Here we report that increased pup licking and grooming (LG) and arched-back nursing (ABN) by rat mothers altered the offspring epigenome at a glucocorticoid receptor (GR) gene promoter in the hippocampus. Offspring of mothers that showed high levels of LG and ABN were found to have differences in DNA methylation, as compared to offspring of 'low-LG-ABN' mothers. These differences emerged over the first week of life, were reversed with cross-fostering, persisted into adulthood and were associated with altered histone acetylation and transcription factor (NGFI-A) binding to the GR promoter. Central infusion of a histone deacetylase inhibitor removed the group differences in histone acetylation, DNA methylation, NGFI-A binding, GR expression and hypothalamic-pituitary-adrenal (HPA) responses to stress, suggesting a causal relation among epigenomic state, GR expression and the maternal effect on stress responses in the offspring. Thus we show that an epigenomic state of a gene can be established through behavioral programming, and it is potentially reversible.

/pdf/epigenetic-programming-by-maternal-behavior-nhsklwyk7o.pdf

Epigenetic programming by maternal behavior.

The unfolded protein response (UPR), caused by stress, matches the folding capacity of endoplasmic reticulum (ER) to the load of client proteins in the organelle. In yeast, processing of HAC1 mRNA by activated Ire1 leads to synthesis of the transcription factor Hac1 and activation of the UPR. The responses to activated IRE1 in metazoans are less well understood. Here we demonstrate that mutations in either ire-1 or the transcription-factor-encoding xbp-1 gene abolished the UPR in Caenorhabditis elegans. Mammalian XBP-1 is essential for immunoglobulin secretion and development of plasma cells, and high levels of XBP-1 messenger RNA are found in specialized secretory cells. Activation of the UPR causes IRE1-dependent splicing of a small intron from the XBP-1 mRNA both in C. elegans and mice. The protein encoded by the processed murine XBP-1 mRNA accumulated during the UPR, whereas the protein encoded by unprocessed mRNA did not. Purified mouse IRE1 accurately cleaved XBP-1 mRNA in vitro, indicating that XBP-1 mRNA is a direct target of IRE1 endonucleolytic activity. Our findings suggest that physiological ER load regulates a developmental decision in higher eukaryotes.

IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA

Interferon-stimulated gene (ISG) products take on a number of diverse roles. Collectively, they are highly effective at resisting and controlling pathogens. In this review, we begin by introducing interferon (IFN) and the JAK-STAT signaling pathway to highlight features that impact ISG production. Next, we describe ways in which ISGs both enhance innate pathogen-sensing capabilities and negatively regulate signaling through the JAK-STAT pathway. Several ISGs that directly inhibit virus infection are described with an emphasis on those that impact early and late stages of the virus life cycle. Finally, we describe ongoing efforts to identify and characterize antiviral ISGs, and we provide a forward-looking perspective on the ISG landscape.

Interferon-Stimulated Genes: A Complex Web of Host Defenses

Twenty-Five Years of the Nucleosome, Fundamental Particle of the Eukaryote Chromosome

Over the past 20 years, breakthrough discoveries of chromatin-modifying enzymes and associated mechanisms that alter chromatin in response to physiological or pathological signals have transformed our knowledge of epigenetics from a collection of curious biological phenomena to a functionally dissected research field. Here, we provide a personal perspective on the development of epigenetics, from its historical origins to what we define as 'the modern era of epigenetic research'. We primarily highlight key molecular mechanisms of and conceptual advances in epigenetic control that have changed our understanding of normal and perturbed development.

The molecular hallmarks of epigenetic control

The distribution of core histone acetylation across the chicken beta-globin locus has been mapped in 15 day chicken embryo erythrocytes by immunoprecipitation of mononucleosomes with an antibody recognizing acetylated histones, followed by hybridization probing at several points in the locus. A continuum of acetylation was observed, covering both genes and intergenic regions. Using the same probes, the generalized sensitivity to DNase I was mapped by monitoring the disappearance of intact genomic restriction fragments from Southern transfers. Close correspondence between the 33 kb of sensitive chromatin and the extent of acetylation indicates that one role of the modification could be the generation and/or maintenance of the open conformation. The precision of acetylation mapping makes it a possible approach to the definition of chromosomal domain boundaries.

https://www.embopress.org/doi/pdf/10.1002/j.1460-2075.1994.tb06451.x

Core histone hyperacetylation co-maps with generalized DNase I sensitivity in the chicken beta-globin chromosomal domain.

Targeted and extended acetylation of histones H4 and H3 at active and inactive genes in chicken embryo erythrocytes

An affinity-purified antibody that recognises the epitope epsilon-acetyl lysine has been used to fractionate chicken erythrocyte mononucleosomes obtained from 5 and 15 day embryos. The antibody bound chromatin was enriched in multiply acetylated forms of the core histones H3, H4 and H2B, but not in ubiquitinated H2A. The DNA of these modified nucleosomes was probed with genomic sequences from the embryonic beta rho gene (active at 5 days) and from the adult beta A gene (active at 15 days). Both genes were found to be highly enriched in the acetylated nucleosomes fractionated from both 5 day and from 15 day erythrocytes. We conclude that globin switching is not linked to a change in acetylation status of the genes and that a 'poised' gene carries histones acetylated to a similar level as a transcriptionally active gene. Core histone acetylation is not therefore a direct consequence of the transcriptional process and might operate at the level of the globin locus as a general enabling step for transcription.

Histone acetylation and globin gene switching

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/0014-5793%2893%2981601-U

Histone acetylation and gene induction in human cells

Publisher Summary This chapter describes the use of chromatin immunoprecipitation assays in the acetylation mapping of higher eukaryotes. Acetylation of specific lysine residues in the N-terminal domains of core histones is a biochemical marker of active genes. Affinity-purified polyclonal antibodies recognizing acetylated core histones (principally H4) and the epitope ɛ-acetyllysine have been used in chromatin immunoselection procedures (CHIP assays) with mononucleosomes and salt-soluble chromatin fragments generated by micrococcal nuclease to determine the spatial and temporal distribution of this reversible posttranslational modification. The methodologies described in the chapter use relatively large amounts of affinity-purified antibody and select large amounts of acetylated histone-rich chromatin. Alternative protocols using cross-linking, for example, with formaldehyde, have also been very successful. The overriding criterion for success in this approach is the quality of the antibody used—that is, its specificity, affinity, and purity.

Alison L. Clayton

Papers

Core histone hyperacetylation co-maps with generalized DNase I sensitivity in the chicken beta-globin chromosomal domain.

Targeted and extended acetylation of histones H4 and H3 at active and inactive genes in chicken embryo erythrocytes

Histone acetylation and globin gene switching

Histone acetylation and gene induction in human cells

Chromatin immunoprecipitation assays in acetylation mapping of higher eukaryotes.