Chromatin Remodelers in the 3D Nuclear Compartment

Magaña-Acosta, Mauro; Valadéz-Graham, Viviana

doi:10.3389/fgene.2020.600615

Cited by 42 publications

(23 citation statements)

References 220 publications

(321 reference statements)

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“…5 ) and mRNA levels (Lorch and Kornberg 2017 ; Rolicka et al 2020 ). Genes are expressed when they can be sufficiently exposed for the transcription machinery to trigger remodeling of the chromatin conformation, and they are less so when they are persistently buried in dense chromatin (Magana-Acosta and Valadez-Graham 2020 ). Chromatin remodeling takes place in cancer (Arildsen et al 2017 ; Lafon-Hughes et al 2008 ; Morgan and Shilatifard 2015 ).…”

Section: Discussionmentioning

confidence: 99%

“…Quantitative super-resolution microscopy assay (Dultz et al 2018 ) and algorithms for the quantification of chromatin condensation from microscopic data have been developed, but to date their applications have been limited (Sosnik et al 2017 ). Chromatin accessibility reflects changes in the local density, or compaction (Magana-Acosta and Valadez-Graham 2020 ). Dynamic changes in chromatin landscapes are associated with cell differentiation during embryogenesis and dedifferentiation in pluripotent stem cell (iPSC) in cancers.…”

Section: Differential Ras Isoform Expressionmentioning

confidence: 99%

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Ras isoform-specific expression, chromatin accessibility, and signaling

et al. 2021

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The anchorage of Ras isoforms in the membrane and their nanocluster formations have been studied extensively, including their detailed interactions, sizes, preferred membrane environments, chemistry, and geometry. However, the staggering challenge of their epigenetics and chromatin accessibility in distinct cell states and types, which we propose is a major factor determining their specific expression, still awaits unraveling. Ras isoforms are distinguished by their C-terminal hypervariable region (HVR) which acts in intracellular transport, regulation, and membrane anchorage. Here, we review some isoform-specific activities at the plasma membrane from a structural dynamic standpoint. Inspired by physics and chemistry, we recognize that understanding functional specificity requires insight into how biomolecules can organize themselves in different cellular environments. Within this framework, we suggest that isoform-specific expression may largely be controlled by the chromatin density and physical compaction, which allow (or curb) access to “chromatinized DNA.” Genes are preferentially expressed in tissues: proteins expressed in pancreatic cells may not be equally expressed in lung cells. It is the rule—not an exception, and it can be at least partly understood in terms of chromatin organization and accessibility state. Genes are expressed when they can be sufficiently exposed to the transcription machinery, and they are less so when they are persistently buried in dense chromatin. Notably, chromatin accessibility can similarly determine expression of drug resistance genes.

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Section: Discussionmentioning

confidence: 99%

Section: Differential Ras Isoform Expressionmentioning

confidence: 99%

Ras isoform-specific expression, chromatin accessibility, and signaling

et al. 2021

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“…The second group is modifications in the histone tail, essentially caused by methylation, acetylation, or phosphorylation of certain lysines located in the N-terminal region of histones 3′, altering the nucleosome charge, affecting the chromatin state, and thus allowing or preventing the recruitment of transcriptional co-activators to it [ 43 ]. These modifications are carried out by chromatin remodeling complexes that add open or close marks to the genome, making it accessible to the transcriptional machinery [ 44 ]. Unlike the hyper-methylation of the CpG islands, in many types of cancer, hypo-methylation of the genome is observed, leading to ectopic activation of specific oncogenes, whose expression is inhibited in homeostatic conditions.…”

Section: Genetic and Epigenetic Contributions Of Lncrna Dysregulation...mentioning

confidence: 99%

Molecular Mechanisms of lncRNAs in the Dependent Regulation of Cancer and Their Potential Therapeutic Use

García-Padilla

Dueñas

García‐López

et al. 2022

IJMS

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Deep whole genome and transcriptome sequencing have highlighted the importance of an emerging class of non-coding RNA longer than 200 nucleotides (i.e., long non-coding RNAs (lncRNAs)) that are involved in multiple cellular processes such as cell differentiation, embryonic development, and tissue homeostasis. Cancer is a prime example derived from a loss of homeostasis, primarily caused by genetic alterations both in the genomic and epigenetic landscape, which results in deregulation of the gene networks. Deregulation of the expression of many lncRNAs in samples, tissues or patients has been pointed out as a molecular regulator in carcinogenesis, with them acting as oncogenes or tumor suppressor genes. Herein, we summarize the distinct molecular regulatory mechanisms described in literature in which lncRNAs modulate carcinogenesis, emphasizing epigenetic and genetic alterations in particular. Furthermore, we also reviewed the current strategies used to block lncRNA oncogenic functions and their usefulness as potential therapeutic targets in several carcinomas.

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“…The process is regulated by histone acetyltransferases (HATs/KATs) and histone deacetylases (HDACs). Tissue specificity is mediated via hub transcription sites that regulate the accessibility of core transcription factors, e. g., for RUNX2 (runt-related transcription factor 2) as a specific transcription factor for skeletal precursors and their osteogenic differentiation capacity (this figure comprises data obtained from [18,34,49,50]). ▶Abb.…”

Section: Three-dimensional Chromatin Organizationmentioning

confidence: 99%

Epigenetics and Noncoding RNA – Principles and Clinical Impact

et al. 2021

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Genetics studies the inheritance of genetic information encoded by the base pair sequence and its variants. Sequence variants can have severe consequences as seen in genetically inherited diseases (e. g. osteogenesis Imperfecta, hypophosphatasia). On the other hand, epigenetics deals with inherited and dynamically reversible modifications of chromatin without changing the base pair sequence, resulting in a change in phenotype without a change in genotype. These modifications primarily exert their effects by influencing gene expression. Initially, the definition of epigenetics exclusively comprised inherited changes that persist across several generations without changes in the DNA sequence. This definition has been extended to include also dynamic and partially reversible changes that occur more short-term. These gene modulatory effects introduce new levels of complexity and are crucial determinants of cell fate and organismal development. With its length of approximately two meters, human DNA has to be compacted to fit into the nuclei and fulfill its functions. DNA is wrapped around histone octamers into so-called nucleosomes. DNA, histones, and other DNA-associated proteins together form what is called chromatin. DNA packaging is achieved by variable degrees of chromatin condensation depending on cell type and context. Epigenetic transcriptional regulation modifies the affinity and accessibility of cis-regulatory elements (CREs) for transcription factors and the basic transcriptional machinery and governs interaction between CREs. CREs include promoters, enhancers, silencers, and insulators and are potent modulators of gene expression impacting core cell biological processes such as proliferation and differentiation. Chromatin looping and remodeling by differential covalent modifications of DNA (e. g., methylation or hydroxylation) and histone tails (e. g., acetylation or methylation) elicit fundamental changes in CRE accessibility, thus impacting gene expression. Chromatin looping depends on a specialized machinery including cohesins. Chromatin modifications are mediated by specific enzymes like DNA methylases (DNMTs), histone-modifying enzymes, like histone methyl- and acetyltransferases (KMTs, HATs/KATs), and histone demethylases and deacetylases (KDMs, HDACs). It becomes increasingly evident that epigenetic (dys)regulation plays a decisive role in physiology and pathophysiology, impacting many age-related diseases like cancer and degenerative pathologies (e. g., osteoporosis, Alzheimer’s, or Parkinson’s) in a significant fashion. Recently, small-molecule inhibitors of chromatin-modifying enzymes (e. g., vorinostat) have been identified and successfully introduced in therapy. Significant progress in high-throughput sequencing technologies and big data analysis has broadened our understanding of noncoding (nc) RNAs and DNA sequence regions in (post-)transcriptional regulation and disease development. Among ncRNAs that play vital roles in gene expression are micro- (miRs) and long noncoding RNAs (lncRNAs; e. g., XIST or HOTAIR). By interacting with the coding genome, these RNAs modulate important genetic programs. Interfering RNAs can, for example, enhance the post-transcriptional degradation of transcripts, altering their translation, or assist in the recruitment of chromatin-modifying enzymes to regulate transcription. They can also be packaged into extracellular vesicles as cargo and thus deliver critical information to the microenvironment or even systemically to distant tissues. Therefore, ncRNAs represent a novel playground for therapeutical investigations and supplement epigenetic mechanisms of gene regulation while being subject to epigenetic regulation themselves. Last but not least, dysregulated ncRNAs can also propagate disease. Until recently, the detection of epigenetic phenomena necessitated invasive diagnostic interventions. However, with the arrival of so-called “liquid biopsies” an analysis of circulating cell-free DNA fragments (cfDNA) and RNAs as well as vesicle-packed RNAs through minimal invasively drawn blood samples can be obtained. Such “fragmentomics” and RNAomics approaches on peripheral blood will ultimately serve as diagnostic tools for personalized clinical interventions.

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Chromatin Remodelers in the 3D Nuclear Compartment

Cited by 42 publications

References 220 publications

Ras isoform-specific expression, chromatin accessibility, and signaling

Ras isoform-specific expression, chromatin accessibility, and signaling

Molecular Mechanisms of lncRNAs in the Dependent Regulation of Cancer and Their Potential Therapeutic Use

Epigenetics and Noncoding RNA – Principles and Clinical Impact

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