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The National Institutes of Health (NIH) organized a three-day human microbiome research workshop, August 16-18, 2017, to highlight the accomplishments of the 10-year Human Microbiome Project program, the outcomes of the investments made by the 21 NIH Institutes and Centers which now fund this area, and the technical challenges and knowledge gaps which will need to be addressed in order for this field to advance over the next 10 years. This report summarizes the key points in the talks, round table discussions, and Joint Agency Panel from this workshop.

The association between obesity and breast cancer risk and prognosis is well established in estrogen receptor (ER)-positive disease but less clear in HER2-positive disease. Here, we report preclinical evidence suggesting weight maintenance through calorie restriction (CR) may limit risk of HER2-positive breast cancer. In female MMTV-HER2/neu transgenic mice, we found that ERα and ERβ expression, mammary tumorigenesis, and survival are energy balance dependent in association with epigenetic reprogramming. Mice were randomized to receive a CR, overweight-inducing, or diet-induced obesity regimen (n = 27/group). Subsets of mice (n = 4/group/time point) were euthanized after 1, 3, and 5 months to characterize diet-dependent metabolic, transcriptional, and epigenetic perturbations. Remaining mice were followed up to 22 months. Relative to the overweight and diet-induced obesity regimens, CR decreased body weight, adiposity, and serum metabolic hormones as expected and also elicited an increase in mammary ERα and ERβ expression. Increased DNA methylation accompanied this pattern, particularly at CpG dinucleotides located within binding or flanking regions for the transcriptional regulator CCCTC-binding factor of ESR1 and ESR2, consistent with sustained transcriptional activation of ERα and ERβ. Mammary expression of the DNA methylation enzyme DNMT1 was stable in CR mice but increased over time in overweight and diet-induced obesity mice, suggesting CR obviates epigenetic alterations concurrent with chronic excess energy intake. In the survival study, CR elicited a significant suppression in spontaneous mammary tumorigenesis. Overall, our findings suggest a mechanistic rationale to prevent or reverse excess body weight as a strategy to reduce HER2-positive breast cancer risk. Cancer Res; 77(9); 2500-11. ©2017 AACR.

A model incorporating the A(y) allele structure, which is a mutation situated at the mouse agouti locus in chromosome 2, was developed to elucidate the observed pleiotropic effects and recessive lethality. Pleiotropic effects due to this mutation include obesity, diabetes resistant to insulin type II and the potential to develop spontaneous and induced tumors.

Combined use of human and mouse genetics was used to study human type II occulocutaneous albinism (OCA). This disease involves multiple genes and complex phenotypes. Human complementary DNA DN10 has been linked to the gene for mouse pink-eyed dilution locus (p). DN10 has also been shown to identify the human homologue (P) of p. P is generally deleted in patients with type II OCA and is thought responsible for hypopigmentation in Prader-Willi and Angelman syndromes.

Background: Cells respond to environmental stressors through several key pathways, including response to reactive oxygen species (ROS), nutrient and ATP sensing, DNA damage response (DDR), and epigenetic alterations. Mitochondria play a central role in these pathways not only through energetics and ATP production but also through metabolites generated in the tricarboxylic acid cycle, as well as mitochondria--nuclear signaling related to mitochondria morphology, biogenesis, fission/fusion, mitophagy, apoptosis, and epigenetic regulation. Objectives: We investigated the concept of bidirectional interactions between mitochondria and cellular pathways in response to environmental stress with a focus on epigenetic regulation, and we examined DNA repair and DDR pathways as examples of biological processes that respond to exogenous insults through changes in homeostasis and altered mitochondrial function. Methods: The National Institute of Environmental Health Sciences sponsored the Workshop on Mitochondria, Energetics, Epigenetics, Environment, and DNA Damage Response on 25-26 March 2013. Here, we summarize key points and ideas emerging from this meeting. Discussion: A more comprehensive understanding of signaling mechanisms (cross-talk) between the mitochondria and nucleus is central to elucidating the integration of mitochondrial functions with other cellular response pathways in modulating the effects of environmental agents. Recent studies have highlighted the importance of mitochondrial functions in epigenetic regulation and DDR with environmental stress. Development and application of novel technologies, enhanced experimental models, and a systems-type research approach will help to discern how environmentally induced mitochondrial dysfunction affects key mechanistic pathways. Conclusions: Understanding mitochondria--cell signaling will provide insight into individual responses to environmental hazards, improving prediction of hazard and susceptibility to environmental stressors. Citation: Shaughnessy DT, McAllister K, Worth L, Haugen AC, Meyer JN, Domann FE, Environ Health Perspect 122:1271-1278; http://dx.doi.org/10.1289/ehp.1408418, Introduction Mitochondria are critical to normal cell and organ function; they play a key role in metabolic homeostasis, in part, because of their central role in energy production. They also [...]

Zygotic genome activation (ZGA), which is a nuclear reprogramming event that transforms the genome from transcriptional quiescence at fertilization to robust transcriptional activity is described. A maternal- effect mutation of Brg1, which encodes a catalytic subunit of SW1/SNF-related complexes, utilizing Cre-loxP gene targeting is generated.

The Brg1 catalytic subunit of SWI/SNF-related complexes has been implicated in; many developmental and physiological processes, but null homozygoes die as blastocysts prior to implantation. To circumvent this early embryonic lethality, an ENU mutagenesis screen was performed and generated a Brg1 hypomorph mutation in the ATPase domain and it was revealed that Brg1 is the first chromatin-modifying factor shown to be required for beta-globin regulation and erythropoiesis in vivo.