Joint research effort pays dividends
NIEHS and NTP report life experiences may alter DNA methylation
Scientists at NIEHS and Division of the National Toxicology Program (NTP), along with their collaborators, reported that DNA sequence may determine where methylation events occur, and that life events such as pregnancy could alter DNA methylation patterns. The researchers used inbred mice to examine methylation, the addition of methyl groups onto DNA.
Researchers intercrossed two inbred mouse strains and measured DNA methylation patterns in the livers of parents and offspring. They found that DNA methylation patterns were closely linked to the genetic makeup of the animal. These patterns were unchanged when passed to male and female offspring. However, in female animals that had experienced pregnancy, hundreds of DNA sites showed decreased methylation compared with virgin females. These findings suggest that genetics influences DNA methylation patterns and that major life events may leave a distinct methylation signature.
Citation: Grimm SA, Shimbo T, Takaku M, Thomas JW, Auerbach S, Bennett BD, Bucher JR, Burkholder AB, Day F, Du Y, Duncan CG, French JE, Foley JF, Li J, Merrick BA, Tice RR, Wang T, Xu X, NISC Comparative Sequencing Program, Buchel PR, Fargo DC, Mullikin JC, Wade PA. 2019. DNA methylation in mice is influenced by genetics as well as sex and life experience. Nat Commun 10(1):305. (Synopsis(https://factor.niehs.nih.gov/2019/3/papers/dir/index.htm#a1))
In-house scientists study causes of cancer, obesity, asthma
Glucocorticoids protect against stomach cancer
NIEHS researchers have revealed that glucocorticoids, a family of anti-inflammatory steroid hormones, are essential for suppressing pathogenic stomach inflammation and may prevent the development of a pre-neoplastic state called spasmolytic polypeptide-expressing metaplasia (SPEM). In this study, the researchers used mouse models to investigate the role of glucocorticoids in stomach inflammation and cancer development.
By performing adrenalectomy that surgically removes both adrenal glands, the scientists depleted circulating glucocorticoids in mice and found that they showed loss of parietal cells and formation of SPEM. Disruption of glucocorticoid signaling also led to rapid activation of proinflammatory genes and a significant increase of total leukocytes in the stomach. Among different types of leukocytes, only Cx3cr1 monocytes were required to initiate adrenalectomy-induced SPEM, which suggests that, in the absence of glucocorticoids, these monocytes are pathogenic within the stomach and may promote the formation of gastric cancer.
Citation: Busada JT, Ramamoorthy S, Cain DW, Xu X, Cook DN, Cidlowski JA. 2019. Endogenous glucocorticoids prevent gastric metaplasia by suppressing spontaneous inflammation. J Clin Invest 129(3):1345–1358. (Synopsis(https://factor.niehs.nih.gov/2019/4/papers/dir/index.htm#a4))
Cryo-EM structure reveals Rix7 functions as a molecular unfoldase
Using cryo-electron microscopy (EM), researchers at NIEHS have taken a more detailed view of the budding yeast Saccharomyces cerevisiae protein Rix7 and its two AAA domains that are critical for its unfoldase activity. Rix7 is an adenosine triphosphatase, which means it uses energy from adenosine triphosphate hydrolysis to drive ribosome assembly. Rix7 captures substrates and drives their removal from the pre-60S large ribosomal unit using a hand-over-hand mechanism for substrate unfolding. This research is the first to show that Rix7 functions as a molecular unfoldase.
The researchers visualized Rix7 and the two AAA domains with high resolution and found that they had an asymmetric configuration. By generating mutations in these domains, the researchers determined that they are crucial for allowing substrates to pass through them, with one domain guiding and the other acting as a motor.
Citation: Lo YH, Sobhany M, Hsu AL, Ford BL, Krahn JM, Borgnia MJ, Stanley RE. 2019. Cryo-EM structure of the essential ribosome assembly AAA-ATPase Rix7. Nat Commun 10(1):513. (Synopsis(https://factor.niehs.nih.gov/2019/4/papers/dir/index.htm#a2))
DNA methylation changes occur years before breast cancer develops
Scientists at NIEHS determined that women who develop breast cancer exhibit methylation differences in their blood DNA years before the tumors are clinically detected. DNA methylation is an epigenetic modification in which methyl groups bind to DNA, potentially altering gene expression. The study identified differentially methylated DNA sites that offer the potential for improved early breast cancer diagnosis.
The authors used blood samples collected from 2,443 women at the time they enrolled in the Sister Study, an NIEHS study of women who have a biological sister with breast cancer. The scientists identified 9,601 sites that were differentially methylated between women who developed breast cancer during follow-up and those who remained breast cancer free. Validating their findings, 2,095 of these differentially methylated sites were replicated in an independent study, and 42 of the methylation sites were located near known breast cancer susceptibility genes.
Citation: Xu Z, Sandler DP, Taylor JA. 2019. Blood DNA methylation and breast cancer: a prospective case-cohort analysis in the Sister Study. J Natl Cancer Inst; doi:10.1093/jnci/djz065 [Online 15 April 2019]. (Synopsis(https://factor.niehs.nih.gov/2019/6/papers/dir/index.htm#a2))
New mouse model of lung cancer reveals key disease drivers
New findings from NIEHS researchers point to a novel strategy for preventing or treating a common type of lung cancer called lung squamous cell carcinoma (LSCC). LSCC includes approximately 25-30% of all lung cancers, which are the leading cause of cancer-related death.
Using a new genetic mouse model, the researchers found that a signaling pathway called JNK1-2, which regulates the cellular stress response, plays a key role in suppressing LSCC development. The researchers also discovered that silencing a gene called Lkb1 in lung airway cells is sufficient to induce LSCC in mice. It is the first demonstration that a single mutation is sufficient to induce LSCC and suggests that Lkb1 plays a greater role in driving LSCC development than previously thought. The animal model could be used to identify environmental agents that promote lung cancer development and to treat the disease.
Citation: Liu J, Wang T, Creighton CJ, Wu SP, Ray M, Janardhan KS, Willson CJ, Cho SN, Castro PD, Ittmann MM, Li JL, Davis RJ, DeMayo FJ. 2019. JNK1-2 represses Lkb1-deficiency-induced lung squamous cell carcinoma progression. Nat Commun 10(1):2148. (Synopsis(https://factor.niehs.nih.gov/2019/7/papers/dir/index.htm#a3)) (Story)
Artificial light while sleeping may lead to obesity in women
Exposure to artificial light at night (ALAN) while sleeping is associated with increased weight gain and development of obesity in women, according to NIEHS researchers. The study is the first to describe the association in humans, perhaps furthering scientists’ understanding of the obesity epidemic.
The researchers used data from 43,722 women participating in the Sister Study, a national cohort that investigates genetic and environmental risk factors for breast cancer. Participants were asked about their exposure to different types of ALAN while sleeping, and responses were categorized into four groups: no light, small nightlight in the room, light outside the room, and light or television on in the room.
Women who slept with televisions or other lights at night were more likely to have been overweight or obese at the start of the study and were more likely to gain weight or become obese during follow-up.
Citation: Park YM, White AJ, Jackson CL, Weinberg CR, Sandler DP. 2019. Association of exposure to artificial light at night while sleeping with risk of obesity in women. JAMA Intern Med 179(8):1061–1071. (Synopsis(https://factor.niehs.nih.gov/2019/8/papers/dir/index.htm#a4)) (Story)
DNA methylation pattern may indicate childhood asthma risk
Novel epigenetic markers, which are chemical tags that attach to DNA, may indicate a newborn’s risk of asthma, according to an international team of scientists led by NIEHS. The data were generated by the Pregnancy and Childhood Epigenetics Consortium and may help researchers identify at birth which children will eventually develop asthma and to determine biomarkers of the disease.
The scientists examined DNA methylation patterns in blood taken from newborns and followed the children until they reached school age. The team also looked at DNA methylation patterns during childhood in different groups of children with and without asthma. The study revealed the children who developed asthma had nine areas, or loci, in their DNA with different levels of methylation compared with children who did not develop asthma. Children with a previous asthma diagnosis had 173 DNA differentially methylated loci in relation to asthma.
Citation: Reese SE, Xu CJ, den Dekker HT, Lee MK, Sikdar S, Ruiz-Arenas C, Merid SK, Rezwan FI, Page CM, Ullemar V, Melton PE, Oh SS, Yang IV, Burrows K, Soderhall C, Jima DD, Gao L, Arathimos R, Kuppers LK, Wielscher M, Rzehak P, Lahti J, Laprise C, Madore AM, Ward J, Bennett BD, Wang T, Bell DA, BIOS consortium, Vonk JM, Haberg SE, Zhao S, Karlsson R, Hollams E, Hu D, Richards AJ, Bergstrom A, Sharp GC, Felix JF, Bustamante M, Gruzieva O, Maguire RL, Gilliland F, Baiz N, Nohr EA, Corpeleijn E, Sebert S, Karmaus W, Grote V, Kajantie E, Magnus MC, Ortqvist AK, Eng C, Liu AH, Kull I, Jaddoe VWV, Sunyer J, Kere J, Hoyo C, Annesi-Maesano I, Arshad SH, Koletzko B, Brunekreef B, Binder EB, Raikkonen K, Reischl E, Holloway JW, Jarvelin MR, Snieder H, Kazmi N, Breton CV, Murphy SK, Pershagen G, Anto JM, Relton CL, Schwartz DA, Burchard EG, Huang RC, Nystad W, Almqvist C, Henderson AJ, Melen E, Duijts L, Koppelman GH, London SJ. 2019. Epigenome-wide meta-analysis of DNA methylation and childhood asthma. J Allergy Clin Immunol 143(6):2062–2074. (Synopsis(https://factor.niehs.nih.gov/2019/3/papers/dir/index.htm#a4)) (Story)
NF-Y protein key for proper transcription initiation
An international research team led by NIEHS scientists showed that a protein called NF-Y plays a crucial role in transcription. Transcription, the process of copying or transcribing a gene’s DNA sequence into messenger RNA, is the first step in making a protein. The researchers determined that NF-Y maintains the nucleosome-depleted region (NDR) at gene promoters while ensuring transcription begins at the right place. NDR maintenance — a previously unknown role for NF-Y — is essential for the proper binding of transcription factors at the appropriate transcription start site (TSS).
Using mouse embryonic stem cells (ESCs), the researchers compared ChIP-Seq and MNase-Seq data to demonstrate that when NF-Y was bound at the promoters, NDR was maintained and transcription started at the correct TSS. However, when NF-Y was removed from mouse ESCs, NDR was not maintained and transcription began at an incorrect TSS.
Citation: Oldfield AJ, Henriques T, Kumar D, Burkholder AB, Cinghu S, Paulet D, Bennett BD, Yang P, Scruggs BS, Lavender CA, Rivals E, Adelman K, Jothi R. 2019. NF-Y controls fidelity of transcription initiation at gene promoters through maintenance of the nucleosome-depleted region. Nat Commun 10(1):3072. (Synopsis(https://factor.niehs.nih.gov/2019/9/papers/dir/index.htm#a3)) (Story)
Crystal structure shows RNA-binding domains collaborate within protein
After obtaining crystal structures for RNA bound to the Pumilio-homology domain (PUM-HD) of PUF protein Puf1, NIEHS researchers and their collaborators demonstrated that two domains in the same protein work together to create a unique RNA-binding specificity. PUF proteins are a family of RNA-binding proteins that are conserved among eukaryotes. These molecules are key for the lifecycle of mRNAs, and their dysfunction is associated with neurological disorders and cancer in humans. Specifically, Puf1 and Puf2 differ from other PUF proteins because they have two RNA-binding domains: a PUM-HD and an RNA recognition motif (RRM).
The crystal structure showed two Puf1 proteins from Schizosaccharomyces pombe bound to one RNA molecule, which contains two binding motifs (UAAU). Using other molecular biology assays, the authors determined that although the RRM domain does not directly bind RNA, it influences PUM-HD to favor dual UAAU motif binding and dimerization.
Citation: Qiu C, Dutcher RC, Porter DF, Arava Y, Wickens M, Hall TMT. 2019. Distinct RNA-binding modules in a single PUF protein cooperate to determine RNA specificity. Nucleic Acids Res 47(16):8770–8784. (Synopsis(https://factor.niehs.nih.gov/2019/9/papers/dir/index.htm#a5))
New roles for Pol delta in DNA replication
Scientists at NIEHS uncovered new roles for polymerase delta (Pol delta), which is responsible for building DNA molecules during DNA replication. The canonical model suggests that polymerase alpha (Pol alpha) initiates the replication process. Then, polymerase epsilon (Pol epsilon) works on the leading strand and Pol delta synthesizes Okazaki fragments of the lagging strand. Okazaki fragments are short pieces of DNA that are joined to make an entire strand. The new findings suggest that Pol delta is also involved in leading strand synthesis and provides a novel mechanism of replication termination involving this enzyme.
Researchers improved upon the hydrolytic end sequencing (HydEn-seq) technique to more accurately map polymerase activity across the genome. Using the budding yeast Saccharomyces cerevisiae, they found that Pol delta was highly involved in leading strand initiation as an intermediary between Pol alpha and Pol epsilon.
Citation: Zhou ZX, Lujan SA, Burkholder AB, Garbacz MA, Kunkel TA. 2019. Roles for DNA polymerase delta in initiating and terminating leading strand DNA replication. Nat Commun 10(1):3992. (Synopsis(https://factor.niehs.nih.gov/2019/11/papers/dir/index.htm#a4))
RUNX1 important in maintaining fetal ovary identity
A study by NIEHS researchers and their international collaborators discovered that transcription factors RUNX1 and FOXL2 coordinate to support normal fetal ovary identity. RUNX1 is known to be well-conserved in multiple vertebrate species, playing a critical role in developmental processes of multiple organs.
Using their genetic mouse model, the scientists showed that RUNX1 interacts closely with FOXL2 at the genomic level to play a complementary role in supporting cell differentiation of the ovary. RUNX1 was much more highly expressed in mouse gonads that develop into the ovary compared to those developing into the testis. The genetic loss of both RUNX1 and FOXL2, compared to the single loss of RUNX1 or FOXL2, led to more abnormal gene expression profiles and a notable masculinization in fetal ovaries. The study also showed the conservation of this ovary-specific enrichment of RUNX1 during gonad development in humans.
Citation: Nicol B, Grimm SA, Chalmel F, Lecluze E, Pannetier M, Pailhoux E, Dupin-De-Beyssat E, Guiguen Y, Capel B, Yao HH. 2019. RUNX1 maintains the identity of the fetal ovary through an interplay with FOXL2. Nat Commun 10(1):5116. (Synopsis(https://factor.niehs.nih.gov/2020/1/papers/dir/index.htm#a3))
Effects of UV exposure on immune system in skin
NIEHS researchers and their collaborators discovered that the ability of UV phototherapy to suppress inflammation depends on a protein called Rubicon (RUBCN). This protein is key to a process called LC3-associated phagocytosis (LAP), which rids the body of dying cells in a manner that does not inappropriately trigger the immune system. The findings give insight into autoimmune and inflammatory disorders.
The researchers studied mice lacking the gene Rubcn, which are susceptible to developing the autoimmune disease systemic lupus erythematosus. They found that exposing the skin cells of Rubcn-deficient mice to UV radiation induced significant inflammation and a hyperactive immune response. Specifically, they showed that skin-resident dendritic cells lacking RUBCN presented more antigens and alerted more immune cells in response to UV exposure. The researchers concluded that RUBCN functions to limit the immune response and is critical in maintaining the balance between homeostasis and inflammation.
Citation: Sil P, Suwanpradid J, Muse G, Gruzdev A, Liu L, Corcoran DL, Willson CJ, Janardhan K, Grimm S, Myers P, Degraff LM, MacLeod AS, Martinez J. 2019. Non-canonical autophagy in dermal dendritic cells mediates immunosuppressive effects of UV exposure. J Allergy Clin Immunol; doi:10.1016/j.jaci.2019.11.041 [Online 11 December 2019].
NTP researchers examine effects of botanicals, processed meat
NTP compares profiles of botanical supplements
NTP researchers used chemical and biological response profiles to evaluate the similarity of two botanical supplements with well-established NTP test articles. The approaches they used could be applied to other types of complex mixtures with unidentified active components. The scientists suggested that confirming similarity was an important step in selecting test articles and extrapolating from a tested mixture to related samples.
Researchers chose black cohosh (Actaea racemosa) and Echinacea purpurea to analyze variability between samples. The scientists used nontargeted chemical analysis to create chemical profiles and gene expression of toxicologically important receptor pathways in human liver cells to assess bioactivity. The combined chemical and biological data for black cohosh identified nine of 14 samples that were similar to the control. Five of 14 samples were similar in terms of both chemistry and bioactivity for Echinacea purpurea.
Citation: Ryan KR, Huang MC, Ferguson SS, Waidyanatha S, Ramaiahgari S, Rice JR, Dunlap PE, Auerbach SS, Mutlu E, Cristy T, Peirfelice J, DeVito MJ, Smith-Roe SL, Rider CV. 2019. Evaluating sufficient similarity of botanical dietary supplements: combining chemical and in vitro biological data. Toxicol Sci 172(2):316–329. (Synopsis(https://factor.niehs.nih.gov/2019/11/papers/dir/index.htm#a1))
NTP screens chemicals for liver injury potential
When applied to human cell culture models, a high-throughput transcriptomics platform called TempO-Seq captures biological responses to chemicals that induce liver injury, according to a study by NTP researchers and NIEHS-funded colleagues. The novel approach may better predict the potentially harmful effects of a wide variety of environmental chemicals or pharmaceutical drugs in humans.
Predicting the responses of the human liver to chemical exposures is a major hurdle. To address this challenge, the researchers used TempO-Seq to generate high-throughput data for approximately 2,700 human transcripts with highly differentiated in vitro liver models that were exposed to wide-ranging concentrations of 24 reference compounds. This approach readily distinguished liver-injury compounds, such as the chemotherapy drug tamoxifen and pharmaceuticals that were withdrawn from the market from compounds rarely associated with liver injury, such as caffeine and sucrose.
Citation: Ramaiahgari SC, Auerbach SS, Saddler TO, Rice JR, Dunlap PE, Sipes NS, DeVito MJ, Shah RR, Bushel PR, Merrick BA, Paules RS, Ferguson SS. 2019. The power of resolution: contextualized understanding of biological responses to liver injury chemicals using high-throughput transcriptomics and benchmark concentration modeling. Toxicol Sci 169(2):553–566. (Synopsis(https://factor.niehs.nih.gov/2019/5/papers/dir/index.htm#a1)) (Story)
Molecular differences in spontaneous versus gingko-induced liver tumors in rodents
Using a mouse model, NTP scientists demonstrated that in a type of liver cancer called hepatocellular carcinoma (HCC), methylation and gene expression profiles differ between HCCs that arise spontaneously and those caused by chronic exposure to gingko biloba extract (GBE). GBE is marketed as an anticancer and antioxidant agent and is a commonly used botanical in the U.S.
Epigenetic modifications, such as methylation, can alter gene expression and play an important role in cancer development. The NTP researchers evaluated the global methylation profiles and the corresponding gene expression profiles in mice with HCCs arising either spontaneously or due to GBE exposure. Although these tumors are morphologically indistinguishable, the methylation and gene expression profiles are different. As more chemicals make their way into the environment, similar studies will potentially allow scientists to differentiate between chemically-induced and spontaneous cancers.
Citation: Kovi RC, Bhusari S, Mav D, Shah RR, Ton TV, Hoenerhoff MJ, Sills RC, Pandiri AR. 2019. Genome-wide promoter DNA methylation profiling of hepatocellular carcinomas arising either spontaneously or due to chronic exposure to Ginkgo biloba extract (GBE) in B6C3F1/N mice. Arch Toxicol 93(8):2219–2235. (Synopsis(https://factor.niehs.nih.gov/2019/9/papers/dir/index.htm#a1))
NTP scopes the future of developmental neurotoxicity screening
NTP scientists published a proof-of-concept study that characterized a set of in vitro and alternative animal assays for their ability to measure how chemicals affected a variety of neurodevelopmental processes. The paper, which leads off a special issue on developmental neurotoxicity (DNT) in the journal Toxicological Sciences, describes the approach to creating the chemical library that was provided to project collaborators; development of a data analysis strategy; the structure of the web application that provides access to results; and key issues and knowledge gaps to address so that the approach can be used in regulatory decision-making.
Nine companion papers highlight details of the data analysis pipeline, findings from zebrafish and planaria studies, how chemicals that showed DNT activity could be compared across models, and insight on using the approach in regulatory decision-making.
Citation: Behl M, Ryan K, Hsieh JH, Parham F, Shapiro AJ, Collins BJ, Sipes NS, Birnbaum LS, Bucher JR, Foster PMD, Walker NJ. Paules RS, Tice RR. 2019. Screening for developmental neurotoxicity at the National Toxicology Program: the future is here. Toxicol Sci 167(1):6–14. (Synopsis(https://factor.niehs.nih.gov/2019/1/papers/dir/index.htm#a1))
Study finds eating processed meat increases colorectal cancer risk in women
NTP and NIEHS researchers reported that increased intake of processed meat and use of high temperature to cook red meats increased the risk of colorectal cancer in women. The study supported previous hazard assessments on processed meat and added information on colorectal cancer (CRC) risks associated with specific processed meat products and cooking practices.
Among 48,704 women in the Sister Study, followed for a median of 8.7 years, 216 developed CRC. Women in the highest quartile of processed meat consumption had a 50% increase in risk of CRC compared to women in the lowest quartile. Bacon was found to be associated with the highest risk of getting CRC, with a twofold increase in risk, followed by consumption of breakfast sausages. In terms of cooking practices reported for steaks and burgers, grilling/barbequing was associated with elevated risk of cancer.
Citation: Mehta SS, Arroyave WD, Lunn RM, Park YM, Boyd WA, Sandler DP. 2019. A prospective analysis of red and processed meat consumption and risk of colorectal cancer in women. Cancer Epidemiol Biomarkers Prev; doi:10.1158/1055-9965.EPI-19-0459 [Online 1 October 2019]. (Synopsis(https://factor.niehs.nih.gov/2019/12/papers/dir/index.htm#a1))
Grant recipients publish research on pollution, early puberty, and more
Gulf Killifish survived polluted waters with genes from another fish
NIEHS grantees found that Gulf Killifish in the Houston Ship Channel rapidly evolved to adapt to lethal levels of aromatic hydrocarbon pollutants. The findings suggest that the Gulf Killifish acquired the resistance genes from breeding with the closely related Atlantic Killifish.
The researchers sampled fish from 12 sites spanning the pollution gradient, spawned them separately in the laboratory, and exposed their embryos to a range of concentrations of pollutants. They found that fish from the most polluted sites were the most resistant to harmful effects, and that resistance was retained through at least two generations in a clean environment. To understand the genetic basis of this resistance, they sequenced the genomes of hundreds of Gulf Killifish from very polluted, moderately polluted, and clean water. Fish with higher resistance had lower activation of the aryl hydrocarbon receptor (AHR), a protein that is involved in cardiac toxicity by aromatic hydrocarbons.
Citation: Oziolor EM, Reid NM, Yair S, Lee KM, VerPloeg SG, Bruns PC, Shaw JR, Whitehead A, Matson CW. 2019. Adaptive introgression enables evolutionary rescue from extreme environmental pollution. Science 364(6439):455-457. (Synopsis(https://factor.niehs.nih.gov/2019/7/papers/dert/index.htm#a1))
Prenatal exposure to chemicals in personal care products linked to earlier puberty in girls
Girls exposed to chemicals commonly found in personal care products before birth may hit puberty earlier, according to an NIEHS-funded study. The research found that mothers who had higher levels of diethyl phthalate, a fragrance and cosmetics stabilizer, and triclosan, an antimicrobial agent, in their bodies during pregnancy had daughters who experienced puberty at younger ages.
The results came from data collected as part of the Center for the Health Assessment of Mothers and Children of Salinas study, which followed 338 children from before birth to adolescence. Girls who had higher prenatal urinary concentrations of triclosan and one of its degradation products were associated with an earlier first occurrence of menstruation. Also, higher prenatal concentrations of the main metabolite of diethyl phthalate were associated with earlier onset of pubic hair development. The same trends were not observed in boys.
Citation: Harley KG, Berger KP, Kogut K, Parra K, Lustig RH, Greenspan LC, Calafat AM, Ye X, Eskenazi B. 2018. Association of phthalates, parabens and phenols found in personal care products with pubertal timing in girls and boys. Hum Reprod 34(1):109–117. (Synopsis(https://factor.niehs.nih.gov/2019/1/papers/dert/index.htm#a2)) (Story)
Compound suppresses DNA pathway, makes tumors more susceptible to chemo
NIEHS grantees have discovered that a small molecule compound can block a DNA pathway that helps tumors withstand damage from chemotherapy drugs. The compound targets translesion synthesis, a damage tolerance process that allows specialized enzymes that copy DNA to replicate past damaged DNA.
Researchers screened 10,000 small molecule compounds looking for a molecule to block or inhibit Rev1, a key protein involved in translesion synthesis. They found that a molecule called JH-RE-06 appeared to block Rev1 from interacting with other key proteins in the translesion synthesis pathway. X-ray crystallography determined that JH-RE-06 locks Rev1 into a chemical structure where it can no longer help cancer cells survive.
In a mouse model of human melanoma, they found that not only did the tumors stop growing in mice treated with a combination of the chemotherapy drug cisplatin and JH-RE-06, those mice also survived longer.
Citation: Wojtaszek JL, Chatterjee N, Najeeb J, Ramos A, Lee M, Bian K, Xue JY, Fenton BA, Park H, Li D, Hemann MT, Hong J, Walker GC, Zhou P. 2019. A small molecule targeting mutagenic translesion synthesis improves chemotherapy. Cell 178(1):152–159.e11. (Synopsis(https://factor.niehs.nih.gov/2019/7/papers/dert/index.htm#a3))
Cataloguing genetic diversity of the human microbiome
An NIEHS-funded study, which is one of the largest of its kind, is the first to look at the DNA of bacteria that reside in both the mouth and the gut.
The team aggregated publicly available microbiome data from nearly 4,000 samples from the human mouth and gut and used computational approaches to identify unique genes. Their analysis uncovered a massive universe of more than 45 million unique bacterial genes. Many of these genes were found in only one sample, pointing to vast genetic variation within bacterial strains. They reported that these unique genes could be profiled to act as microbial fingerprints that might provide important information about past exposures. These data were used to build a publicly available microbiome gene catalog, which could shed light on the interaction between genes and the environment that leads to health or disease.
Citation: Tierney BT, Yang Z, Luber JM, Beaudin M, Wibowo MC, Baek C, Mehlenbacher E, Patel CJ, Kostic AD. 2019. The landscape of genetic content in the gut and oral human microbiome. Cell Host Microbe 26(2):283−295.e8. (Synopsis(https://factor.niehs.nih.gov/2019/10/papers/dert/index.htm#a4))
Molecule senses DNA damage and supervises repair
A team of NIEHS grantees working with an NIEHS in-house researcher found that a protein that helps safeguard against DNA damage from the sun is also useful for finding general DNA damage and overseeing its repair. The protein, ultraviolet-damaged DNA-binding protein (UV-DDB), is a known key protein in human global nucleotide excision repair, an important mechanism for removing DNA damage caused by UV light. This study showed that the protein also senses damage and plays a key role in base excision repair (BER), another important DNA repair pathway.
The research team developed a new method to track enzymes involved in DNA repair in 3D using real-time single molecule imaging. They induced oxidative stress in DNA and observed UV-DDB being rapidly recruited to sites containing specific DNA damage. UV-DDB also stimulated repair activity by forming complexes with enzymes that are essential in BER.
Citation: Jang S, Kumar N, Beckwitt EC, Kong M, Fouquerel E, Rapic-Otrin V, Prasad R, Watkins SC, Khuu C, Majumdar C, David SS, Wilson SH, Bruchez MP, Opresko PL, Van Houten B. 2019. Damage sensor role of UV-DDB during base excision repair. Nat Struct Mol Biol 26(8):695–703. (Synopsis(https://factor.niehs.nih.gov/2019/9/papers/dert/index.htm#a2)) (Story)
Gut microbiome protects against arsenic toxicity
Gut microbes play an important role in protecting against arsenic toxicity in mice, according to a new NIEHS study. Researchers found that antibiotics disrupted the gut microbiome, allowing more arsenic to accumulate in organs, rather than being excreted. They also found that germ-free mice, which are mice raised without any microorganisms, excreted less and accumulated more arsenic compared to mice with conventional microbiomes.
The researchers also examined mice lacking As3mt, the enzyme primarily responsible for arsenic detoxification in humans and other animals. They found that these mice were even more sensitive to arsenic after antibiotic treatment or when raised without microorganisms, compared to mice with unaltered microbiomes. When they introduced organisms from the human microbiome to germ-free mice lacking As3mt, they found that certain transplanted microorganisms had a protective effect, depending on microbiome stability and the presence of specific bacteria, including Faecalibacterium.
Citation: Coryell M, McAlpine M, Pinkham NV, McDermott TR, Walk ST. 2018. The gut microbiome is required for full protection against acute arsenic toxicity in mouse models. Nat Commun 9(1):5424. (Synopsis(https://factor.niehs.nih.gov/2019/2/papers/dert/index.htm#a4))
Novel mechanism for manganese regulation in the brain
NIEHS grantees showed that brain manganese is regulated by activity of the gene SLC30A10 in the digestive system. This finding provides a novel mechanism for how manganese levels are normally regulated and suggests that changes to SLC30A10 activity in the digestive system may affect neurological outcomes from manganese exposure.
The researchers compared brain manganese levels in mice lacking SLC30A10 in the whole body to mice lacking SLC30A10 in the liver, brain, and gastrointestinal tract. The researchers observed the unexpected result that, under normal body conditions, activity of SLC30A10 in the gastrointestinal tract and liver, and not the brain or just the liver, regulated brain manganese. They also found that expression of SLC30A10 in the brain became important when tissue manganese levels increased. With increased manganese exposure, activity of SLC30A10 in the brain reduced manganese levels and protected against neurotoxicity.
Citation: Taylor CA, Hutchens S, Liu C, Jursa T, Shawlot W, Aschner M, Smith DR, Mukhopadhyay S. 2019. SLC30A10 transporter in the digestive system regulates brain manganese under basal conditions while brain SLC30A10 protects against neurotoxicity. J Biol Chem 294(6):1860–1876. (Synopsis(https://factor.niehs.nih.gov/2019/3/papers/dert/index.htm#a1))
Transposable elements contribute to tumor growth
An NIEHS-funded study revealed that transposable elements, which are sequences of DNA that move around in the genome, are important drivers of tumor growth. The study provides the first comprehensive look at the role transposable elements play in activating cancer genes.
Typical genome sequencing methods that look for genetic mutations that drive cancer do not detect transposable elements. Therefore, the researchers used more powerful sequencing techniques to analyze 7,769 tumor samples from 15 different types of cancer. They discovered 129 transposable elements that played a part in tumor growth by influencing 106 different cancer genes. The authors reported that transposable elements switch on cancer-related genes that are usually silent and keep them switched on. A better understanding of transposable elements may provide more information about what leads to accelerated tumor growth in some cancers and new targets to study for future cancer therapies.
Citation: Jang HS, Shah NM, Du AY, Dailey ZZ, Pehrsson EC, Godoy PM, Zhang D, Li D, Xing X, Kim S, O'Donnell D, Gordon JI, Wang T. 2019. Transposable elements drive widespread expression of oncogenes in human cancers. Nat Genet 51(4):611–617. (Synopsis(https://factor.niehs.nih.gov/2019/6/papers/dert/index.htm#a1))
Omega-3 and omega-6 may play opposite roles in asthma
An NIEHS-funded study found that children with more dietary omega-3 fatty acids, which are present in foods such as salmon, had less severe asthma and fewer symptoms triggered by indoor air pollution. The same study showed an opposite effect for high levels of dietary omega-6 fatty acids, found in corn oil and other foods, which were linked to more severe asthma and symptoms.
The researchers studied 135 children with asthma in Baltimore. The researchers found that for each additional gram of omega-6 in their reported diet, children had 29% higher odds of experiencing severe asthma. Each 0.1-gram increase in omega-3 fatty acid intake resulted in 3-4% lower odds of daytime asthma symptoms. Overall, children who ate more omega-3 were less likely to have symptoms even at the same level of air pollution exposure.
Citation: Brigham EP, Woo H, McCormack M, Rice J, Koehler K, Vulcain T, Wu T, Koch A, Sharma S, Kolahdooz F, Bose S, Hanson C, Romero K, Diette G, Hansel NN. 2019. Omega-3 and omega-6 intake modifies asthma severity and response to indoor air pollution in children. Am J Respir Crit Care Med 199(12):1478–1486. (Synopsis(https://factor.niehs.nih.gov/2019/5/papers/dert/index.htm#a2))