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Neurodevelopmental disorders (NDDs) affect about 1% of the population and can be caused by mutations in genes that affect the epigenetic code. There is limited functional understanding of most of these epigenetic modifiers, and we suggest that associated NDDs are caused, in part, by deficits in epigenetic priming, a prepatterning step that alters the genome in preparation to make cells competent to signaling cues. We provide evidence from high-resolution epigenetic and transcriptomic mapping studies to demonstrate how a failure to adequately prime the genome for neural induction could lead to impairment of terminally differentiated cells. This idea provides a framework for NDD pathogenesis and treatment.

Epigenetics involves changing the gene function without any change in the sequence of the genes. In the case of tuberculosis (TB) infections, the bacilli, Mycobacterium tuberculosis (M.tb), uses epigenetics as a tool to protect itself from the host immune system. TB is a deadly disease-causing maximum death per year due to a single infectious agent. In the case of TB, there is an urgent need for novel host-directed therapies which can effectively target the survival and long-term persistence of the bacteria without developing drug resistance in the bacterial strains while also reducing the duration and toxicity associated with the mainstream anti-TB drugs. Recent studies have suggested that TB infection has a significant effect on the host epigenome thereby manipulating the host immune response in the favor of the pathogen. M.tb alters the activation status of key genes involved in the immune response against TB to promote its survival and subvert the antibacterial strategies of the host. These changes are reversible and can be exploited to design very efficient host-directed therapies to fight against TB. This review has been written with the purpose of discussing the role of epigenetic changes in TB pathogenesis and the therapeutic approaches involving epigenetics, which can be utilized for targeting the pathogen.

We hypothesized that the highly controlled pattern of gene expression that is essential for liver regeneration is encoded by an epigenetic code set in quiescent hepatocytes. Here we report that epigenetic and transcriptomic profiling of quiescent and regenerating mouse livers define chromatin states that dictate gene expression and transposon repression. We integrate ATACseq and DNA methylation profiling with ChIPseq for the histone marks H3K4me3, H3K27me3 and H3K9me3 and the histone variant H2AZ to identify 6 chromatin states with distinct functional characteristics. We show that genes involved in proliferation reside in active states, but are marked with H3K27me3 and silenced in quiescent livers. We find that during regeneration, H3K27me3 is depleted from their promoters, facilitating their dynamic expression. These findings demonstrate that hepatic chromatin states in quiescent livers predict gene expression and that pro-regenerative genes are maintained in active chromatin states, but are restrained by H3K27me3, permitting a rapid and synchronized response during regeneration., Few studies have provided functional analysis of the epigenetic landscape in the regenerating liver. Here the authors define chromatin states in the quiescent vs. regenerating mouse liver through integration of genome wide profiles of DNA methylation, histone modifications, and chromatin accessibility, identifying H3K27me3 as an epigenetic mark conferring regenerative potential.

We present a theoretical model that demonstrates the integral role chromosome organization and structural mechanics play in the spreading of histone modifications involved in epigenetic regulation. Our model shows that heterogeneous nucleosome positioning, and the resulting position-dependent mechanical properties, must be included to reproduce several qualitative features of experimental data of histone methylation spreading around an artificially induced “nucleation site.” We show that our model recreates both the extent of spreading and the presence of a subdominant peak upstream of the transcription start site. Our model indicates that the spreading of epigenetic modifications is sensitive to heterogeneity in chromatin organization and the resulting variability in the chromatin’s mechanical properties, suggesting that nucleosome spacing can directly control the conferral of epigenetic marks by modifying the structural mechanics of the chromosome. It further illustrates how the physical organization of the DNA polymer may play a significant role in re-establishing the epigenetic code upon cell division.

The interaction of microbiota with its host has the ability to alter the cellular functions of both, through several mechanisms. Recent work, from many laboratories including our own, has shown that epigenetic mechanisms play an important role in the alteration of these cellular functions. Epigenetics broadly refers to change in the phenotype without a corresponding change in the DNA sequence. This change is usually brought by epigenetic modifications of the DNA itself, the histone proteins associated with the DNA in the chromatin, non-coding RNA or the modifications of the transcribed RNA. These modifications, also known as epigenetic code, do not change the DNA sequence but alter the expression level of specific genes. Microorganisms seem to have learned how to modify the host epigenetic code and modulate the host transcriptome in their favour. In this review, we explore the literature that describes the epigenetic interaction of bacteria, fungi and viruses, with their mammalian hosts.

Predicting cis-regulatory modules(CRMs) in a genome and predicting their functional states in various cell/tissue types of the organism are two related challenging computational tasks. Most current methods attempt to achieve both simultaneously using epigenetic data. Though conceptually attractive, they suffer high false discovery rates and limited applications. To fill the gaps, we proposed a two-step strategy to first predict a map of CRMs in the genome, and then predict functional states of the CRMs in various cell/tissue types of the organism. We have recently developed an algorithm for accurately predicting CRMs in a genome by integrating numerous transcription factor ChIP-seq datasets. Here, we showed that only three or four epigenetic marks data in a cell/tissue type were sufficient for a machine-learning model to accurately predict functional states of all CRMs. Our predictions are substantially more accurate than the best achieved so far. Interestingly, a model trained on different cell/tissue types in a mammal can accurately predict functional states of CRMs in different cell/tissue types of the mammal as well as in various cell/tissue types of a different mammal. Therefore, epigenetic code that defines functional states of CRMs in various cell/tissue types is universal at least in mammals. Moreover, we found that from tens to hundreds of thousands of CRMs were active in a human and mouse cell/tissue type, and up to 99.98% of them were reutilized in different cell/tissue types, while as small as 0.02% of them were unique to a cell/tissue type that might define the cell/tissue type.

Bilaterian animals operate the clusters of Hox genes through a rich repertoire of diverse mechanisms. In this review, we will summarize and analyze the accumulated data concerning long non-coding RNAs (lncRNAs) that are transcribed from sense (coding) DNA strands of Hox clusters. It was shown that antisense regulatory RNAs control the work of Hox genes in cis and trans, participate in the establishment and maintenance of the epigenetic code of Hox loci, and can even serve as a source of regulatory peptides that switch cellular energetic metabolism. Moreover, these molecules can be considered as a force that consolidates the cluster into a single whole. We will discuss the examples of antisense transcription of Hox genes in well-studied systems (cell cultures, morphogenesis of vertebrates) and bear upon some interesting examples of antisense Hox RNAs in non-model Protostomia.

Ubiquitin-like with plant homeodomain and really interesting new gene finger domains 1 (UHRF1) functions as an epigenetic regulator recruiting PCNA, DNMT1, histone deacetylase 1, G9a, SuV39H, herpes virus-associated ubiquitin-specific protease, and Tat-interactive protein by multiple corresponding domains of DNA and H3 to maintain DNA methylation and histone modifications. Overexpression of UHRF1 has been found as a potential biomarker in various cancers resulting in either DNA hypermethylation or global DNA hypo-methylation, which participates in the occurrence, progression, and invasion of cancer. The role of UHRF1 in the reciprocal interaction between DNA methylation and histone modifications, the dynamic structural transformation of UHRF1 protein within epigenetic code replication machinery in epigenetic regulations, as well as modifications during cell cycle and chemotherapy targeting UHRF1 are evaluated in this study., Video abstract

Understanding how genes are expressed in the correct cell types and at the correct level is a key goal of developmental biology research. Gene regulation has traditionally been approached largely through observational methods, whereas perturbational approaches have lacked precision. CRISPR-Cas9 has begun to transform the study of gene regulation, allowing for precise manipulation of genomic sequences, epigenetic functionalization and gene expression. CRISPR-Cas9 technology has already led to the discovery of new paradigms in gene regulation and, as new CRISPR-based tools and methods continue to be developed, promises to transform our knowledge of the gene regulatory code and our ability to manipulate cell fate. Here, we discuss the current and future application of the emerging CRISPR toolbox toward predicting gene regulatory network behavior, improving stem cell disease modeling, dissecting the epigenetic code, reprogramming cell fate and treating diseases of gene dysregulation.

Conrad Waddington's theory of epigenetic landscape epitomize the process of cell fate and cellular decision-making during development. Wherein the epigenetic code maintains patterns of gene expression in pluripotent and differentiated cellular states during embryonic development and differentiation. Over the years disruption or reprogramming of the epigenetic landscape has been extensively studied in the course of cancer progression. Cellular dedifferentiation being a key hallmark of cancer allow us to take cues from the biological processes involving epigenetic reprogramming in development such as the cellular differentiation and morphogenesis. Here, we discuss the role of epigenetic landscape and its modifiers in cell-fate determination, differentiation and prostate cancer progression. Lately, the emergence of RNA-modifications has also furthered our understanding of epigenetics in cancer. The overview of the epigenetic code regulating androgen signalling, and progression to aggressive neuroendocrine stage of PCa reinforces its gene regulatory functions during the development of prostate gland as well as cancer progression. Additionally, we also highlight the clinical implications of cancer cell epigenome, and discuss the recent advancements in the therapeutic strategies targeting the advanced stage disease.

Evidence suggests that engineered nanomaterials (ENM) can induce epigenetic modifications. In this review, we provide an overview of the epigenetic modulation of gene expression induced by ENM used in a variety of applications: titanium dioxide (TiO2), silver (Ag), gold (Au), silica (SiO2) nanoparticles and carbon-based nanomaterials (CNM). Exposure to these ENM can trigger alterations in cell patterns of DNA methylation, post-transcriptional histone modifications and expression of non-coding RNA. Such effects are dependent on ENM dose and physicochemical properties including size, shape and surface chemistry, as well as on the cell/organism sensitivity. The genes affected are mostly involved in the regulation of the epigenetic machinery itself, as well as in apoptosis, cell cycle, DNA repair and inflammation related pathways, whose long-term alterations might lead to the onset or progression of certain pathologies. In addition, some DNA methylation patterns may be retained as a form of epigenetic memory. Prenatal exposure to ENM may impair the normal development of the offspring by transplacental effects and/or putative transmission of epimutations in imprinting genes. Thus, understanding the impact of ENM on the epigenome is of paramount importance and epigenetic evaluation must be considered when assessing the risk of ENM to human health. This work was supported by the NanoBioBarriers project (PTDC/MED‐TOX/31162/2017), co-financed by the Operational Program for Competitiveness and Internationalization (POCI) through European Regional Development Funds (FEDER/FNR) and through national funds by the Portuguese Foundation for Science and Technology (FCT). Thanks are also due to FCT/MCTES for the financial support to EPIUnit (info:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB/04750/2020/PT).

The mechanisms underlying gene repression and silencers are poorly understood. Here we investigate the hypothesis that H3K27me3-rich regions of the genome, defined from clusters of H3K27me3 peaks, may be used to identify silencers that can regulate gene expression via proximity or looping. We find that H3K27me3-rich regions are associated with chromatin interactions and interact preferentially with each other. H3K27me3-rich regions component removal at interaction anchors by CRISPR leads to upregulation of interacting target genes, altered H3K27me3 and H3K27ac levels at interacting regions, and altered chromatin interactions. Chromatin interactions did not change at regions with high H3K27me3, but regions with low H3K27me3 and high H3K27ac levels showed changes in chromatin interactions. Cells with H3K27me3-rich regions knockout also show changes in phenotype associated with cell identity, and altered xenograft tumor growth. Finally, we observe that H3K27me3-rich regions-associated genes and long-range chromatin interactions are susceptible to H3K27me3 depletion. Our results characterize H3K27me3-rich regions and their mechanisms of functioning via looping., Mechanisms underlying gene repression and silencers remain poorly understood. Here the authors investigate the role of H3K27me3-rich regions in the genome, as defined from clusters of H3K27me3 peaks, in regulating gene expression via looping.

International audience; Neurodegenerative diseases, including Huntington’s disease (HD) and Alzheimer's disease (AD), are progressive conditions characterized by selective, disease-dependent loss of neuronal regions and/or subpopulations. Neuronal loss is preceded by a long period of neuronal dysfunction, during which glial cells also undergo major changes, including neuroinflammatory response. Those dramatic changes affecting both neuronal and glial cells associate with epigenetic and transcriptional dysregulations, characterized by defined cell-type-specific signatures. Notably, increasing studies support the view that altered regulation of transcriptional enhancers, which are distal regulatory regions of the genome capable of modulating the activity of promoters through chromatin looping, play a critical role in transcriptional dysregulation in HD and AD. We review current knowledge on enhancers in HD and AD, and highlight challenging issues to better decipher the epigenetic code of neurodegenerative diseases.

Alcohol use disorder (AUD) is a leading cause of morbidity and mortality. Despite AUD's substantial contributions to lost economic productivity and quality of life, there are only a limited number of approved drugs for treatment of AUD in the United States. This chapter will update progress made on the epigenetic basis of AUD, with particular focus on histone post-translational modifications and DNA methylation and how these two epigenetic mechanisms interact to contribute to neuroadaptive processes leading to initiation, maintenance and progression of AUD pathophysiology. We will also evaluate epigenetic therapeutic strategies that have arisen from preclinical models of AUD and epigenetic biomarkers that have been discovered in human populations with AUD.

Adolescence is a critical developmental period characterized by ongoing brain maturation processes including myelination and synaptic pruning. Adolescents experience heightened reward sensitivity, sensation seeking, impulsivity, and diminished inhibitory self-control, which contribute to increased participation in risky behaviors, including the initiation of alcohol use. Ethanol exposure in adolescence alters memory and cognition, anxiety-like behavior, and ethanol sensitivity as well as brain myelination and dendritic spine morphology, with effects lasting into adulthood. Emerging evidence suggests that epigenetic modifications may explain these lasting effects. Focusing on the amygdala, prefrontal cortex and hippocampus, we review studies investigating the epigenetic consequences of adolescent ethanol exposure. Ethanol metabolism globally increases donor substrates for histone acetylation and histone and DNA methylation, and this chapter discusses how this can further impact epigenetic programming of the adolescent brain. Elucidation of the mechanisms through which ethanol can alter the epigenetic code at specific transcripts may provide therapeutic targets for intervention.

Background Transcription of genes residing within constitutive heterochromatin is paradoxical to the tenets of epigenetic code. The regulatory mechanisms of Drosophila melanogaster heterochromatic gene transcription remain largely unknown. Emerging evidence suggests that genome organization and transcriptional regulation are inter-linked. However, the pericentromeric genome organization is relatively less studied. Therefore, we sought to characterize the pericentromeric genome organization and understand how this organization along with the pericentromeric factors influences heterochromatic gene expression. Results Here, we characterized the pericentromeric genome organization in Drosophila melanogaster using 5C sequencing. Heterochromatic topologically associating domains (Het TADs) correlate with distinct epigenomic domains of active and repressed heterochromatic genes at the pericentromeres. These genes are known to depend on the heterochromatic landscape for their expression. However, HP1a or Su(var)3-9 RNAi has minimal effects on heterochromatic gene expression, despite causing significant changes in the global Het TAD organization. Probing further into this observation, we report the role of two other chromatin proteins enriched at the pericentromeres-dMES-4 and dADD1 in regulating the expression of a subset of heterochromatic genes. Conclusions Distinct pericentromeric genome organization and chromatin landscapes maintained by the interplay of heterochromatic factors (HP1a, H3K9me3, dMES-4 and dADD1) are sufficient to support heterochromatic gene expression despite the loss of global Het TAD structure. These findings open new avenues for future investigations into the mechanisms of heterochromatic gene expression.

During meiosis, homologous chromosomes pair and recombine, enabling balanced segregation and generating genetic diversity. In many vertebrates, double-strand breaks (DSBs) initiate recombination within hotspots where PRDM9 binds, and deposits H3K4me3 and H3K36me3. However, no protein(s) recognising this unique combination of histone marks have been identified. We identified Zcwpw1, containing H3K4me3 and H3K36me3 recognition domains, as having highly correlated expression with Prdm9. Here, we show that ZCWPW1 has co-evolved with PRDM9 and, in human cells, is strongly and specifically recruited to PRDM9 binding sites, with higher affinity than sites possessing H3K4me3 alone. Surprisingly, ZCWPW1 also recognises CpG dinucleotides. Male Zcwpw1 knockout mice show completely normal DSB positioning, but persistent DMC1 foci, severe DSB repair and synapsis defects, and downstream sterility. Our findings suggest ZCWPW1 recognition of PRDM9-bound sites at DSB hotspots is critical for synapsis, and hence fertility., eLife digest Sexual reproduction – that is, the combination of sex cells from two different individuals to produce an embryo – is one of the many mechanisms that have evolved to maintain genetic diversity. Most human cells contain 23 pairs of chromosomes, with each chromosome in a pair carrying either a paternal or maternal copy of the same gene. To form an embryo with the right number of chromosomes, each sex cell (the egg or sperm cell) must only contain one chromosome from each pair. Sex cells are produced from parent cells containing two sets of paternal and maternal chromosomes: these cells then divide twice to form four sex cells which contain only one chromosome from each pair. Before the parent cell divides, a process known as ‘recombination’ takes place, which allows chromosomes in a pair to exchange bits of genetic information. This reshuffling ensures that each chromosome in a sex cell is unique. A protein called PRDM9 helps control which sections of genetic information are recombined by modifying proteins attached to the chromosomes, marking them as locations for exchange. The DNA at each of these sites is then broken and repaired using the genetic sequence of the chromosome it is paired with as a template, thus causing the two chromosomes to swap genes. In 2019, a group of researchers found a set of genes in the testis of mice that are expressed at the same time as the gene for PRDM9. This suggested that another protein called ZCWPW1 is likely involved in recombination, but the precise role of this protein was unclear. To answer this question, Wells, Bitoun et al. – including many of the researchers involved in the 2019 study – examined human cells grown in the laboratory to determine where ZCWPW1 binds to in the chromosome. This revealed that ZCWPW1 can be found at the same sites as PRDM9, which is responsible for bringing it there. Furthermore, cells from male mice lacking the gene for ZCWPW1 cannot complete the exchange of genetic information between chromosomes, meaning that the mice are infertile. As such, ZCWPW1 seems to connect location selection by PRDM9 to the DNA repair mechanisms needed for gene exchange between chromosomes. Infertility is a significant issue for humans affecting as many as one in every six couples. Fertility is complex and many of the biological mechanisms involved are not fully understood. This work suggests that both PRDM9 and ZCWPW1 are key to the production of sex cells and may be worth investigating as factors that affect fertility in humans.

It has been suggested that DNA methylation can work in concert with other epigenetic factors, leading to changes in cellular phenotypes. For example, DNA demethylation modifications producing 5-hydroxymethylcytosine (5hmC) are thought to interact with histone modifications to influence the acquisition of embryonic stem cell (ESC) potency. However, the mechanism by which this occurs is still unknown. Thus, we systematically analysed the co-occurrence of DNA and histone modifications at genic regions as well as their relationship with ESC-specific expression using a number of heterogeneous public datasets. From a set of 19 epigenetic factors, we found remarkable co-occurrence of 5hmC and H4K8ac, accompanied by H3K4me1. This enrichment was more prominent at gene body regions. The results were confirmed using data obtained from different detection methods and species. Our analysis shows that these marks work cooperatively to influence ESC-specific gene expression. We also found that this trivalent mark is relatively enriched in genes related with immunity, which is a bit specific in ESCs. We propose that a trivalent epigenetic mark, composed of 5hmC, H4K8ac and H3K4me1, regulates gene expression and modulates the nature of human ESCs as a novel epigenetic code.

We develop a predictive theoretical model of the physical mechanisms that govern the heritability and maintenance of epigenetic modifications. This model focuses on a particular modification, methylation of lysine-9 of histone H3 (H3K9), which is one of the most representative and critical epigenetic marks that affects chromatin organization and gene expression. Our model combines the effect of segregation and compaction on chromosomal organization with the effect of the interaction between proteins that compact the chromatin (heterochromatin protein 1) and the methyltransferases that affect methyl spreading. Our chromatin model demonstrates that a block of H3K9 methylations in the epigenetic sequence determines the compaction state at any particular location in the chromatin. Using our predictive model for chromatin compaction, we develop a methylation model to address the reestablishment of the methylation sequence following DNA replication. Our model reliably maintains methylation over generations, thereby establishing the robustness of the epigenetic code.

Methylated non-CpGs (mCpHs) in mammalian cells yield weak enrichment signals and colocalize with methylated CpGs (mCpGs), thus have been considered byproducts of hyperactive methyltransferases. However, mCpHs are cell type-specific and associated with epigenetic regulation, although their dependency on mCpGs remains to be elucidated. In this study, we demonstrated that mCpHs colocalize with mCpGs in pluripotent stem cells, but not in brain cells. In addition, profiling genome-wide methylation patterns using a hidden Markov model revealed abundant genomic regions in which CpGs and CpHs are differentially methylated in brain. These regions were frequently located in putative enhancers, and mCpHs within the enhancers increased in correlation with brain age. The enhancers with hypermethylated CpHs were associated with genes functionally enriched in immune responses, and some of the genes were related to neuroinflammation and degeneration. This study provides insight into the roles of non-CpG methylation as an epigenetic code in the mammalian brain genome.

N6-methyladenine (6mA) is a DNA base modification at the 6th nitrogen position; recently, it has been resurfaced as a potential reversible epigenetic mark in eukaryotes. Despite its existence, 6mA was considered to be absent due to its undetectable level. However, with the new advancements in methods, considerable 6mA distribution is identified across the plant genome. Unlike 5-methylcytosine (5mC) in the gene promoter, 6mA does not have a definitive role in repression but is exposed to have divergent regulation in gene expression. Though 6mA information is less known, the available evidences suggest its function in plant development, tissue differentiation, and regulations in gene expression. The current review article emphasizes the research advances in DNA 6mA modifications, identification, available databases, analysis tools and its significance in plant development, cellular functions and future perspectives of research.

A wealth of studies over several decades has revealed an epigenetic prepattern that determines the competence of cellular differentiation in the developing liver. More recently, studies focused on the impact of epigenetic factors during liver regeneration suggest that an epigenetic code in the quiescent liver may establish its regenerative potential. We review work on the pioneer factors and other chromatin remodelers that impact the gene expression patterns instructing hepatocyte and biliary cell specification and differentiation, along with the requirement of epigenetic regulatory factors for hepatic outgrowth. We then explore recent studies involving the role of epigenetic regulators, Arid1a and Uhrf1, in efficient activation of proregenerative genes during liver regeneration, thus highlighting the epigenetic mechanisms of liver disease and tumor development.

Increasing evidences have indicated histone posttranslational modifications (PTMs) play crucial roles in regulating a wide range of chromatin-templated nuclear processes, such as gene transcription, DNA replication and DNA damage repair [1]. PTMs on histones have been proposed to serve as histone code that provides epigenetic information from a mother cell to daughter cells [2]. Histone code is under control of opposing enzymes that ‘write’ or ‘erase’ modifications on histones [1, 3]. Meanwhile, this epigenetic code could be translated by ‘reader’ proteins, which can recognize specific histone modifications, into biological readout, without alteration of genetic information [4, 5].

In the recent decade, mostly because of the development of new techniques for large-scale measurement of different types of epigenetic marks, epigenomics has become a very active field of research. The availability of hundreds of genome-wide datasets has made the task of reconstructing the epigenetic code or its parts a very attractive target for study. As, at the same time, the machine learning methodology was undergoing a phase of rapid growth with the advent of new techniques, most notably the deep learning methods, it was natural for researchers from both fields to apply different machine learning methods to the growing body of the epigenomic data. This was both useful for the advancement of our understanding of the epigenetic mechanisms and a great test bed for the newly developed machine learning tools. This chapter first gives an introduction to the typical problem setting for machine learning in epigenomics and then discusses some of the representative works in the area.

The contribution of epigenetic alterations in tumor development and progression is firmly established. The epigenetic code comprises both DNA and histone modifications that must be flexible enough to adapt and respond to developmental and environmental cues in an appropriate way. This plasticity is essential for correct gene expression in a cell-type-specific and time-precise manner. The epigenetic status of a given cell is the net result of the action of multiple enzymes that add, interpret, or remove specific epigenetic marks. The frequent deregulation of epigenetic proteins’ expression and function in many diseases, including cancer, makes them predictable therapeutic targets. As the number of inhibitors targeting these epigenetic proteins grows, much effort is being put into improving isoform selectivity and decreasing systemic toxicity without compromising potency. However, so far, only five HDAC inhibitors have been approved as a second or third line of treatment for three distinct hematological malignancies. Unfortunately, their efficacy on solid tumors remains disappointing. Nevertheless, as our understanding of the biological processes underlying diseases increases, so does the opportunity for drug combinations. We anticipate that clinical trials aiming to explore the combination of epigenetic modulators with targeted therapies and immunomodulatory drugs will improve patients’ care in the short/median term.

We build a theoretical model of morphogenesis. This model describes cell fate in the developing organism using the notion of epigenetic code of each cell. Namely, given the epigenetic spectra of a cell and its neighboring cells, we can determine the corresponding cell event it will perform. This means that the properties of a group of cells (comprising an embryo or its part) at any time point are also known, and thus, the evolution of an embryo can be described. By this strategy, it is possible to establish the tissue, organ, or embryo shapes at any time, starting from a zygote. As an essential part of the model, the formalization of the notion of cell potency is introduced, and the related properties are discussed.

Histones are wrapped around by genomic DNA to form nucleosomes which are the basic units of chromatin. In eukaryotes histones undergo various covalent modifications such as methylation, phosphorylation, acetylation, ubiquitination and ribosylation. Histone modifications play a fundamental role in the epigenetic regulation of gene expression in multicellular eukaryotes. Histone methylation is one of the most important modifications occurring on Lysine (K) and Arginine (R) residues of histones, dynamically regulated by histone methyltransferases and demethylases. Identifications of such histone modification enzymes and to study how they work are the most fundamental questions needs to be answered. Uncovering the regulation and functions of the various histone methylation enzymes will help us to better understand the epigenetic code. This review summarizes the regulation of histone methyltransferases activity, the recruitment of methyltransferases and the distribution patterns and function of histone methylations.

While the central role of locus-specific acetylation of histone proteins in eukaryotic gene expression is well established, the availability of designer tools to regulate acetylation at particular nucleosome sites remains limited. Here, we develop a unique strategy to introduce acetylation by constructing a bifunctional molecule designated Bi-PIP. Bi-PIP has a P300/CBP-selective bromodomain inhibitor (Bi) as a P300/CBP recruiter and a pyrrole–imidazole polyamide (PIP) as a sequence-selective DNA binder. Biochemical assays verified that Bi-PIPs recruit P300 to the nucleosomes having their target DNA sequences and extensively accelerate acetylation. Bi-PIPs also activated transcription of genes that have corresponding cognate DNA sequences inside living cells. Our results demonstrate that Bi-PIPs could act as a synthetic programmable histone code of acetylation, which emulates the bromodomain-mediated natural propagation system of histone acetylation to activate gene expression in a sequence-selective manner., 特定の場所の遺伝子を活性化できる新しい分子を開発. 京都大学プレスリリース. 2018-05-25.

Diabetes is a chronic metabolic disorder that poses a global burden to healthcare. Increasing incidence of diabetes-related complications in the affected population includes a delay in wound healing that often results in non-traumatic limb amputations. Owing to the intricacies of the healing process and crosstalk between the multitude of participating cells, the identification of hyperglycaemia-induced changes at both cellular and molecular levels poses a challenge. Macrophages are one of the key participants in wound healing and continue to exert functional changes at the wound site since the time of injury. In the present review, we discuss the role of these cells and their aberrant functions in diabetic wounds. We have extensively studied the process of macrophage polarization (MP) and its modulation through epigenetic modifications. Data from both pre-clinical and clinical studies on diabetes have co-related hyperglycaemia induced changes in gene expression to an increased incidence of diabetic complications. Hyperglycaemia and oxidative stress, create an environment prone to changes in the epigenetic code, that is manifested as an altered inflammatory gene expression. Here, we have attempted to understand the different epigenetic modulations that possibly contribute towards dysregulated MP, resulting in delayed wound healing.

Combinatorial histone post-translational modifications (HPTMs) form a complex epigenetic code that can be decoded by specific binding proteins, termed as readers. Their specific interplays have been thought to determine gene expression and downstream biological functions. However, it is still a big challenge to analyze such interactions due to various limitations including rather weak, transient, and complicated interactions between HPTMs and readers, the high dynamic property of HPTMs, and the low abundance of reader proteins. Here we sought to take advantage of DNA-templated and photo-cross-linking techniques to design a group of combinatorial histone PTM peptide probes for the identification of multivalent interactions among histone PTMs and readers. By use of trimethylation on histone H3K4 (H3K4me3) and phosphorylation on H3T3, we demonstrated that this approach can be successfully utilized for identification of the PTM crosstalk on the same histone. By use of H3K4me3 and acetylation on H4K16, we showed the potential application of the probe in the multivalent interactions among PTMs on different histones. Thus, this new chemical proteomics tool combined with mass spectrometry holds a promising potential in profiling of the readers of combinatorial HPTMs and characterization of crosstalk among multiple PTMs on histones and can be adapted for broad biomedical applications.