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Hi-C and chromatin immunoprecipitation (ChIP) have been combined to identify long-range chromatin interactions genome-wide at reduced cost and enhanced resolution, but extracting information from the resulting datasets has been challenging. Here we describe a computational method, MAPS, Model-based Analysis of PLAC-seq and HiChIP, to process the data from such experiments and identify long-range chromatin interactions. MAPS adopts a zero-truncated Poisson regression framework to explicitly remove systematic biases in the PLAC-seq and HiChIP datasets, and then uses the normalized chromatin contact frequencies to identify significant chromatin interactions anchored at genomic regions bound by the protein of interest. MAPS shows superior performance over existing software tools in the analysis of chromatin interactions from multiple PLAC-seq and HiChIP datasets centered on different transcriptional factors and histone marks. MAPS is freely available at https://github.com/ijuric/MAPS.

Hematopoietic stem cell (HSC) utilizes its quiescence feature to combat exhaustion for lifetime blood cell supply. To date, how certain chromatin architecture and subsequent transcription profile permit HSC quiescence remains unclear. Here, we show an essential role of chromatin remodeler zinc finger HIT-type containing 1 (Znhit1) in maintaining HSC quiescence. We find that loss of Znhit1 leads to exhaustion of stem cell pool and impairment of hematopoietic function. Mechanically, Znhit1 determines the chromatin accessibility at distal enhancers of HSC quiescence genes, including Pten, Fstl1, and Klf4, for sustained transcription and consequent PI3K–Akt signaling inhibition. Moreover, Znhit1–Pten–PI3K–Akt axis also participates in controlling myeloid expansion and B-lymphoid specification. Our findings therefore identify a dominant role of Znhit1-mediated chromatin remodeling in preserving HSC function for hematopoietic homeostasis.

During development and throughout life, a variety of specialized cells must be generated to ensure the proper function of each tissue and organ. Chromatin plays a key role in determining cellular state, whether totipotent, pluripotent, multipotent, or differentiated. We highlight chromatin dynamics involved in the generation of pluripotent stem cells as well as their influence on cell fate decision and reprogramming. We focus on the capacity of histone variants, chaperones, modifications, and heterochromatin factors to influence cell identity and its plasticity. Recent technological advances have provided tools to elucidate the underlying chromatin dynamics for a better understanding of normal development and pathological conditions, with avenues for potential therapeutic application.

Reported classifications of germinal vesicle (GV) chromatin configurations in pig oocytes were not done by uniform standards and they were not well correlated with oocyte competence. In this study, GV chromatin of pig oocytes was classified into nonsurrounded nucleolus (NSN), surrounded nucleolus (SN), partly NSN (pNSN) and SN (pSN), prematurely condensed NSN (cNSN), pNSN (cpNSN) and pSN (cpSN), and early diakinesis (ED) patterns. During in vitro maturation in 199 medium, NSN oocytes from 1 to 2 mm follicles went consecutively through pNSN, pSN, cpSN, and ED before undergoing GV breakdown, and chromatin in some SN oocytes from 3 to 6 mm follicles re-decondensed into a re-decondensation (RDC) configuration. Under unfavorable conditions such as follicle atresia, ovary handling or maturation in simple MEM medium, however, premature chromatin condensation occurred, forming cNSN, cpNSN, and cpSN patterns. While all NSN and pNSN and some pSN and RDC oocytes actively transcribed, no cNSN, cpNSN, or cpSN oocytes showed transcription. Maturation and embryo culture suggested that SN and pSN oocytes were more competent than NSN and pNSN oocytes; cpSN oocytes were more competent than cNSN/cpNSN oocytes; and only RDC oocytes could develop into blastocysts. It is concluded that the newly classified chromatin configurations are more closely correlated with oocyte competence than those reported previously. Summary Sentence The newly classified GV chromatin configurations in pig oocytes are more closely correlated with oocyte transcriptional activity and developmental competence than previously reported ones.

Metabolism and gene expression, which are two fundamental biological processes that are essential to all living organisms, reciprocally regulate each other to maintain homeostasis and regulate cell growth, survival and differentiation. Metabolism feeds into the regulation of gene expression via metabolic enzymes and metabolites, which can modulate chromatin directly or indirectly — through regulation of the activity of chromatin trans-acting proteins, including histone-modifying enzymes, chromatin-remodelling complexes and transcription regulators. Deregulation of these metabolic activities has been implicated in human diseases, prominently including cancer.

Shankar Balasubramanian and colleagues examine endogenous DNA G-quadruplex (G4) structures in the context of chromatin by using G4 antibody-based ChIP–seq. They find that G4 structures are enriched in nucleosome-depleted regions and the promoters and 5′ UTRs of highly transcribed genes, suggesting a relationship between chromatin state, transcriptional output and G4 status. G-quadruplex (G4) structural motifs have been linked to transcription 1 , 2 , replication 3 and genome instability 4 , 5 and are implicated in cancer and other diseases 6 , 7 , 8 . However, it is crucial to demonstrate the bona fide formation of G4 structures within an endogenous chromatin context 9 , 10 . Herein we address this through the development of G4 ChIP–seq, an antibody-based G4 chromatin immunoprecipitation and high-throughput sequencing approach. We find ∼10,000 G4 structures in human chromatin, predominantly in regulatory, nucleosome-depleted regions. G4 structures are enriched in the promoters and 5′ UTRs of highly transcribed genes, particularly in genes related to cancer and in somatic copy number amplifications, such as MYC . Strikingly, de novo and enhanced G4 formation are associated with increased transcriptional activity, as shown by HDAC inhibitor–induced chromatin relaxation and observed in immortalized as compared to normal cellular states. Our findings show that regulatory, nucleosome-depleted chromatin and elevated transcription shape the endogenous human G4 DNA landscape.

Molecular inputs to chromatin via cellular metabolism are modifiers of the epigenome. These inputs — which include both nutrient availability as a result of diet and growth factor signalling — are implicated in linking the environment to the maintenance of cellular homeostasis and cell identity. Recent studies have demonstrated that these inputs are much broader than had previously been known, encompassing metabolism from a wide variety of sources, including alcohol and microbiotal metabolism. These factors modify DNA and histones and exert specific effects on cell biology, systemic physiology and pathology. In this Review, we discuss the nature of these molecular networks, highlight their role in mediating cellular responses and explore their modifiability through dietary and pharmacological interventions.Various cellular metabolites provide the chemical moieties for DNA and histone modifications, resulting in a complex interplay between metabolism and epigenetics. In this Review, Dai, Ramesh and Locasale discuss the metabolic regulation of diverse types of chromatin modifications and the functional consequences of these modifications at the molecular, cellular and organismal levels, as well as influences from diet and microbiota.

Mitotic errors can activate cyclic GMP–AMP synthase (cGAS) and induce type I interferon (IFN) signaling. Current models propose that chromosome segregation errors generate micronuclei whose rupture activates cGAS. We used a panel of antimitotic drugs to perturb mitosis in human fibroblasts and measured abnormal nuclear morphologies, cGAS localization, and IFN signaling in the subsequent interphase. Micronuclei consistently recruited cGAS without activating it. Instead, IFN signaling correlated with formation of cGAS-coated chromatin bridges that were selectively generated by microtubule stabilizers and MPS1 inhibitors. cGAS activation by chromatin bridges was suppressed by drugs that prevented cytokinesis. We confirmed cGAS activation by chromatin bridges in cancer lines that are unable to secrete IFN by measuring paracrine transfer of 2′3′-cGAMP to fibroblasts, and in mouse cells. We propose that cGAS is selectively activated by self-chromatin when it is stretched in chromatin bridges. Immunosurveillance of cells that fail mitosis, and antitumor actions of taxanes and MPS1 inhibitors, may depend on this effect.

Chromatin instability and mitochondrial decline are conserved processes that contribute to cellular aging. Although both processes have been explored individually in the context of their distinct signaling pathways, the mechanism that determines which process dominates during aging of individual cells is unknown. We show that interactions between the chromatin silencing and mitochondrial pathways lead to an epigenetic landscape of yeast replicative aging with multiple equilibrium states that represent different types of terminal states of aging. The structure of the landscape drives single-cell differentiation toward one of these states during aging, whereby the fate is determined quite early and is insensitive to intracellular noise. Guided by a quantitative model of the aging landscape, we genetically engineered a long-lived equilibrium state characterized by an extended life span.

Key Points Histone acetylation is an epigenetic modification that is unequivocally associated with increasing the propensity for gene transcription. As gene transcription is a crucial feature of long-lasting forms of memories, increments in histone acetylation generally favour learning and memory, and can be considered molecular memory aids. Histone acetylation readily responds to neuronal activity in terms of neuronal depolarization and synaptic plasticity. So far, two pathways that mediate this response have been identified: the mitogen-activated protein kinase (MAPK) pathway and the dissociation of histone deacetylase 2 (HDAC2) from the chromatin. A reduction in histone acetylation has been causally implicated in memory impairment associated with neurodegeneration, ageing and neurodevelopment disorders such as Rubinstein–Taybi syndrome. From these studies, a gain-of-function of HDAC2 and a loss-of-function of the histone acetyl transferase cyclic AMP-responsive element-binding (CREB)-binding protein (CBP) emerge as chief culprits. The reduction of histone acetylation can be counteracted by the use of small molecule inhibitors of HDACs, so-called HDAC inhibitors (HDACis). Several HDACis have already been proven successful in rescuing cognitive deficits in animal models of neurodegeneration, Alzheimer's disease, ageing, and Rubinstein–Taybi syndrome, and might thus constitute a new template for pharmacological strategies against cognitive impairments. Although their precise mode of action is still not fully characterized, HDACis might act through a process called epigenetic priming, a term originally used in cancer research. Epigenetic priming refers to a support-only mode of action of HDACis, whereby HDACis alone have little effect (on histone acetylation and gene transcription), but when applied in conjunction with ongoing treatments that increase gene expression programmes, HDACis further potentiate them. concept of epigenetic priming can be applied to neuroplasticity as well, in that HDACs would further support neuronal activity-driven gene expression programmes while having little or no effect on genes with constant rates of transcription. Long-lasting memories require specific gene expression programmes that are, in part, orchestrated by epigenetic mechanisms such as histone acetylation. Gräff and Tsai review the roles of histone acetylation in memory and consider whether histone deacetylase inhibitors might have promise as therapeutic interventions against cognitive frailty. Long-lasting memories require specific gene expression programmes that are, in part, orchestrated by epigenetic mechanisms. Of the epigenetic modifications identified in cognitive processes, histone acetylation has spurred considerable interest. Whereas increments in histone acetylation have consistently been shown to favour learning and memory, a lack thereof has been causally implicated in cognitive impairments in neurodevelopmental disorders, neurodegeneration and ageing. As histone acetylation and cognitive functions can be pharmacologically restored by histone deacetylase inhibitors, this epigenetic modification might constitute a molecular memory aid on the chromatin and, by extension, a new template for therapeutic interventions against cognitive frailty.