The ability of cells to respond to external stimuli is one of the characteristics of life as we know it. Multicellular organisms have developed a huge machinery that interprets the cellular environment and instigates an appropriate cellular response by changing gene expression, metabolism, proliferation state and motility. Decades of research have studied the pathways transmitting the various signals within the cell. However, whilst we know most of the players, we know surprisingly little about the mechanistic details of how extrinsic signals are interpreted and integrated within the genome. In this article we revisit the long-standing debate of whether factors regulating cellular growth (cytokines) act in an instructive or permissive fashion on cell fate decisions. We touch upon this topic by highlighting the paradigm of AP-1 as one of the most important signaling-responsive transcription factor family and summarize our work and that of others to explain what is known about cytokine responsive cis-regulatory elements driving differential gene expression. We propose that cytokines and, by extension, multiple types of external signals are the main drivers of cell differentiation and act via inducible transcription factors that transmit signaling processes to the genome and are essential for changing gene expression to drive transitions between gene regulatory networks. Importantly, inducible transcription factors cooperate with cell type specific factors within a pre-existing chromatin landscape and integrate multiple signaling pathways at specific enhancer elements, to both maintain and alter cellular identities. We also propose that signaling processes and signaling responsive transcription factors are at the heart of tumor development.
The covalent modification of specific DNA nucleotides by addition of a methyl group, termed DNA methylation, was observed in bacteria in 1925 and in mammals in 1948. Yet, the function of this modification was uncertain for many years, particularly its roles in mammalian cells. During the past five decades, work from Howard Cedar and his lab has provided fundamental and groundbreaking insight into the role DNA methylation plays in regulating gene expression in health and disease. Using simple yet elegant experiments, Cedar and his team provided unequivocal evidence for the direct role of DNA methylation in transcription regulation, and demonstrated that DNA methylation serves as a stable heritable epigenetic mark. Building on these foundational discoveries, Howard Cedar and his team have further illuminated the critical role of DNA methylation in organismal development and cellular function, as well as the contribution of altered DNA methylation to cancer. Further, Cedar and his lab also demonstrated that the developmentally regulated removal of DNA methylation is pre-programmed in the genome via sequence motifs that recruit trans-acting factors at specific developmental phases. Howard Cedar's pioneering scientific contributions have resulted in paradigm shifts in the study of transcription as well as DNA replication and set up the groundwork for fields of research that continue to thrive and expand into areas such as diagnostics, modeling of aging and targeted treatments.
Aging is associated with a decline in visual function and increased prevalence of ocular disease, correlating with changes in the transcriptome and epigenome of cells in the eye. Here, we sought to identify the transcriptional mechanisms that are necessary to maintain photoreceptor viability and function during aging. To do this, we performed a targeted photoreceptor-specific RNAi screen in Drosophila to identify transcriptional regulators whose knockdown results in premature, age-dependent retinal degeneration. From an initial set of 155 RNAi lines each targeting a unique gene and spanning a diverse set of transcription factors, chromatin remodelers, and histone modifiers, we identified 18 high-confidence target genes whose decreased expression in adult photoreceptors leads to premature and progressive retinal degeneration. These 18 target genes were enriched for factors involved in the regulation of transcription initiation, pausing, and elongation, suggesting that these processes are essential for maintaining the health of aging photoreceptors. To identify the genes regulated by these factors, we profiled the photoreceptor transcriptome in a subset of lines. Strikingly, two of the 18 target genes, Spt5 and domino, show similar changes in gene expression to those observed in photoreceptors with advanced age. Together, our data suggest that dysregulation of factors involved in transcription initiation and elongation plays a key role in shaping the transcriptome of aging photoreceptors. Further, our findings indicate that the age-dependent changes in gene expression not only correlate but might also contribute to an increased risk of retinal degeneration.
The crosstalk between metabolism and epigenetics is an emerging field that is gaining importance in different areas such as cancer and aging, where changes in metabolism significantly impacts the cellular epigenome, in turn dictating changes in chromatin as an adaptive mechanism to bring back metabolic homeostasis. A key metabolic pathway influencing an organism's epigenetic state is one-carbon metabolism (OCM), which includes the folate and methionine cycles. Together, these cycles generate S-adenosylmethionine (SAM), the universal methyl donor essential for DNA and histone methylation. SAM serves as the sole methyl group donor for DNA and histone methyltransferases, making it a crucial metabolite for chromatin modifications. In this review, we will discuss how SAM and its byproduct, S-adenosylhomocysteine (SAH), along with the enzymes and cofactors involved in OCM, may function in the different cellular compartments, particularly in the nucleus, to directly regulate the epigenome in aging and cancer.
Circadian rhythms play an essential role in the regulation of intestinal absorption and barrier function. Tight junctions, including claudins, are fundamental components of the intestinal epithelial barrier. However, the regulatory mechanisms governing their diurnal expression remain poorly understood. Furthermore, the impact of circadian rhythms on intestinal permeability through claudin modulation has yet to be fully explored. Here we investigated the expression and the diurnal rhythms of claudin transcripts in the intestinal epithelium. We identified histone deacetylase 3 (HDAC3) as an epigenetic regulator that represses claudin expression and drives the diurnal rhythms via histone deacetylation. Loss of HDAC3 leads to increased intestinal permeability and dampened its diurnal rhythm. We further revealed that HDAC3 affects the basolateral localization of claudin-3. Together, our findings give insights into epigenetic modification in regulating tight junction and its diurnal rhythms, providing targets for therapeutic mediations in gastrointestinal disorders.
The attachment of mono-ubiquitin to histones as a post-translational modification plays important roles in regulating chromatin structure and function. Like other epigenetic modifications, the site of ubiquitin attachment is critically important in determining its functional outcome. Depending on the type of histone and the specific lysine residue that is modified, ubiquitination acts in diverse pathways including DNA damage repair, transcription elongation, and transcription repression. Specific reader, writer and eraser activities have evolved to distinguish nucleosomes by ubiquitination of different sites. To facilitate biochemical studies of ubiquitinated nucleosomes, we have developed an efficient strategy to chemically ligate intact ubiquitin and histone proteins at specific sites to generate near-native ubiquitin-histone conjugates. Because these chemically-ligated ubiquitin conjugates are hydrolysable, they enabled us to characterize in vitro the specificities of several histone deubiquitinases. To gain insight into the mechanisms that contribute to the specificities of these deubiquitinases, we used a free Ub sensor-based real-time assay to determine their Michaelis-Menten kinetics. Our results confirmed previously reported specificities of BAP1 and USP22, but also revealed specificities of other histone deubiquitinases that have been less well defined in the literature.
Interactions between epigenetics and metabolites play critical roles in regulating the pluripotency and differentiation of embryonic stem cells. Proper glucose metabolism and DNA methylation are essential for orchestrating accurate lineage specification and the normal functions of embryonic stem cells. However, the impact of Ten-eleven Translocation (TET)-mediated DNA methylation modifications on the metabolism of mouse embryonic stem cells (mESCs) remains less well defined. In this study, we investigated the consequences of Tet triple knockout (Tet-TKO) in mESCs and observed notable alterations in glucose metabolism. These changes were marked by enhanced glucose uptake and glycolysis, likely owing to the upregulation of genes critical for glucose metabolism. Furthermore, Tet-TKO mESCs exhibited defects in glucose-dependent differentiation, suggesting that cells with epigenetic defects might display metabolic vulnerability when exposed to external nutritional cues. Collectively, our findings establish the pivotal role of the TET family of dioxygenases in maintaining proper glucose metabolism and safeguarding stem cell lineage specification, thus enhancing our understanding of the intricate interplay between epigenetic modifications and cellular metabolism in stem cells.
The development of multicellular organisms occurs through a series of cell state transitions controlled by gene regulatory networks. Central to these networks are transcription factors (TFs) which bind enhancers and activate the expression of other genes, some of which are also TFs. Gene regulatory networks (GRN) connect TFs and enhancers in a nonlinear circuit capable of producing complex behavior such as bifurcations between stable cell states. Our dynamic network modelling of the Embryonic Stem Cell (ESC) to Definitive Endoderm (DE) transition requires an as yet unknown negative feedback mechanism for stability. Here, we show that cell state specific microRNAs (miRNAs) can provide this negative feedback by inactivating other cell lineage determining TFs (ESC or DE) during the transition. Our model provides a mechanism to maintain stable cell states without requiring a large set of cell-type-specific repressive TFs, of which there are fewer known examples than activators. In support of this model, we use computational models and analyze gene and miRNA expression and chromatin accessibility data from human cell lines to detect enhancers activating the miRNAs consistent with our network model. Our analysis highlights the interplay between TFs and miRNAs during ESC to DE transition and proposes a novel model for gene regulation.
Early-onset preeclampsia (EOPE) is a severe maternal hypertensive disorder of pregnancy, where placental dysfunction is a component of the pathophysiology. Previously, we developed the eoPRED tool, which is a DNA methylation (DNAme)-based method that estimates the likelihood that a placenta came from a pregnancy complicated by EOPE. We hypothesize that this score may reflect maternal vascular malperfusion (MVM), which is the most common placental pathology observed in early-onset preeclampsia (EOPE), but is also associated with preterm birth and fetal growth restriction. To test this we evaluated whether eoPRED score is associated with the severity of MVM pathology in placentas from both preeclamptic and non-preeclamptic pregnancies. We utilized 493 placentas with both Infinium EPICv1.0 DNA methylation data and histopathologic characterization by a placental pathologist. We evaluated associations between eoPRED score and four major classes of placental pathology: maternal vascular malperfusion (MVM), fetal vascular malperfusion (FVM), chronic inflammation (CI), and acute inflammation (AI). eoPRED score was higher in placentas from pregnancies with EOPE (n = 7) than controls without preeclampsia (n = 402, p < 0.001). Independent of EOPE, eoPRED correlated with the grade of MVM (R = 0.34, p < 0.01), but was not associated with any other pathology class. eoPRED score can not only be used to identify cases of likely EOPE but is also associated with placental maternal vascular dysfunction in the absence of preeclampsia. This score may thus be useful in placental DNAme datasets lacking pathology information to identify associations between exposures/and or birth outcomes with placental dysfunction.
Transcription is one of the central dogmas of life. Most genes in eukaryotes are transcribed by RNA polymerase II (Pol II). For Pol II to transcribe along the gene body, it must overcome nucleosomes, which are barriers for Pol II. It is still a mystery how Pol II ejects nucleosomes during transcription elongation. I hypothesize that a group of chromatin remodelers (SWI/SNF, RSC, SWR1, INO80) carry a group of histone acetyltransferases (NuA4, Spt-Ada-Gcn-acetyltransferase, NuA3) to deposit acetyl-groups on histone tails to generate pan-acetylated nucleosomes or fragile nucleosomes along gene bodies for Pol II to transcribe. Specifically, for the first round of transcription, the RSC complex works with NuA4 to acetylate histone tails of H2A and H4; the SWI/SNF complex carries SAGA to add acetyl-groups to histone tails of H2B and H3. For the second and subsequent rounds, SWR1 pairs with a piccolo NuA4 to acetylate the histone tails of H2A and H4 of newly inserted nucleosomes, while INO80 pairs with NuA3 to acetylate the histone tails of H2B and H3 within newly inserted nucleosomes along the gene body. After the mission is accomplished, ISW1b couples with Rpd3s to remove acetyl groups on H2A and H4, while CHD1 carries HDA1 along the gene body to remove acetyl groups on H2B and H3.
Land use expansion is linked to major sustainability concerns including climate change, food security and biodiversity loss. This expansion is largely concentrated in so-called frontiers, defined here as places experiencing marked transformations due to rapid resource exploitation. Understanding the mechanisms shaping these frontiers is crucial for sustainability. Previous work focused mainly on explaining how active frontiers advance, in particular into tropical forests. Comparatively, our understanding of how frontiers emerge in territories considered marginal in terms of agricultural productivity and global market integration remains weak. We synthesize conceptual tools explaining resource and land-use frontiers, including theories of land rent and agglomeration economies, of frontiers as successive waves, spaces of territorialization, friction, and opportunities, anticipation and expectation. We then propose a new theory of frontier emergence, which identifies exogenous pushes, legacies of past waves, and actors anticipations as key mechanisms by which frontiers emerge. Processes of abnormal rent creation and capture and the built-up of agglomeration economies then constitute k
Single-cell transcriptomics, epigenomics, and other 'omics applied at single-cell resolution can significantly advance hypotheses and understanding of glial biology. Omics technologies are revealing a large and growing number of new glial cell subtypes, defined by their gene expression profile. These subtypes have significant implications for understanding glial cell function, cell-cell communications, and glia-specific changes between homeostasis and conditions such as neurological disease. For many, the training in how to analyze, interpret, and understand these large datasets has been through reading and understanding literature from other fields like biostatistics. Here, we provide a primer for glial biologists on experimental design and analysis of single-cell RNA-seq datasets. Our goal is to further the understanding of why decisions might be made about datasets and to enhance biologists' ability to interpret and critique their work and the work of others. We review the steps involved in single-cell analysis with a focus on decision points and particular notes for glia. The goal of this primer is to ensure that single-cell 'omics experiments continue to advance glial biology
Essential life processes take place across multiple space and time scales in living organisms but understanding their mechanistic interactions remains an ongoing challenge. Advanced multiscale modeling techniques are providing new opportunities and insights into these complex processes. In cells, meters of chromatin are folded into a nucleus with a diameter on the order of microns. The three-dimensional chromatin structure coupled with biochemical processes that turn genes on or off, specify a given cell type through a complicated set of interactions collectively referred to as epigenetics. Important epigenetic processes include the differential accessibility of genomic loci to transcription factors and chemical modifications to DNA and DNA-binding molecules such as histones. The dynamics of these epigenetic processes span timescales from milliseconds to years. How do chemical modifications consisting of a handful of atoms cooperate to modulate genome folding at the scale of the nucleus and impact organism outcomes? In this review, we highlight the inherently multiscale nature of chromatin organization, with a focus on computational modeling to bridge the gaps in our understanding
The spreading and regulation of epigenetic marks on chromosomes is crucial to establish and maintain cellular identity. Nonetheless, the dynamical mechanism leading to the establishment and maintenance of a given, cell-line specific, epigenetic pattern is still poorly understood. In this work we propose, and investigate in silico, a possible experimental strategy to illuminate the interplay between 3D chromatin structure and epigenetic dynamics. We consider a set-up where a reconstituted chromatin fibre is stretched at its two ends (e.g., by laser tweezers), while epigenetic enzymes (writers) and chromatin-binding proteins (readers) are flooded into the system. We show that, by tuning the stretching force and the binding affinity of the readers for chromatin, the fibre undergoes a sharp transition between a stretched, epigenetically disordered, state and a crumpled, epigenetically coherent, one. We further investigate the case in which a knot is tied along the chromatin fibre, and find that the knotted segment enhances local epigenetic order, giving rise to "epigenetic solitons" which travel and diffuse along chromatin. Our results point to an intriguing coupling between 3D chromat
Language models encode text as subword tokens, raw bytes, or rendered pixels, but these encodings are usually compared under modeling constraints that expose different amounts of linguistic content to models across different languages. We instead ask what each encoding preserves when both the content and the downstream capacity are controlled. Using verified parallel sentences across thirteen languages and five scripts, we compare tokens, bytes, and pixels through a shared bottleneck whose width is swept to trace rate-utility frontiers. This separates three quantities that are often conflated: the number of input positions an encoding creates, the latent capacity available after encoding, and the task-relevant information that survives compression. We evaluate three utilities: surface form preservation, cross-lingual sentence alignment, and topic classification. No encoding dominates across tasks or capacity regimes. Pixels preserve surface form best, bytes preserve cross-lingual alignment best, especially in same-script multilingual settings, and tokens support topic prediction best. These performances are not explained by sequence length alone. Short inputs can discard useful mea
Epigenetics plays a key role in cellular differentiation and maintaining cell identity, enabling cells to regulate their genetic activity without altering the DNA sequence. Epigenetic regulation occurs within the context of hierarchically folded chromatin, yet the interplay between the dynamics of epigenetic modifications and chromatin architecture remains poorly understood. In addition, it remains unclear what mechanisms drive the formation of rugged epigenetic patterns, characterised by alternating genomic regions enriched in activating and repressive marks. In this study, we focus on post-translational modifications of histone H3 tails, particularly H3K27me3, H3K4me3, and H3K27ac. We introduce a mesoscopic stochastic model that incorporates chromatin architecture and competition of histone-modifying enzymes into the dynamics of epigenetic modifications in small genomic loci comprising several nucleosomes. Our approach enables us to investigate the mechanisms by which epigenetic patterns form on larger scales of chromatin organisation, such as loops and domains. Through bifurcation analysis and stochastic simulations, we demonstrate that the model can reproduce uniform chromatin
Emerging empirical and theoretical thinking about human aging places considerable value upon the role of the environment as a major factor which can promote prolonged healthy longevity. Our contemporary, information-rich environment is taken to mean not merely the actual physical surroundings of a person but it is also considered in a more abstract sense, to denote cultural, societal and technological influences. Our modern environment is far from being static or stable. In fact, it is continually changing in an exponential manner, necessitating constant adaptive responses on behalf of our developmental and evolutionary mechanisms. In this paper, I attempt to describe how a continual, balanced and meaningful exposure to a stimulating environment, including exposure to information-that-requires-action (but NOT trivial information), has direct or indirect repercussions on epigenetic mechanisms which may then act to prolong healthy longevity. Information gained from our environment acts as a hormetic stimulus which up-regulates biological responses and feedback loops, eventually leading to improved repair of age-related damage. The consequence of this biological information-processing
Epigenetic changes -- heritable, long-lived, yet actively reversible modifications of the chromatin state -- display memory, threshold activation and hysteresis, features that are the hallmark of rate-independent dissipative evolution. We propose a mathematical framework, Rate-Independent Epigenetics, that models epigenetic change within the theory of rate-independent systems and is consistent with two fundamental principles identified with the laws of thermodynamics. In this framework, a model is specified by a state space of epigenetic configurations, a stored-energy functional depending on the state and on an external loading, and a 1-homogeneous dissipation potential encoding the resistance of the epigenetic machinery to change. Assuming an energetic evolution principle, the governing equations follow, with no further modelling hypotheses. The energy balance is exact energy conservation, and the 1-homogeneity of the dissipation potential forces a non-negative, minimal (economical) dissipation. Under natural coercivity and continuity assumptions we establish existence of energetic solutions and, via vanishing viscosity, of balanced-viscosity solutions that resolve the ambiguity
Epigenetics encompasses mechanisms that can alter the expression of genes without changing the underlying genetic sequence. The epigenetic regulation of gene expression is initiated and sustained by several mechanisms such as DNA methylation, histone modifications, chromatin conformation, and non-coding RNA. The changes in gene regulation and expression can manifest in the form of various diseases and disorders such as cancer and congenital deformities. Over the last few decades, high throughput experimental approaches have been used to identify and understand epigenetic changes, but these laboratory experimental approaches and biochemical processes are time-consuming and expensive. To overcome these challenges, machine learning and artificial intelligence (AI) approaches have been extensively used for mapping epigenetic modifications to their phenotypic manifestations. In this paper we provide a narrative review of published research on AI models trained on epigenomic data to address a variety of problems such as prediction of disease markers, gene expression, enhancer promoter interaction, and chromatin states. The purpose of this review is twofold as it is addressed to both AI e
It is obvious that both epigenetic and non-epigenetic actors contribute to tumorigenesis in chondrosarcomas and more generally in other cancers. Thus, the main altered pathways in chondrosarcomas are now well established and include both epigenetic and non-epigenetic pathways such as the PI3K-AKT signaling, EGFR overexpression, SPARC overexpression, c-myc overexpression, IHH/GLI1 axis, loss of Rb function, HIF1-alpha stabilization, IDH1 mutations, hypermethylation and SIRT1. This review aims to provide a detailed analysis of these pathways and highlights recurrent interactions between non-epigenetic and epigenetic actors in chondrosarcomas, raising the intriguing possibility of developing therapeutics targeting both epigenetic and non-epigenetic actors and supporting data from previous studies. Finally, we propose some strategies for targeting chondrosarcomas in vivo based on properties of this tumor.