Long RNA-Mediated Chromatin Regulation in Fission Yeast and Mammals

As part of a complex network of genome control, long regulatory RNAs exert significant influences on chromatin dynamics. Understanding how this occurs could illuminate new avenues for disease treatment and lead to new hypotheses that would advance gene regulatory research. Recent studies using the model fission yeast Schizosaccharomyces pombe (S. pombe) and powerful parallel sequencing technologies have provided many insights in this area. This review will give an overview of key findings in S. pombe that relate long RNAs to multiple levels of chromatin regulation: histone modifications, gene neighborhood regulation in cis and higher-order chromosomal ordering. Moreover, we discuss parallels recently found in mammals to help bridge the knowledge gap between the study systems.

Unconventional metabolites in chromatin regulation

Chromatin, the complex of DNA and histone proteins, serves as a main integrator of cellular signals. Increasing evidence links cellular functional to chromatin state. Indeed, different metabolites are emerging as modulators of chromatin function and structure. Alterations in chromatin state are decisive for regulating all aspects of genome function and ultimately have the potential to produce phenotypic changes. Several metabolites such as acetyl-CoA, S-adenosyl methionine (SAM) or adenosine triphosphate (ATP) have now been well characterized as main substrates or cofactors of chromatin modifying enzymes. However, there are other metabolites that can directly interact with chromatin influencing its state or that modulate the properties of chromatin regulatory factors. Also, there is a growing list of atypical enzymatic and non-enzymatic chromatin modifications that originate from different cellular pathways that have not been in the limelight of chromatin research. Here, we summarize different properties and functions of uncommon regulatory molecules originating from intermediate metabolism of lipids, carbohydrates and amino acids. Based on the various modes of action on chromatin and the plethora of putative, so far not described chromatin regulating metabolites, we propose that there are more links between cellular functional state and chromatin regulation to be discovered. We hypothesize that these connections could provide interesting starting points for interfering with cellular epigenetic states at a molecular level.

The Role of lncRNAs in Regulating the Intestinal Mucosal Mechanical Barrier

lncRNA is a transcript that is more than 200 bp in length. Currently, evidence has shown that lncRNA is of great significance in cell activity, involved in epigenetics, gene transcription, chromatin regulation, etc. The existence of an intestinal mucosal mechanical barrier hinders the invasion of pathogenic bacteria and toxins, maintaining the stability of the intestinal environment. Serious destruction or dysfunction of the mechanical barrier often leads to intestinal diseases. This review first summarizes the ability of lncRNAs to regulate the intestinal mucosal mechanical barrier. We then discussed how lncRNAs participate in various intestinal diseases by regulating the intestinal mucosal mechanical barrier. Finally, we envision its potential as a new marker for diagnosing and treating intestinal inflammatory diseases.

Macrophages, Metabolites, and Nucleosomes: Chromatin at the Intersection between Aging and Inflammation

Inflammation is the body’s means of defense against harmful stimuli, with the ultimate aim being to restore homeostasis. Controlled acute inflammation transiently activates an immune response and can be beneficial as protection against infection or injury. However, dysregulated inflammatory responses, including chronic inflammation, disrupt the immune system’s ability to maintain homeostatic balance, leading to increased susceptibility to infection, continuous tissue damage, and dysfunction. Aging is a risk factor for chronic inflammation; their coincidence is termed “inflammaging”. Metabolic disorders including obesity, neurodegenerative diseases, and atherosclerosis are often encountered in old age. Therefore, it is important to understand the mechanistic relationship between aging, chronic inflammation, and metabolism. It has been established that the expression of inflammatory mediators is transcriptionally and translationally regulated. In addition, the post-translational modification of the mediators plays a crucial role in the response to inflammatory signaling. Chromatin regulation responds to metabolic status and controls homeostasis. However, chromatin structure is also changed by aging. In this review, we discuss the functional contributions of chromatin regulation to inflammaging.

Live-Cell Imaging Probes to Track Chromatin Modification Dynamics

The spatiotemporal organization of chromatin is regulated at different levels in the nucleus. Epigenetic modifications such as DNA methylation and histone modifications are involved in chromatin regulation and play fundamental roles in genome function. While the one-dimensional epigenomic landscape in many cell types has been revealed by chromatin immunoprecipitation and sequencing, the dynamic changes of chromatin modifications and their relevance to chromatin organization and genome function remain elusive. Live-cell probes to visualize chromatin and its modifications have become powerful tools to monitor dynamic chromatin regulation. Bulk chromatin can be visualized both by small fluorescent dyes and fluorescent proteins, and specific endogenous genomic loci have been detected by adapting genome-editing tools. To track chromatin modifications in living cells, various types of probes have been developed. Protein domains that bind to specific modifications weakly, such as chromodomains for histone methylation, can be repeated to create a tighter binding probe that can then be tagged with a fluorescent protein. It has also been demonstrated that antigen-binding fragments and single-chain variable fragments from modification-specific antibodies can serve as binding probes without disturbing cell division, development and, differentiation. These modification-binding modules are used in modification sensors based on fluorescence/Förster resonance energy transfer to measure the intramolecular conformation changes triggered by modifications. Other probes can be created using a bivalent binding system, such as fluorescence complementation, or luciferase chemiluminescence. Live-cell chromatin modification imaging using these probes will address dynamic chromatin regulation and will be useful for assaying and screening effective epigenome drugs in cells and organisms.

Histone mimics: more tales to read

Post-translational modifications (PTMs) on histone proteins are known as epigenetic marks that demarcate the status of chromatin. These modifications are ‘read' by specific reader proteins, which in turn recruit additional factors to modulate chromatin accessibility and the activity of the underlying DNA. Accumulating evidence suggests that these modifications are not restricted solely to histones, many non-histone proteins may function in a similar way through mimicking the histones. In this commentary, we briefly discuss a systematic study of the discovery of histone H3 N-terminal mimicry proteins (H3TMs), and their implications in chromatin regulation and drug discoveries.

VAL1 as an assembly platform co-ordinating co-transcriptional repression and chromatin regulation at Arabidopsis FLC

Polycomb (PcG) silencing is crucial for development across eukaryotes, but how PcG targets are regulated is still incompletely understood. The slow timescale of cold-induced PcG silencing at Arabidopsis thaliana FLOWERING LOCUS C (FLC) makes it an excellent system to dissect this mechanism. Binding of the DNA binding protein VAL1 to an FLC intronic RY motif within the PcG nucleation region is an early step in the silencing process. VAL1 interacts with APOPTOSIS AND SPLICING ASSOCIATED PROTEIN (ASAP) complex and POLYCOMB REPRESSIVE COMPLEX 1 (PRC1). Here, we show that ASAP and PRC1 function as co-repressors that quantitatively regulate FLC transcription. Upon the shift to cold PRC1-mediated H2Aub accumulates only at the nucleation region, is transiently maintained after transfer back to warm, but unlike the PRC2-delivered H3K27me3 does not spread across the locus. H2K27me3 thus provides long-term epigenetic silencing, whereas H2Aub is a transient repression signal. Overall, our work highlights how a DNA sequence-specific binding protein can act as an assembly platform co-ordinating the co-transcriptional repression and chromatin regulation necessary for Polycomb silencing.