to understanding MRT tumorigenesis, it is necessary to fully examine the mechanism of chromatin remodeling by the SWI/SNF complexes. Herein, we review the current understanding of chromatin remodeling by focusing on SWI/SNF complexes. In addition, we describe the molecular mechanisms and influences of hSNF5 deficiency in rhabdoid tumors and the prospects for developing new therapeutic targets to overcome the epigenetic drive of cancer that is caused by abnormal chromatin remodeling.

Epigenetic modification in Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disorder caused by genetic, epigenetic, and environmental factors. Recent advance in genomics and epigenetics have revealed epigenetic mechanisms in PD. These epigenetic modifications include DNA methylation, post-translational histone modifications, chromatin remodeling, and RNA-based mechanisms, which regulate cellular functions in almost all cells. Epigenetic alterations are involved in multiple aspects of neuronal development and neurodegeneration in PD. In this review, we discuss current understanding of the epigenetic mechanisms that regulate gene expression and neural degeneration and then highlight emerging epigenetic targets and diagnostic and therapeutic biomarkers for treating or preventing PD.

LncRNA H19 Regulates Intestinal Serotonin Transporter (SERT) Expression

Background: Serotonin transporter (SLC6A4; SERT) plays a key role in regulating the availability of 5-HT (5-hydroxytryptamine, a neurotransmitter and hormone) in the brain and the gut mucosa. A decrease in intestinal SERT expression, associated with increased availability of 5-HT, is implicated in the pathogenesis of infectious and inflammatory disorders of the gut. Therefore, it is critical to understand the regulation of SERT, as a novel target for the treatment of gastrointestinal disorders. In this regard, long noncoding RNAs (LncRNAs, small transcripts >200 nucleotides) are known to modulate gene expression via chromatin remodeling, transcriptional and posttranscriptional mechanisms. Notably, elevated levels of LncRNA H19 are observed in IBD patients and mouse models of inflammation and are known to promote mucosal regeneration and wound healing and restore the intestinal homeostasis. Whether LncRNA H19 regulates SERT expression remains unknown and was the focus of the current study. Methods: Caco-2 cells were transiently transfected with either H19 mammalian expression vector or H19 siRNA using Lipofectamine 2000. Protein and mRNA expression was measured by immunoblotting and real-time PCR, respectively. Age-matched H19 lncRNA- deficient mice and wild-type (WT) littermates were used to determine the role of genetic deletion of H19 on SERT expression in ileum. Results: H19 overexpression in Caco-2 cells increased SERT mRNA levels (~13-fold; p<0.05) at 48h post-transfection compared to an empty vector. Consistent with the mRNA levels, H19 also increased SERT protein expression (~2-fold, p<0.05). Furthermore, siRNA-mediated knockdown of H19 in Caco-2 cells resulted in a significant decrease in SERT mRNA levels (~80%, p<0.05). Parallel to the in vitro results, H19 deficient mice also showed a significant decrease in SERT mRNA expression (~69 %, p<0.05) in the ileum compared to the WT mice. Interestingly, in comparison to WT, the expression of other key transporters involved in intestinal NaCl absorption (SLC9A3, SLC26A3, and SLC26A6) remained unaltered in H19 deficient mice. Conclusion: These data demonstrate a novel role of LncRNA H19 in regulating the expression of SERT in the intestine under physiological conditions. We speculate that H19 mediated increase in SERT expression may provide valuable insights into the mechanisms restoring decreased SERT expression in inflammatory or infectious diseases of the gut. (Supported by VA/NIH). VA and NIH This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Hyperglycemia-Suppressed SMARCA5 Disrupts Transcriptional Homeostasis to Facilitate Endothelial Dysfunction in Diabetes.

Dysfunction of vascular endothelial cells (ECs) plays a central role in the pathogenesis of cardiovascular complications in diabetes. SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 5 (SMARCA5) is a key regulator of chromatin structure and DNA repair, but its role in ECs remains surprisingly unexplored. The current study was designed to elucidate the regulated expression and function of SMARCA5 in diabetic ECs. SMARCA5 expression was evaluated in ECs from diabetic mouse and human circulating CD34+ cells using quantitative reverse transcription polymerase chain reaction and Western blot. Effects of SMARCA5 manipulation on ECs function were evaluated using cell migration, in vitro tube formation and in vivo wound healing assays. Interaction among oxidative stress, SMARCA5 and transcriptional reprogramming was elucidated using luciferase reporter assay, electrophoretic mobility shift assay and chromatin immunoprecipitation. Endothelial SMARCA5 expression was significantly decreased in diabetic rodents and humans. Hyperglycemia-suppressed SMARCA5 impaired EC migration and tube formation in vitro, and blunted vasculogenesis in vivo. Contrarily, overexpression of SMARCA5 in situ by a SMARCA5 adenovirus-incorporated hydrogel effectively promoted the rate of wound healing in a dorsal skin punch injury model of diabetic mice. Mechanistically, hyperglycemia-elicited oxidative stress suppressed SMARCA5 transactivation in a signal transducer and activator of transcription 3 (STAT3)-dependent manner. Moreover, SMARCA5 maintained transcriptional homeostasis of several pro-angiogenic factors through both direct and indirect chromatin-remodeling mechanisms. In contrast, depletion of SMARCA5 disrupted transcriptional homeostasis to render ECs unresponsive to established angiogenic factors, which ultimately resulted in endothelial dysfunction in diabetes. Suppression of endothelial SMARCA5 contributes to, at least in part, multiple aspects of endothelial dysfunction, which may thereby exacerbate cardiovascular complications in diabetes.

The Current Therapeutic Role of Chromatin Remodeling for the Prognosis and Treatment of Heart Failure.

Cardiovascular diseases are a major cause of death globally, with no cure to date. Many interventions have been studied and suggested, of which epigenetics and chromatin remodeling have been the most promising. Over the last decade, major advancements have been made in the field of chromatin remodeling, particularly for the treatment of heart failure, because of innovations in bioinformatics and gene therapy. Specifically, understanding changes to the chromatin architecture have been shown to alter cardiac disease progression via variations in genomic sequencing, targeting cardiac genes, using RNA molecules, and utilizing chromatin remodeler complexes. By understanding these chromatin remodeling mechanisms in an injured heart, treatments for heart failure have been suggested through individualized pharmaceutical interventions as well as biomarkers for major disease states. By understanding the current roles of chromatin remodeling in heart failure, a potential therapeutic approach may be discovered in the future.

Phase Separation: Direct and Indirect Driving Force for High-Order Chromatin Organization.

The multi-level spatial chromatin organization in the nucleus is closely related to chromatin activity. The mechanism of chromatin organization and remodeling attract much attention. Phase separation describes the biomolecular condensation which is the basis for membraneless compartments in cells. Recent research shows that phase separation is a key aspect to drive high-order chromatin structure and remodeling. In addition, chromatin functional compartmentalization in the nucleus which is formed by phase separation also plays an important role in overall chromatin structure. In this review, we summarized the latest work about the role of phase separation in spatial chromatin organization, focusing on direct and indirect effects of phase separation on 3D chromatin organization and its impact on transcription regulation.

Epstein-Barr Virus Synergizes with BRD7 to Conquer c-Myc-Mediated Viral Latency Maintenance via Chromatin Remodeling.

Epstein-Barr virus (EBV) switches between latent and lytic phases in hosts, which is important in the development of related diseases. However, the underlying mechanism of controlling the viral biphasic life cycle and how EBV mediates this regulation remain largely unknown. This study identified bromodomain-containing protein 7 (BRD7) as a crucial host protein in EBV latent infection. Based on the chromatin immunoprecipitation (ChIP) sequencing of endogenous BRD7 in Burkitt lymphoma cells, we found that EBV drove BRD7 to regulate cellular and viral genomic loci, including the transcriptional activation of c-Myc, a recently reported regulator of EBV latency. Additionally, EBV-mediated BRD7 signals were enriched around the FUSE (far-upstream sequence element) site in chromosome 8 and the enhancer LOC108348026 in the lgH locus, which might activate the c-Myc alleles. Mechanically, EBV-encoded nuclear antigen 1 (EBNA1) bound to BRD7 and colocalized at promoter regions of the related genes, thus serving as cofactors for the maintenance of viral latency. Moreover, the disruption of BRD7 decreased the c-Myc expression, induced the BZLF1 expression, and reactivated the lytic cycle. Our findings reveal the unique role of BRD7 to synergize with EBV in maintaining the viral latency state via chromatin remodeling. This study paves the way for understanding the new molecular mechanism of EBV-induced chromatin remodeling and latent-lytic switch, providing novel therapeutic candidate targets for EBV persistent infection. IMPORTANCE When establishing persistent infection in most human hosts, EBV is usually latent. How the viral latency is maintained in cells remains largely unknown. c-Myc was recently reported to act as a controller of the lytic switch, while whether and how EBV regulates it remain to be explored. Here, we identified that BRD7 is involved in controlling EBV latency. We found that EBV-mediated BRD7 was enriched in both the normal promoter regions and the translocation alleles of c-Myc, and disruption of BRD7 decreased c-Myc expression to reactivate the lytic cycle. We also demonstrated that EBV-encoded EBNA1 bound to and regulated BRD7. Therefore, we reveal a novel mechanism by which EBV can regulate its infection state by coordinating with host BRD7 to target c-Myc. Our findings will help future therapeutic intervention strategies for EBV infection and pathogenesis.

Epigenetic modifications and metabolic memory in diabetic retinopathy: beyond the surface.

Epigenetics focuses on DNA methylation, histone modification, chromatin remodeling, noncoding RNAs, and other gene regulation mechanisms beyond the DNA sequence. In the past decade, epigenetic modifications have drawn more attention as they participate in the development and progression of diabetic retinopathy despite tight control of glucose levels. The underlying mechanisms of epigenetic modifications in diabetic retinopathy still urgently need to be elucidated. The diabetic condition facilitates epigenetic changes and influences target gene expression. In this review, we summarize the involvement of epigenetic modifications and metabolic memory in the development and progression of diabetic retinopathy and propose novel insights into the treatment of diabetic retinopathy.

Targeting Chromatin-Remodeling Factors in Cancer Cells: Promising Molecules in Cancer Therapy.

ATP-dependent chromatin-remodeling complexes can reorganize and remodel chromatin and thereby act as important regulator in various cellular processes. Based on considerable studies over the past two decades, it has been confirmed that the abnormal function of chromatin remodeling plays a pivotal role in genome reprogramming for oncogenesis in cancer development and/or resistance to cancer therapy. Recently, exciting progress has been made in the identification of genetic alteration in the genes encoding the chromatin-remodeling complexes associated with tumorigenesis, as well as in our understanding of chromatin-remodeling mechanisms in cancer biology. Here, we present preclinical evidence explaining the signaling mechanisms involving the chromatin-remodeling misregulation-induced cancer cellular processes, including DNA damage signaling, metastasis, angiogenesis, immune signaling, etc. However, even though the cumulative evidence in this field provides promising emerging molecules for therapeutic explorations in cancer, more research is needed to assess the clinical roles of these genetic cancer targets.

A pan-cancer bioinformatic analysis of the carcinogenic role of SMARCA1 in human carcinomas

SMARCA1is a mammalian imitation switch (ISWI) gene that encodes for SNF2L. SNF2L is involved in regulating cell transition from a committed progenitor state to a differentiated state. Although many papers have detailed the correlation between SMARCA1 and different cancers, no pan-cancer analysis has been conducted to date. We started by exploring the potential carcinogenic role of SMARCA1 across 33 carcinomas using the cancer genome atlas (TCGA) and the genotype-tissue expression (GTEx) databases. The expression of SMARCA1 was significantly elevated in some tumor types but not in others. There was a distinct relationship between SMARCA1 expression and patient prognosis. S116 phosphorylation levels were up-regulated in both lung adenocarcinoma and uterine corpus endometrial carcinoma. The expression level of SMARCA1 was positively correlated with cancer-associated fibroblasts infiltration in a number of tumors, such as colon adenocarcinoma, cervical squamous cell carcinoma and endocervical adenocarcinoma. It was also associated with CD8+ T-cell infiltration in head and neck squamous cell carcinoma and lung adenocarcinoma. Furthermore, SMARCA1 is involved in chromatin remodeling and protein processing-associated mechanisms. Our study presents an initial assessment and illustration of the carcinogenic role of SMARCA1 in different carcinomas.

Epigenetic modulation of visceral nociception.

Epigenetics is a process that alters gene activity or phenotype without any changes in the underlying DNA sequence or genotype. These biological changes may have deleterious effects and can lead to various human diseases. Ongoing research is continuing to illuminate the role of epigenetics in a variety of pathophysiologic processes. Several categories of epigenetic mechanisms have been studied including chromatin remodeling, DNA methylation, histone modification, and non-coding RNA mechanisms. These epigenetic changes can have a long-term effect on gene expression without any underlying changes in the DNA sequences. The underlying pathophysiology of disorders of brain-gut interaction and stress-induced visceral pain are not fully understood and the role of epigenetic mechanisms in these disorders are starting to be better understood. Current work is underway to determine how epigenetics plays a role in the neurobiology of patients with chronic visceral pain and heightened visceral nociception. More recently, both animal models and human studies have shown how epigenetic regulation modulates stress-induced visceral pain. While much more work is needed to fully delineate the mechanistic role of epigenetics in the neurobiology of chronic visceral nociception, the current study by Louwies et al., in Neurogastroenterology and Motility provides additional evidence supporting the involvement of epigenetic alterations in the central nucleus of the amygdala in stress-induced visceral hypersensitivity in rodents.

Modeling chromatin state from sequence across angiosperms using recurrent convolutional neural networks.

Accessible chromatin regions are critical components of gene regulation but modeling them directly from sequence remains challenging, especially within plants, whose mechanisms of chromatin remodeling are less understood than in animals. We trained an existing deep-learning architecture, DanQ, on data from 12 angiosperm species to predict the chromatin accessibility in leaf of sequence windows within and across species. We also trained DanQ on DNA methylation data from 10 angiosperms because unmethylated regions have been shown to overlap significantly with ACRs in some plants. The across-species models have comparable or even superior performance to a model trained within species, suggesting strong conservation of chromatin mechanisms across angiosperms. Testing a maize (Zea mays L.) held-out model on a multi-tissue chromatin accessibility panel revealed our models are best at predicting constitutively accessible chromatin regions, with diminishing performance as cell-type specificity increases. Using a combination of interpretation methods, we ranked JASPAR motifs by their importance to each model and saw that the TCP and AP2/ERF transcription factor (TF) families consistently ranked highly. We embedded the top three JASPAR motifs for each model at all possible positions on both strands in our sequence window and observed position- and strand-specific patterns in their importance to the model. With our publicly available across-species 'a2z' model it is now feasible to predict the chromatin accessibility and methylation landscape of any angiosperm genome.

Characterization of Chromatin Remodeling Genes Involved in Thermal Tolerance of Biologically Invasive Bemisia tabaci.

As an invasive species, Bemisia tabaci Mediterranean (MED) has notable potential to adapt to a wide range of environmental temperatures, which enables it to successfully spread after invasion and occupy habitats over a wide latitude range. It has been postulated that chromatin remodeling mechanisms are related to the rapid acquisition of adaptive traits and thermal resistance in invasive species; however, relevant experimental evidence is scarce. To identify the molecular characteristics and assess the role of chromatin remodelers in thermal stress within invasive MED and native Asia II 1 of the B. tabaci species complex, we identified 13 switching defective/sucrose non-fermenting (SWI/SNF) and 10 imitation switch (ISWI) family members in the B. tabaci genome, analyzed their molecular characteristics and structures, and identified key mutation sites between MED and Asia II 1, then cloned the catalytic subunits, and revealed the difference in thermal tolerance function. The results showed that the expression levels of Bt-BRM-1 and Bt-BRM-2 were significantly higher in MED than in Asia II 1 during heat stress, and Bt-BRM-2 expression was significantly higher during cold stress. In addition, RNA interference results indicated that the two target genes had similar temperature tolerance function in the both two cryptic species. This study is the first to identify and analyze the molecular characteristics of SWI/SNF and ISWI family members and reveal their potential key roles in temperature tolerance in poikilothermic ectotherms. The results will assist in understanding the underlying temperature adaptation mechanism of invasive insects and will enrich stress adaptation research systems from an epigenetic perspective.

Dynamic nucleosome organization after fertilization reveals regulatory factors for mouse zygotic genome activation

Chromatin remodeling is essential for epigenome reprogramming after fertilization. However, the underlying mechanisms of chromatin remodeling remain to be explored. Here, we investigated the dynamic changes in nucleosome occupancy and positioning in pronucleus-stage zygotes using ultra low-input MNase-seq. We observed distinct features of inheritance and reconstruction of nucleosome positioning in both paternal and maternal genomes. Genome-wide de novo nucleosome occupancy in the paternal genome was observed as early as 1 h after the injection of sperm into ooplasm. The nucleosome positioning pattern was continually rebuilt to form nucleosome-depleted regions (NDRs) at promoters and transcription factor (TF) binding sites with differential dynamics in paternal and maternal genomes. NDRs formed more quickly on the promoters of genes involved in zygotic genome activation (ZGA), and this formation is closely linked to histone acetylation, but not transcription elongation or DNA replication. Importantly, we found that NDR establishment on the binding motifs of specific TFs might be associated with their potential pioneer functions in ZGA. Further investigations suggested that the predicted factors MLX and RFX1 played important roles in regulating minor and major ZGA, respectively. Our data not only elucidate the nucleosome positioning dynamics in both male and female pronuclei following fertilization, but also provide an efficient method for identifying key transcription regulators during development.

Structural and molecular determinants of mineralocorticoid receptor signalling

During the past decades, the mineralocorticoid receptor (MR) has evolved from a much-overlooked member of the steroid hormone receptor family to an important player, not only in volume and electrolyte homeostasis but also in pathological changes occurring in an increasing number of tissues, especially the renal and cardiovascular systems. Simultaneously, a wealth of information about the structure, interaction partners and chromatin requirements for genomic signalling of steroid hormone receptors became available. However, much of the information for the MR has been deduced from studies of other family members and there is still a lack of knowledge about MR-specific features in ligand binding, chromatin remodelling, co-factor interactions and general MR specificity-conferring mechanisms that can completely explain the differences in pathophysiological function between MR and its closest relative, the glucocorticoid receptor. This review aims to give an overview of the current knowledge of MR structure, signalling and co-factors modulating its activity. LINKED ARTICLES: This article is part of a themed issue on Emerging Fields for Therapeutic Targeting of the Aldosterone-Mineralocorticoid Receptor Signaling Pathway. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.13/issuetoc.

Deciphering genes associated with diffuse large B-cell lymphoma with lymphomatous effusions: A mutational accumulation scoring approach

IntroductionEarlier studies have shown that lymphomatous effusions in patients with diffuse large B-cell lymphoma (DLBCL) are associated with a very poor prognosis, even worse than for non-effusion-associated patients with stage IV disease. We hypothesized that certain genetic abnormalities were associated with lymphomatous effusions, which would help to identify related pathways, oncogenic mechanisms, and therapeutic targets.MethodsWe compared whole-exome sequencing on DLBCL samples involving solid organs (n = 22) and involving effusions (n = 9). We designed a mutational accumulation-based approach to score each gene and used mutation interpreters to identify candidate pathogenic genes associated with lymphomatous effusions. Moreover, we performed gene-set enrichment analysis from a microarray comparison of effusion-associated versus non-effusion-associated DLBCL cases to extract the related pathways.ResultsWe found that genes involved in identified pathways or with high accumulation scores in the effusion-based DLBCL cases were associated with migration/invasion. We validated expression of 8 selected genes in DLBCL cell lines and clinical samples: MUC4, SLC35G6, TP53BP2, ARAP3, IL13RA1, PDIA4, HDAC1 and MDM2, and validated expression of 3 proteins (MUC4, HDAC1 and MDM2) in an independent cohort of DLBCL cases with (n = 31) and without (n = 20) lymphomatous effusions. We found that overexpression of HDAC1 and MDM2 correlated with the presence of lymphomatous effusions, and HDAC1 overexpression was associated with the poorest prognosis. ConclusionOur findings suggest that DLBCL associated with lymphomatous effusions may be associated mechanistically with TP53-MDM2 pathway and HDAC-related chromatin remodeling mechanisms.

Complexes and complexities: INO80 takes center stage

Chromatin remodeling and transcriptional reprogramming are key mechanisms through which plants respond to environmental challenges. Nucleosomal dynamics associated with the presence/absence (incorporation/eviction) of the histone variant H2A.Z is one of the key chromatin remodeling mechanisms associated with environmental response (Coleman-Derr and Zilberman, 2012). Very recently, some excellent papers (Shang et al., 2021; Willige et al., 2021; Xue et al., 2021) have addressed the role of a less-explored component of this chromatin remodeling—the INO80 complex.