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1. Trigonelline is an NAD+ precursor that improves muscle function during ageing and is reduced in human sarcopenia

Author

Membrez, Mathieu, Migliavacca, Eugenia, Christen, Stefan, Yaku, Keisuke, Trieu, Jennifer, Lee, Alaina K., Morandini, Francesco, Giner, Maria Pilar, Stiner, Jade, Makarov, Mikhail V., Garratt, Emma S., Vasiloglou, Maria F., Chanvillard, Lucie, Dalbram, Emilie, Ehrlich, Amy M., Sanchez-Garcia, José Luis, Canto, Carles, Karagounis, Leonidas G., Treebak, Jonas T., Migaud, Marie E., Heshmat, Ramin, Razi, Farideh, Karnani, Neerja, Ostovar, Afshin, Farzadfar, Farshad, Tay, Stacey K.H., Sanders, Matthew J., Lillycrop, Karen A., Godfrey, Keith M., Nakagawa, Takashi, Moco, Sofia, Koopman, René, Lynch, Gordon S., Sorrentino, Vincenzo, Feige, Jerome N., Membrez, Mathieu, Migliavacca, Eugenia, Christen, Stefan, Yaku, Keisuke, Trieu, Jennifer, Lee, Alaina K., Morandini, Francesco, Giner, Maria Pilar, Stiner, Jade, Makarov, Mikhail V., Garratt, Emma S., Vasiloglou, Maria F., Chanvillard, Lucie, Dalbram, Emilie, Ehrlich, Amy M., Sanchez-Garcia, José Luis, Canto, Carles, Karagounis, Leonidas G., Treebak, Jonas T., Migaud, Marie E., Heshmat, Ramin, Razi, Farideh, Karnani, Neerja, Ostovar, Afshin, Farzadfar, Farshad, Tay, Stacey K.H., Sanders, Matthew J., Lillycrop, Karen A., Godfrey, Keith M., Nakagawa, Takashi, Moco, Sofia, Koopman, René, Lynch, Gordon S., Sorrentino, Vincenzo, and Feige, Jerome N.

Abstract

Mitochondrial dysfunction and low nicotinamide adenine dinucleotide (NAD+) levels are hallmarks of skeletal muscle ageing and sarcopenia1–3, but it is unclear whether these defects result from local changes or can be mediated by systemic or dietary cues. Here we report a functional link between circulating levels of the natural alkaloid trigonelline, which is structurally related to nicotinic acid4, NAD+ levels and muscle health in multiple species. In humans, serum trigonelline levels are reduced with sarcopenia and correlate positively with muscle strength and mitochondrial oxidative phosphorylation in skeletal muscle. Using naturally occurring and isotopically labelled trigonelline, we demonstrate that trigonelline incorporates into the NAD+ pool and increases NAD+ levels in Caenorhabditis elegans, mice and primary myotubes from healthy individuals and individuals with sarcopenia. Mechanistically, trigonelline does not activate GPR109A but is metabolized via the nicotinate phosphoribosyltransferase/Preiss–Handler pathway5,6 across models. In C. elegans, trigonelline improves mitochondrial respiration and biogenesis, reduces age-related muscle wasting and increases lifespan and mobility through an NAD+-dependent mechanism requiring sirtuin. Dietary trigonelline supplementation in male mice enhances muscle strength and prevents fatigue during ageing. Collectively, we identify nutritional supplementation of trigonelline as an NAD+-boosting strategy with therapeutic potential for age-associated muscle decline.

Published
2024

2. Trigonelline is an NAD+ precursor that improves muscle function during ageing and is reduced in human sarcopenia

Author

Membrez, Mathieu, Migliavacca, Eugenia, Christen, Stefan, Yaku, Keisuke, Trieu, Jennifer, Lee, Alaina K., Morandini, Francesco, Giner, Maria Pilar, Stiner, Jade, Makarov, Mikhail V., Garratt, Emma S., Vasiloglou, Maria F., Chanvillard, Lucie, Dalbram, Emilie, Ehrlich, Amy M., Sanchez-Garcia, José Luis, Canto, Carles, Karagounis, Leonidas G., Treebak, Jonas T., Migaud, Marie E., Heshmat, Ramin, Razi, Farideh, Karnani, Neerja, Ostovar, Afshin, Farzadfar, Farshad, Tay, Stacey K.H., Sanders, Matthew J., Lillycrop, Karen A., Godfrey, Keith M., Nakagawa, Takashi, Moco, Sofia, Koopman, René, Lynch, Gordon S., Sorrentino, Vincenzo, Feige, Jerome N., Membrez, Mathieu, Migliavacca, Eugenia, Christen, Stefan, Yaku, Keisuke, Trieu, Jennifer, Lee, Alaina K., Morandini, Francesco, Giner, Maria Pilar, Stiner, Jade, Makarov, Mikhail V., Garratt, Emma S., Vasiloglou, Maria F., Chanvillard, Lucie, Dalbram, Emilie, Ehrlich, Amy M., Sanchez-Garcia, José Luis, Canto, Carles, Karagounis, Leonidas G., Treebak, Jonas T., Migaud, Marie E., Heshmat, Ramin, Razi, Farideh, Karnani, Neerja, Ostovar, Afshin, Farzadfar, Farshad, Tay, Stacey K.H., Sanders, Matthew J., Lillycrop, Karen A., Godfrey, Keith M., Nakagawa, Takashi, Moco, Sofia, Koopman, René, Lynch, Gordon S., Sorrentino, Vincenzo, and Feige, Jerome N.

Abstract

Mitochondrial dysfunction and low nicotinamide adenine dinucleotide (NAD+) levels are hallmarks of skeletal muscle ageing and sarcopenia1–3, but it is unclear whether these defects result from local changes or can be mediated by systemic or dietary cues. Here we report a functional link between circulating levels of the natural alkaloid trigonelline, which is structurally related to nicotinic acid4, NAD+ levels and muscle health in multiple species. In humans, serum trigonelline levels are reduced with sarcopenia and correlate positively with muscle strength and mitochondrial oxidative phosphorylation in skeletal muscle. Using naturally occurring and isotopically labelled trigonelline, we demonstrate that trigonelline incorporates into the NAD+ pool and increases NAD+ levels in Caenorhabditis elegans, mice and primary myotubes from healthy individuals and individuals with sarcopenia. Mechanistically, trigonelline does not activate GPR109A but is metabolized via the nicotinate phosphoribosyltransferase/Preiss–Handler pathway5,6 across models. In C. elegans, trigonelline improves mitochondrial respiration and biogenesis, reduces age-related muscle wasting and increases lifespan and mobility through an NAD+-dependent mechanism requiring sirtuin. Dietary trigonelline supplementation in male mice enhances muscle strength and prevents fatigue during ageing. Collectively, we identify nutritional supplementation of trigonelline as an NAD+-boosting strategy with therapeutic potential for age-associated muscle decline.

Published
2024

3. Longitudinal characterization of determinants associated with obesogenic growth patterns in early childhood

Author

Michael, Navin, Gupta, Varsha, Fogel, Anna, Huang, Jonathan, Chen, Li, Sadananthan, Suresh Anand, Ong, Yi Ying, Aris, Izzuddin M., Pang, Wei Wei, Yuan, Wen Lun, Loy, See Ling, Thway Tint, Mya, Tan, Kok Hian, Chan, Jerry Ky, Chan, Shiao-Yng, Shek, Lynette Pei-Chi, Yap, Fabian, Godfrey, Keith, Chong, Yap Seng, Gluckman, Peter, Velan, S.S., Forde, Ciarán G., Lee, Yung Seng, Eriksson, Johan G., Karnani, Neerja, Michael, Navin, Gupta, Varsha, Fogel, Anna, Huang, Jonathan, Chen, Li, Sadananthan, Suresh Anand, Ong, Yi Ying, Aris, Izzuddin M., Pang, Wei Wei, Yuan, Wen Lun, Loy, See Ling, Thway Tint, Mya, Tan, Kok Hian, Chan, Jerry Ky, Chan, Shiao-Yng, Shek, Lynette Pei-Chi, Yap, Fabian, Godfrey, Keith, Chong, Yap Seng, Gluckman, Peter, Velan, S.S., Forde, Ciarán G., Lee, Yung Seng, Eriksson, Johan G., and Karnani, Neerja

Abstract

Background: Longitudinal assessment of the determinants of obesogenic growth trajectories in childhood can suggest appropriate developmental windows for intervention.Methods: Latent class growth mixture modelling was used to identify body mass index (BMI) z-score trajectories from birth to age 6 years in 994 children from a prospective mother–offspring cohort (Chinese, Indian and Malay ethnicities) based in Singapore. We evaluated the early-life determinants of the trajectories as well as their associations with cardiometabolic risk markers at age 6 years.Results: Five BMI z-score trajectory patterns were identified, three within the healthy weight range, alongside early-acceleration and late-acceleration obesogenic trajectories. The early-acceleration pattern was characterized by elevated fetal abdominal circumference growth velocity, BMI acceleration immediately after birth and crossing of the obesity threshold by age 2 years. The late-acceleration pattern had normal fetal growth and BMI acceleration after infancy, and approached the obesity threshold by age 6 years. Abdominal fat, liver fat, insulin resistance and odds of pre-hypertension/hypertension were elevated in both groups. Indian ethnicity, high pre-pregnancy BMI, high polygenic risk scores for obesity and shorter breastfeeding duration were common risk factors for both groups. Malay ethnicity and low maternal educational attainment were uniquely associated with early BMI acceleration, whereas nulliparity and obesogenic eating behaviours in early childhood were uniquely associated with late BMI acceleration.Conclusion: BMI acceleration starting immediately after birth or after infancy were both linked to early cardiometabolic alterations. The determinants of these trajectories may be useful for developing early risk stratification and intervention approaches to counteract metabolic adversities linked to childhood obesity.

Published
2023

4. Evaluation of Stool Short Chain Fatty Acids Profiles in the First Year of Life With Childhood Atopy-Related Outcomes

Author

Cheng, Hsin Y., Chan, James C.Y., Yap, Gaik C., Huang, Chiung-Hui, Kioh, Dorinda Y.Q., Tham, Elizabeth H., Loo, Evelyn X.L., Shek, Lynette, Karnani, Neerja, Goh, Anne, van Bever, Hugo, Teoh, Oon H., Chan, Yiong H., Lay, Christophe, Knol, Jan, Yap, Fabian, Hian Tan, Kok, Chong, Yap-Seng, Godfrey, Keith M., Chan, Eric C.Y., Lee, Bee W., Ta, Le D.H., Cheng, Hsin Y., Chan, James C.Y., Yap, Gaik C., Huang, Chiung-Hui, Kioh, Dorinda Y.Q., Tham, Elizabeth H., Loo, Evelyn X.L., Shek, Lynette, Karnani, Neerja, Goh, Anne, van Bever, Hugo, Teoh, Oon H., Chan, Yiong H., Lay, Christophe, Knol, Jan, Yap, Fabian, Hian Tan, Kok, Chong, Yap-Seng, Godfrey, Keith M., Chan, Eric C.Y., Lee, Bee W., and Ta, Le D.H.

Abstract

Introduction: Short chain fatty acids (SCFAs) are the main intestinal intermediate and end products of metabolism of dietary fibers/polyphenols by the gut microbiota. The aim of this study was to evaluate the biological implication of stool SCFA profiles determined in the first year of life on the clinical presentation of allergic outcomes in childhood.Methods: From the Growing Up in Singapore Toward healthy Outcomes (GUSTO) cohort, a sub-cohort of 75 participants was recruited. Scheduled questionnaire data was collected for cumulative prevalence of physician-diagnosed eczema, wheezing with the use of nebuliser, and allergen sensitization till the age of 8 years. Stool samples collected at week 3 and months 3, 6 and 12 were quantitated for 9 SCFAs using LC/MS/MS. SCFA data were grouped into lower (below the 25th) and higher (above the 75th percentiles) categories. Generalized Linear Mixed Models was employed to analyse longitudinal association between SCFAs and atopy-related outcomes.Results: Children with lower stool butyric acid levels (≤25th percentile) over the first 3 time points had higher odds ratio (OR) for wheezing (adjOR = 14.6), eczema (adjOR = 13.2), food sensitization (adjOR = 12.3) and combined outcomes of both wheezing and eczema (adjOR = 22.6) till age 8 years, compared to those with higher levels (≥75 percentile). Additionally, lower longitudinal levels of propionic acid (≤25th percentile) over 4 time points in first year of life was associated with recurrent wheezing (≥2 episodes) till 8 years (adjOR = 7.4) (adj p < 0.05).Conclusion: Our results suggest that relatively low levels of gut SCFAs in early life are associated with increased susceptibility to atopic-related outcomes in childhood.

Published
2022

5. Cohort profile : Singapore Preconception Study of Long-Term Maternal and Child Outcomes (S-PRESTO)

Author

Loo, Evelyn Xiu Ling, Soh, Shu E., Loy, See Ling, Ng, Sharon, Tint, Mya Thway, Chan, Shiao Yng, Huang, Jonathan Yinhao, Yap, Fabian, Tan, Kok Hian, Chern, Bernard S.M., Tan, Heng Hao, Meaney, Michael J., Karnani, Neerja, Godfrey, Keith M., Lee, Yung Seng, Chan, Jerry Kok Yen, Gluckman, Peter D., Chong, Yap Seng, Shek, Lynette Pei Chi, Eriksson, Johan G., Chia, Airu, Fogel, Anna Magdalena, Goh, Anne Eng Neo, Chu, Anne Hin Yee, Rifkin-Graboi, Anne, Qiu, Anqi, Lee, Bee Wah, Cheon, Bobby Kyungbeom, Vaz, Candida, Henry, Christiani Jeyakumar, Forde, Ciaran Gerard, Chi, Claudia, Koh, Dawn Xin Ping, Phua, Desiree Y., Loh, Doris Ngiuk Lan, Quah, Elaine Phaik Ling, Tham, Elizabeth Huiwen, Law, Evelyn Chung Ning, Magkos, Faidon, Mueller-Riemenschneider, Falk, Yeo, George Seow Heong, Yong, Hannah Ee Juen, Chen, Helen Yu, Pan, Hong, van Bever, Hugo P.S., Tan, Hui Min, Aris, Izzuddin Bin Mohd, Tay, Jeannie, Xu, Jia, Yoong, Joanne Su Yin, Loo, Evelyn Xiu Ling, Soh, Shu E., Loy, See Ling, Ng, Sharon, Tint, Mya Thway, Chan, Shiao Yng, Huang, Jonathan Yinhao, Yap, Fabian, Tan, Kok Hian, Chern, Bernard S.M., Tan, Heng Hao, Meaney, Michael J., Karnani, Neerja, Godfrey, Keith M., Lee, Yung Seng, Chan, Jerry Kok Yen, Gluckman, Peter D., Chong, Yap Seng, Shek, Lynette Pei Chi, Eriksson, Johan G., Chia, Airu, Fogel, Anna Magdalena, Goh, Anne Eng Neo, Chu, Anne Hin Yee, Rifkin-Graboi, Anne, Qiu, Anqi, Lee, Bee Wah, Cheon, Bobby Kyungbeom, Vaz, Candida, Henry, Christiani Jeyakumar, Forde, Ciaran Gerard, Chi, Claudia, Koh, Dawn Xin Ping, Phua, Desiree Y., Loh, Doris Ngiuk Lan, Quah, Elaine Phaik Ling, Tham, Elizabeth Huiwen, Law, Evelyn Chung Ning, Magkos, Faidon, Mueller-Riemenschneider, Falk, Yeo, George Seow Heong, Yong, Hannah Ee Juen, Chen, Helen Yu, Pan, Hong, van Bever, Hugo P.S., Tan, Hui Min, Aris, Izzuddin Bin Mohd, Tay, Jeannie, Xu, Jia, and Yoong, Joanne Su Yin

Abstract

The Singapore Preconception Study of Long-Term Maternal and Child Outcomes (S-PRESTO) is a preconception, longitudinal cohort study that aims to study the effects of nutrition, lifestyle, and maternal mood prior to and during pregnancy on the epigenome of the offspring and clinically important outcomes including duration of gestation, fetal growth, metabolic and neural phenotypes in the offspring. Between February 2015 and October 2017, the S-PRESTO study recruited 1039 Chinese, Malay or Indian (or any combinations thereof) women aged 18–45 years and who intended to get pregnant and deliver in Singapore, resulting in 1032 unique participants and 373 children born in the cohort. The participants were followed up for 3 visits during the preconception phase and censored at 12 months of follow up if pregnancy was not achieved (N = 557 censored). Women who successfully conceived (N = 475) were characterised at gestational weeks 6–8, 11–13, 18–21, 24–26, 27–28 and 34–36. Follow up of their index offspring (N = 373 singletons) is on-going at birth, 1, 3 and 6 weeks, 3, 6, 12, 18, 24 and 36 months and beyond. Women are also being followed up post-delivery. Data is collected via interviewer-administered questionnaires, metabolic imaging (magnetic resonance imaging), standardized anthropometric measurements and collection of diverse specimens, i.e. blood, urine, buccal smear, stool, skin tapes, epithelial swabs at numerous timepoints. S-PRESTO has extensive repeated data collected which include genetic and epigenetic sampling from preconception which is unique in mother–offspring epidemiological cohorts. This enables prospective assessment of a wide array of potential determinants of future health outcomes in women from preconception to post-delivery and in their offspring across the earliest development from embryonic stages into early childhood. In addition, the S-PRESTO study draws from the three major Asian ethnic groups that represent 50% of the global population, increa

Published
2021

6. Cohort profile: Singapore Preconception Study of Long-Term Maternal and Child Outcomes (S-PRESTO)

Author

Loo, Evelyn Xiu Ling, Soh, Shu-E, Loy, See Ling, Ng, Sharon, Tint, Mya Thway, Chan, Shiao-Yng, Huang, Jonathan Yinhao, Yap, Fabian, Tan, Kok Hian, Chern, Bernard S M, Tan, Heng Hao, Meaney, Michael J, Karnani, Neerja, Godfrey, Keith M, Lee, Yung Seng, Chan, Jerry Kok Yen, Gluckman, Peter D, Chong, Yap-Seng, Shek, Lynette Pei-Chi, Eriksson, Johan G, Magkos, Faidon, Loo, Evelyn Xiu Ling, Soh, Shu-E, Loy, See Ling, Ng, Sharon, Tint, Mya Thway, Chan, Shiao-Yng, Huang, Jonathan Yinhao, Yap, Fabian, Tan, Kok Hian, Chern, Bernard S M, Tan, Heng Hao, Meaney, Michael J, Karnani, Neerja, Godfrey, Keith M, Lee, Yung Seng, Chan, Jerry Kok Yen, Gluckman, Peter D, Chong, Yap-Seng, Shek, Lynette Pei-Chi, Eriksson, Johan G, and Magkos, Faidon

Abstract

The Singapore Preconception Study of Long-Term Maternal and Child Outcomes (S-PRESTO) is a preconception, longitudinal cohort study that aims to study the effects of nutrition, lifestyle, and maternal mood prior to and during pregnancy on the epigenome of the offspring and clinically important outcomes including duration of gestation, fetal growth, metabolic and neural phenotypes in the offspring. Between February 2015 and October 2017, the S-PRESTO study recruited 1039 Chinese, Malay or Indian (or any combinations thereof) women aged 18-45 years and who intended to get pregnant and deliver in Singapore, resulting in 1032 unique participants and 373 children born in the cohort. The participants were followed up for 3 visits during the preconception phase and censored at 12 months of follow up if pregnancy was not achieved (N = 557 censored). Women who successfully conceived (N = 475) were characterised at gestational weeks 6-8, 11-13, 18-21, 24-26, 27-28 and 34-36. Follow up of their index offspring (N = 373 singletons) is on-going at birth, 1, 3 and 6 weeks, 3, 6, 12, 18, 24 and 36 months and beyond. Women are also being followed up post-delivery. Data is collected via interviewer-administered questionnaires, metabolic imaging (magnetic resonance imaging), standardized anthropometric measurements and collection of diverse specimens, i.e. blood, urine, buccal smear, stool, skin tapes, epithelial swabs at numerous timepoints. S-PRESTO has extensive repeated data collected which include genetic and epigenetic sampling from preconception which is unique in mother-offspring epidemiological cohorts. This enables prospective assessment of a wide array of potential determinants of future health outcomes in women from preconception to post-delivery and in their offspring across the earliest development from embryonic stages into early childhood. In addition, the S-PRESTO study draws from the three major Asian ethnic groups that represent 50% of the global population, inc

Published
2021

7. The PedBE clock accurately estimates DNA methylation age in pediatric buccal cells.

Author

McEwen, Lisa M, McEwen, Lisa M, O'Donnell, Kieran J, McGill, Megan G, Edgar, Rachel D, Jones, Meaghan J, MacIsaac, Julia L, Lin, David Tse Shen, Ramadori, Katia, Morin, Alexander, Gladish, Nicole, Garg, Elika, Unternaehrer, Eva, Pokhvisneva, Irina, Karnani, Neerja, Kee, Michelle ZL, Klengel, Torsten, Adler, Nancy E, Barr, Ronald G, Letourneau, Nicole, Giesbrecht, Gerald F, Reynolds, James N, Czamara, Darina, Armstrong, Jeffrey M, Essex, Marilyn J, de Weerth, Carolina, Beijers, Roseriet, Tollenaar, Marieke S, Bradley, Bekh, Jovanovic, Tanja, Ressler, Kerry J, Steiner, Meir, Entringer, Sonja, Wadhwa, Pathik D, Buss, Claudia, Bush, Nicole R, Binder, Elisabeth B, Boyce, W Thomas, Meaney, Michael J, Horvath, Steve, Kobor, Michael S, McEwen, Lisa M, McEwen, Lisa M, O'Donnell, Kieran J, McGill, Megan G, Edgar, Rachel D, Jones, Meaghan J, MacIsaac, Julia L, Lin, David Tse Shen, Ramadori, Katia, Morin, Alexander, Gladish, Nicole, Garg, Elika, Unternaehrer, Eva, Pokhvisneva, Irina, Karnani, Neerja, Kee, Michelle ZL, Klengel, Torsten, Adler, Nancy E, Barr, Ronald G, Letourneau, Nicole, Giesbrecht, Gerald F, Reynolds, James N, Czamara, Darina, Armstrong, Jeffrey M, Essex, Marilyn J, de Weerth, Carolina, Beijers, Roseriet, Tollenaar, Marieke S, Bradley, Bekh, Jovanovic, Tanja, Ressler, Kerry J, Steiner, Meir, Entringer, Sonja, Wadhwa, Pathik D, Buss, Claudia, Bush, Nicole R, Binder, Elisabeth B, Boyce, W Thomas, Meaney, Michael J, Horvath, Steve, and Kobor, Michael S

Abstract

The development of biological markers of aging has primarily focused on adult samples. Epigenetic clocks are a promising tool for measuring biological age that show impressive accuracy across most tissues and age ranges. In adults, deviations from the DNA methylation (DNAm) age prediction are correlated with several age-related phenotypes, such as mortality and frailty. In children, however, fewer such associations have been made, possibly because DNAm changes are more dynamic in pediatric populations as compared to adults. To address this gap, we aimed to develop a highly accurate, noninvasive, biological measure of age specific to pediatric samples using buccal epithelial cell DNAm. We gathered 1,721 genome-wide DNAm profiles from 11 different cohorts of typically developing individuals aged 0 to 20 y old. Elastic net penalized regression was used to select 94 CpG sites from a training dataset (n = 1,032), with performance assessed in a separate test dataset (n = 689). DNAm at these 94 CpG sites was highly predictive of age in the test cohort (median absolute error = 0.35 y). The Pediatric-Buccal-Epigenetic (PedBE) clock was characterized in additional cohorts, showcasing the accuracy in longitudinal data, the performance in nonbuccal tissues and adult age ranges, and the association with obstetric outcomes. The PedBE tool for measuring biological age in children might help in understanding the environmental and contextual factors that shape the DNA methylome during child development, and how it, in turn, might relate to child health and disease.

Published
2020

8. Maternal plasma metabolic markers of neonatal adiposity and associated maternal characteristics:The GUSTO study

Author

Chia, Ai-Ru, de Seymour, Jamie, Wong, Gerard, Sulek, Karolina, Han, Ting-Li, McKenzie, Elizabeth J., Aris, Izzuddin M., Godfrey, Keith M., Yap, Fabian, Tan, Kok Hian, Shek, Lynette Pei-Chi, Lee, Yung Seng, Kramer, Michael S., Karnani, Neerja, Chong, Mary Foong-Fong, Baker, Philip N., Chia, Ai-Ru, de Seymour, Jamie, Wong, Gerard, Sulek, Karolina, Han, Ting-Li, McKenzie, Elizabeth J., Aris, Izzuddin M., Godfrey, Keith M., Yap, Fabian, Tan, Kok Hian, Shek, Lynette Pei-Chi, Lee, Yung Seng, Kramer, Michael S., Karnani, Neerja, Chong, Mary Foong-Fong, and Baker, Philip N.

Abstract

Infant adiposity may be related to later metabolic health. Maternal metabolite profiling reflects both genetic and environmental influences and allows elucidation of metabolic pathways associated with infant adiposity. In this multi-ethnic Asian cohort, we aimed to (i) identify maternal plasma metabolites associated with infant adiposity and other birth outcomes and (ii) investigate the maternal characteristics associated with those metabolites. In 940 mother-offspring pairs, we performed gas chromatography-mass spectrometry and identified 134 metabolites in maternal fasting plasma at 26-28 weeks of gestation. At birth, neonatal triceps and subscapular skinfold thicknesses were measured by trained research personnel, while weight and length measures were abstracted from delivery records. Gestational age was estimated from first-trimester dating ultrasound. Associations were assessed by multivariable linear regression, with p-values corrected using the Benjamini-Hochberg approach. At a false discovery rate of 5%, we observed associations between 28 metabolites and neonatal sum of skinfold thicknesses (13 amino acid-related, 4 non-esterified fatty acids, 6 xenobiotics, and 5 unknown compounds). Few associations were observed with gestational duration, birth weight, or birth length. Maternal ethnicity, pre-pregnancy BMI, and diet quality during pregnancy had the strongest associations with the specific metabolome related to infant adiposity. Further studies are warranted to replicate our findings and to understand the underlying mechanisms.

Published
2020

9. Maternal plasma metabolic markers of neonatal adiposity and associated maternal characteristics:The GUSTO study

Author

Chia, Ai-Ru, de Seymour, Jamie, Wong, Gerard, Sulek, Karolina, Han, Ting-Li, McKenzie, Elizabeth J., Aris, Izzuddin M., Godfrey, Keith M., Yap, Fabian, Tan, Kok Hian, Shek, Lynette Pei-Chi, Lee, Yung Seng, Kramer, Michael S., Karnani, Neerja, Chong, Mary Foong-Fong, Baker, Philip N., Chia, Ai-Ru, de Seymour, Jamie, Wong, Gerard, Sulek, Karolina, Han, Ting-Li, McKenzie, Elizabeth J., Aris, Izzuddin M., Godfrey, Keith M., Yap, Fabian, Tan, Kok Hian, Shek, Lynette Pei-Chi, Lee, Yung Seng, Kramer, Michael S., Karnani, Neerja, Chong, Mary Foong-Fong, and Baker, Philip N.

Abstract

Infant adiposity may be related to later metabolic health. Maternal metabolite profiling reflects both genetic and environmental influences and allows elucidation of metabolic pathways associated with infant adiposity. In this multi-ethnic Asian cohort, we aimed to (i) identify maternal plasma metabolites associated with infant adiposity and other birth outcomes and (ii) investigate the maternal characteristics associated with those metabolites. In 940 mother-offspring pairs, we performed gas chromatography-mass spectrometry and identified 134 metabolites in maternal fasting plasma at 26-28 weeks of gestation. At birth, neonatal triceps and subscapular skinfold thicknesses were measured by trained research personnel, while weight and length measures were abstracted from delivery records. Gestational age was estimated from first-trimester dating ultrasound. Associations were assessed by multivariable linear regression, with p-values corrected using the Benjamini-Hochberg approach. At a false discovery rate of 5%, we observed associations between 28 metabolites and neonatal sum of skinfold thicknesses (13 amino acid-related, 4 non-esterified fatty acids, 6 xenobiotics, and 5 unknown compounds). Few associations were observed with gestational duration, birth weight, or birth length. Maternal ethnicity, pre-pregnancy BMI, and diet quality during pregnancy had the strongest associations with the specific metabolome related to infant adiposity. Further studies are warranted to replicate our findings and to understand the underlying mechanisms.

Published
2020

10. A compromised developmental trajectory of the infant gut microbiome and metabolome in atopic eczema

Author

Ta, Le Duc Huy, Chan, James Chun Yip, Yap, Gaik Chin, Purbojati, Rikky W., Drautz-Moses, Daniela I., Koh, Yanqing Michelle, Tay, Carina Jing Xuan, Huang, Chiung Hui, Kioh, Dorinda Yan Qin, Woon, Jia Yun, Tham, Elizabeth Huiwen, Loo, Evelyn Xiu Ling, Shek, Lynette P.C., Karnani, Neerja, Goh, Anne, Van Bever, Hugo P.S., Teoh, Oon Hoe, Chan, Yiong Huak, Lay, Christophe, Knol, Jan, Yap, Fabian, Tan, Kok Hian, Chong, Yap Seng, Godfrey, Keith M., Kjelleberg, Staffan, Schuster, Stephan C., Chan, Eric Chun Yong, Lee, Bee Wah, Ta, Le Duc Huy, Chan, James Chun Yip, Yap, Gaik Chin, Purbojati, Rikky W., Drautz-Moses, Daniela I., Koh, Yanqing Michelle, Tay, Carina Jing Xuan, Huang, Chiung Hui, Kioh, Dorinda Yan Qin, Woon, Jia Yun, Tham, Elizabeth Huiwen, Loo, Evelyn Xiu Ling, Shek, Lynette P.C., Karnani, Neerja, Goh, Anne, Van Bever, Hugo P.S., Teoh, Oon Hoe, Chan, Yiong Huak, Lay, Christophe, Knol, Jan, Yap, Fabian, Tan, Kok Hian, Chong, Yap Seng, Godfrey, Keith M., Kjelleberg, Staffan, Schuster, Stephan C., Chan, Eric Chun Yong, and Lee, Bee Wah

Abstract

Evidence is accumulating that the establishment of the gut microbiome in early life influences the development of atopic eczema. In this longitudinal study, we used integrated multi-omics analyses to infer functional mechanisms by which the microbiome modulates atopic eczema risk. We measured the functionality of the gut microbiome and metabolome of 63 infants between ages 3 weeks and 12 months with well-defined eczema cases and controls in a sub-cohort from the Growing Up in Singapore Toward healthy Outcomes (GUSTO) mother-offspring cohort. At 3 weeks, the microbiome and metabolome of allergen-sensitized atopic eczema infants were characterized by an enrichment of Escherichia coli and Klebsiella pneumoniae, associated with increased stool D-glucose concentration and increased gene expression of associated virulence factors. A delayed colonization by beneficial Bacteroides fragilis and subsequent delayed accumulation of butyrate and propionate producers after 3 months was also observed. Here, we describe an aberrant developmental trajectory of the gut microbiome and stool metabolome in allergen sensitized atopic eczema infants. The infographic describes an impaired developmental trajectory of the gut microbiome and metabolome in allergen-sensitized atopic eczema (AE) infants and infer its contribution in modulating allergy risk in the Singaporean mother-offspring GUSTO cohort. The key microbial signature of AE is characterized by (1) an enrichment of Escherichia coli and Klebsiella pneumoniae which are associated with accumulation of pre-glycolysis intermediates (D-glucose) via the trehalose metabolic pathway, increased gene expression of associated virulence factors (invasin, adhesin, flagellin and lipopolysaccharides) by utilizing ATP from oxidative phosphorylation and delayed production of butyrate and propionate, (2) depletion of Bacteroides fragilis which resulted in lower expression of immunostimulatory bacterial cell envelope structure and folate (vitamin B9)

Published
2020

11. Large-Scale Whole-Genome Sequencing of Three Diverse Asian Populations in Singapore

Author

Wu, Degang, Dou, Jinzhuang, Chai, Xiaoran, Bellis, Claire, Wilm, Andreas, Shih, Chih Chuan, Soon, Wendy Wei Jia, Bertin, Nicolas, Lin, Clarabelle Bitong, Khor, Chiea Chuen, DeGiorgio, Michael, Cheng, Shanshan, Bao, Li, Karnani, Neerja, Hwang, William Ying Khee, Davila, Sonia, Tan, Patrick, Shabbir, Asim, Moh, Angela, Tan, Eng King, Foo, Jia Nee, Goh, Liuh Ling, Leong, Khai Pang, Foo, Roger S.Y., Lam, Carolyn Su Ping, Richards, Arthur Mark, Cheng, Ching Yu, Aung, Tin, Wong, Tien Yin, Ng, Huck Hui, Ackers-Johnson, Matthew Andrew, Aliwarga, Edita, Ban, Kenneth Hon Kim, Bertrand, Denis, Chambers, John C., Chan, Dana Leng Hui, Chan, Cheryl Xue Li, Chee, Miao Li, Chee, Miao Ling, Chen, Pauline, Chen, Yunxin, Chew, Elaine Guo Yan, Chew, Wen Jie, Chiam, Lynn Hui Yun, Chong, Jenny Pek Ching, Chua, Ivan, Cook, Stuart A., Dai, Wei, Dorajoo, Rajkumar, Foo, Chuan Sheng, Goh, Rick Siow Mong, Hillmer, Axel M., Irwan, Ishak D., Jaufeerally, Fazlur, Javed, Asif, Jeyakani, Justin, Koh, John Tat Hung, Koh, Jia Yu, Krishnaswamy, Pavitra, Kuan, Jyn Ling, Kumari, Neelam, Lee, Ai Shan, Lee, Seow Eng, Lee, Sheldon, Lee, Yen Ling, Leong, See Ting, Li, Zheng, Li, Peter Yiqing, Liew, Jun Xian, Liew, Oi Wah, Lim, Su Chi, Lim, Weng Khong, Lim, Chia Wei, Lim, Tingsen Benson, Lim, Choon Kiat, Loh, Seet Yoong, Lok, Au Wing, Chin, Calvin W.L., Majithia, Shivani, Maurer-Stroh, Sebastian, Meah, Wee Yang, Mok, Shi Qi, Nargarajan, Niranjan, Ng, Pauline, Ng, Sarah B., Ng, Zhenyuan, Ng, Jessica Yan Xia, Ng, Ebonne, Ng, Shi Ling, Nusinovici, Simon, Ong, Chin Thing, Pan, Bangfen, Pedergnana, Vincent, Poh, Stanley, Prabhakar, Shyam, Prakash, Kumar M., Quek, Ivy, Sabanayagam, Charumathi, See, Wei Qiang, Sia, Yee Yen, Sim, Xueling, Sim, Wey Cheng, So, Jimmy, Soon, Dinna K.N., Tai, E. Shyong, Tan, Nicholas Y., Tan, Louis C.S., Tan, Hong Chang, Tan, Wilson Lek Wen, Tandiono, Moses, Tay, Amanda, Thakur, Sahil, Tham, Yih Chung, Tiang, Zenia, Toh, Grace Li Xian, Tsai, Pi Kuang, Veeravalli, Lavanya, Verma, Chandra S., Wang, Ling, Wang, Min Rui, Wong, Wing Cheong, Xie, Zhicheng, Yeo, Khung Keong, Zhang, Liang, Zhai, Weiwei, Zhao, Yi, Liu, Jianjun, Wang, Chaolong, other, and, Wu, Degang, Dou, Jinzhuang, Chai, Xiaoran, Bellis, Claire, Wilm, Andreas, Shih, Chih Chuan, Soon, Wendy Wei Jia, Bertin, Nicolas, Lin, Clarabelle Bitong, Khor, Chiea Chuen, DeGiorgio, Michael, Cheng, Shanshan, Bao, Li, Karnani, Neerja, Hwang, William Ying Khee, Davila, Sonia, Tan, Patrick, Shabbir, Asim, Moh, Angela, Tan, Eng King, Foo, Jia Nee, Goh, Liuh Ling, Leong, Khai Pang, Foo, Roger S.Y., Lam, Carolyn Su Ping, Richards, Arthur Mark, Cheng, Ching Yu, Aung, Tin, Wong, Tien Yin, Ng, Huck Hui, Ackers-Johnson, Matthew Andrew, Aliwarga, Edita, Ban, Kenneth Hon Kim, Bertrand, Denis, Chambers, John C., Chan, Dana Leng Hui, Chan, Cheryl Xue Li, Chee, Miao Li, Chee, Miao Ling, Chen, Pauline, Chen, Yunxin, Chew, Elaine Guo Yan, Chew, Wen Jie, Chiam, Lynn Hui Yun, Chong, Jenny Pek Ching, Chua, Ivan, Cook, Stuart A., Dai, Wei, Dorajoo, Rajkumar, Foo, Chuan Sheng, Goh, Rick Siow Mong, Hillmer, Axel M., Irwan, Ishak D., Jaufeerally, Fazlur, Javed, Asif, Jeyakani, Justin, Koh, John Tat Hung, Koh, Jia Yu, Krishnaswamy, Pavitra, Kuan, Jyn Ling, Kumari, Neelam, Lee, Ai Shan, Lee, Seow Eng, Lee, Sheldon, Lee, Yen Ling, Leong, See Ting, Li, Zheng, Li, Peter Yiqing, Liew, Jun Xian, Liew, Oi Wah, Lim, Su Chi, Lim, Weng Khong, Lim, Chia Wei, Lim, Tingsen Benson, Lim, Choon Kiat, Loh, Seet Yoong, Lok, Au Wing, Chin, Calvin W.L., Majithia, Shivani, Maurer-Stroh, Sebastian, Meah, Wee Yang, Mok, Shi Qi, Nargarajan, Niranjan, Ng, Pauline, Ng, Sarah B., Ng, Zhenyuan, Ng, Jessica Yan Xia, Ng, Ebonne, Ng, Shi Ling, Nusinovici, Simon, Ong, Chin Thing, Pan, Bangfen, Pedergnana, Vincent, Poh, Stanley, Prabhakar, Shyam, Prakash, Kumar M., Quek, Ivy, Sabanayagam, Charumathi, See, Wei Qiang, Sia, Yee Yen, Sim, Xueling, Sim, Wey Cheng, So, Jimmy, Soon, Dinna K.N., Tai, E. Shyong, Tan, Nicholas Y., Tan, Louis C.S., Tan, Hong Chang, Tan, Wilson Lek Wen, Tandiono, Moses, Tay, Amanda, Thakur, Sahil, Tham, Yih Chung, Tiang, Zenia, Toh, Grace Li Xian, Tsai, Pi Kuang, Veeravalli, Lavanya, Verma, Chandra S., Wang, Ling, Wang, Min Rui, Wong, Wing Cheong, Xie, Zhicheng, Yeo, Khung Keong, Zhang, Liang, Zhai, Weiwei, Zhao, Yi, Liu, Jianjun, Wang, Chaolong, and other, and

Abstract

Because of Singapore's unique history of immigration, whole-genome sequence analysis of 4,810 Singaporeans provides a snapshot of the genetic diversity across East, Southeast, and South Asia.

Published
2019

12. Optimizing drug combinations against multiple myeloma using a quadratic phenotypic optimization platform (QPOP).

Author

Rashid, Masturah Bte Mohd Abdul, Rashid, Masturah Bte Mohd Abdul, Toh, Tan Boon, Hooi, Lissa, Silva, Aleidy, Zhang, Yanzhou, Tan, Pei Fang, Teh, Ai Ling, Karnani, Neerja, Jha, Sudhakar, Ho, Chih-Ming, Chng, Wee Joo, Ho, Dean, Chow, Edward Kai-Hua, Rashid, Masturah Bte Mohd Abdul, Rashid, Masturah Bte Mohd Abdul, Toh, Tan Boon, Hooi, Lissa, Silva, Aleidy, Zhang, Yanzhou, Tan, Pei Fang, Teh, Ai Ling, Karnani, Neerja, Jha, Sudhakar, Ho, Chih-Ming, Chng, Wee Joo, Ho, Dean, and Chow, Edward Kai-Hua

Abstract

Multiple myeloma is an incurable hematological malignancy that relies on drug combinations for first and secondary lines of treatment. The inclusion of proteasome inhibitors, such as bortezomib, into these combination regimens has improved median survival. Resistance to bortezomib, however, is a common occurrence that ultimately contributes to treatment failure, and there remains a need to identify improved drug combinations. We developed the quadratic phenotypic optimization platform (QPOP) to optimize treatment combinations selected from a candidate pool of 114 approved drugs. QPOP uses quadratic surfaces to model the biological effects of drug combinations to identify effective drug combinations without reference to molecular mechanisms or predetermined drug synergy data. Applying QPOP to bortezomib-resistant multiple myeloma cell lines determined the drug combinations that collectively optimized treatment efficacy. We found that these combinations acted by reversing the DNA methylation and tumor suppressor silencing that often occur after acquired bortezomib resistance in multiple myeloma. Successive application of QPOP on a xenograft mouse model further optimized the dosages of each drug within a given combination while minimizing overall toxicity in vivo, and application of QPOP to ex vivo multiple myeloma patient samples optimized drug combinations in patient-specific contexts.

Published
2018

13. Optimizing drug combinations against multiple myeloma using a quadratic phenotypic optimization platform (QPOP).

Author

Rashid, Masturah Bte Mohd Abdul, Rashid, Masturah Bte Mohd Abdul, Toh, Tan Boon, Hooi, Lissa, Silva, Aleidy, Zhang, Yanzhou, Tan, Pei Fang, Teh, Ai Ling, Karnani, Neerja, Jha, Sudhakar, Ho, Chih-Ming, Chng, Wee Joo, Ho, Dean, Chow, Edward Kai-Hua, Rashid, Masturah Bte Mohd Abdul, Rashid, Masturah Bte Mohd Abdul, Toh, Tan Boon, Hooi, Lissa, Silva, Aleidy, Zhang, Yanzhou, Tan, Pei Fang, Teh, Ai Ling, Karnani, Neerja, Jha, Sudhakar, Ho, Chih-Ming, Chng, Wee Joo, Ho, Dean, and Chow, Edward Kai-Hua

Abstract

Multiple myeloma is an incurable hematological malignancy that relies on drug combinations for first and secondary lines of treatment. The inclusion of proteasome inhibitors, such as bortezomib, into these combination regimens has improved median survival. Resistance to bortezomib, however, is a common occurrence that ultimately contributes to treatment failure, and there remains a need to identify improved drug combinations. We developed the quadratic phenotypic optimization platform (QPOP) to optimize treatment combinations selected from a candidate pool of 114 approved drugs. QPOP uses quadratic surfaces to model the biological effects of drug combinations to identify effective drug combinations without reference to molecular mechanisms or predetermined drug synergy data. Applying QPOP to bortezomib-resistant multiple myeloma cell lines determined the drug combinations that collectively optimized treatment efficacy. We found that these combinations acted by reversing the DNA methylation and tumor suppressor silencing that often occur after acquired bortezomib resistance in multiple myeloma. Successive application of QPOP on a xenograft mouse model further optimized the dosages of each drug within a given combination while minimizing overall toxicity in vivo, and application of QPOP to ex vivo multiple myeloma patient samples optimized drug combinations in patient-specific contexts.

Published
2018

14. Effects of Antenatal Maternal Depressive Symptoms and Socio-Economic Status on Neonatal Brain Development are Modulated by Genetic Risk.

Author

Qiu, Anqi, Qiu, Anqi, Shen, Mojun, Buss, Claudia, Chong, Yap-Seng, Kwek, Kenneth, Saw, Seang-Mei, Gluckman, Peter D, Wadhwa, Pathik D, Entringer, Sonja, Styner, Martin, Karnani, Neerja, Heim, Christine M, O'Donnell, Kieran J, Holbrook, Joanna D, Fortier, Marielle V, Meaney, Michael J, the GUSTO study group, Qiu, Anqi, Qiu, Anqi, Shen, Mojun, Buss, Claudia, Chong, Yap-Seng, Kwek, Kenneth, Saw, Seang-Mei, Gluckman, Peter D, Wadhwa, Pathik D, Entringer, Sonja, Styner, Martin, Karnani, Neerja, Heim, Christine M, O'Donnell, Kieran J, Holbrook, Joanna D, Fortier, Marielle V, Meaney, Michael J, and the GUSTO study group

Abstract

This study included 168 and 85 mother-infant dyads from Asian and United States of America cohorts to examine whether a genomic profile risk score for major depressive disorder (GPRSMDD) moderates the association between antenatal maternal depressive symptoms (or socio-economic status, SES) and fetal neurodevelopment, and to identify candidate biological processes underlying such association. Both cohorts showed a significant interaction between antenatal maternal depressive symptoms and infant GPRSMDD on the right amygdala volume. The Asian cohort also showed such interaction on the right hippocampal volume and shape, thickness of the orbitofrontal and ventromedial prefrontal cortex. Likewise, a significant interaction between SES and infant GPRSMDD was on the right amygdala and hippocampal volumes and shapes. After controlling for each other, the interaction effect of antenatal maternal depressive symptoms and GPRSMDD was mainly shown on the right amygdala, while the interaction effect of SES and GPRSMDD was mainly shown on the right hippocampus. Bioinformatic analyses suggested neurotransmitter/neurotrophic signaling, SNAp REceptor complex, and glutamate receptor activity as common biological processes underlying the influence of antenatal maternal depressive symptoms on fetal cortico-limbic development. These findings suggest gene-environment interdependence in the fetal development of brain regions implicated in cognitive-emotional function. Candidate biological mechanisms involve a range of brain region-specific signaling pathways that converge on common processes of synaptic development.

Published
2017

15. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project

Author

Birney, Ewan, Stamatoyannopoulos, John A., Dutta, Anindya, Guigó, Roderic, Gingeras, Thomas R., Margulies, Elliott H., Weng, Zhiping, Snyder, Michael, Dermitzakis, Emmanouil T., Thurman, Robert E., Kuehn, Michael S., Taylor, Christopher M., Neph, Shane, Koch, Christoph M., Asthana, Saurabh, Malhotra, Ankit, Adzhubei, Ivan, Greenbaum, Jason A., Andrews, Robert M., Flicek, Paul, Boyle, Patrick J., Cao, Hua, Carter, Nigel P., Clelland, Gayle K., Davis, Sean, Day, Nathan, Dhami, Pawandeep, Dillon, Shane C., Dorschner, Michael O., Fiegler, Heike, Giresi, Paul G., Goldy, Jeff, Hawrylycz, Michael, Haydock, Andrew, Humbert, Richard, James, Keith D., Johnson, Brett E., Johnson, Ericka M., Frum, Tristan T., Rosenzweig, Elizabeth R., Karnani, Neerja, Lee, Kirsten, Lefebvre, Gregory C., Navas, Patrick A., Neri, Fidencio, Parker, Stephen C., Sabo, Peter J., Sandstrom, Richard, Shafer, Anthony, Vetrie, David, Weaver, Molly, Wilcox, Sarah, Yu, Man, Collins, Francis S., Dekker, Job, Lieb, Jason D., Tullius, Thomas D., Crawford, Gregory E., Sunyaev, Shamil, Noble, William S., Dunham, Ian, Denoeud, France, Reymond, Alexandre, Kapranov, Philipp, Rozowsky, Joel, Zheng, Deyou, Castelo, Robert, Frankish, Adam, Harrow, Jennifer, Ghosh, Srinka, Sandelin, Albin, Hofacker, Ivo L., Baertsch, Robert, Keefe, Damian, Dike, Sujit, Cheng, Jill, Hirsch, Heather A., Sekinger, Edward A., Lagarde, Julien, Abril, Josep F., Shahab, Atif, Flamm, Christoph, Fried, Claudia, Hackermüller, Jörg, Hertel, Jana, Lindemeyer, Manja, Missal, Kristin, Tanzer, Andrea, Washietl, Stefan, Korbel, Jan, Emanuelsson, Olof, Pedersen, Jakob S., Holroyd, Nancy, Taylor, Ruth, Swarbreck, David, Matthews, Nicholas, Dickson, Mark C., Thomas, Daryl J., Weirauch, Matthew T., Gilbert, James, Drenkow, Jorg, Bell, Ian, Zhao, XiaoDong, Srinivasan, K. G., Sung, Wing-Kin, Ooi, Hong Sain, Chiu, Kuo Ping, Foissac, Sylvain, Alioto, Tyler, Brent, Michael, Pachter, Lior, Tress, Michael L., Valencia, Alfonso, Choo, Siew Woh, Choo, Chiou Yu, Ucla, Catherine, Manzano, Caroline, Wyss, Carine, Cheung, Evelyn, Clark, Taane G., Brown, James B., Ganesh, Madhavan, Patel, Sandeep, Tammana, Hari, Chrast, Jacqueline, Henrichsen, Charlotte N., Kai, Chikatoshi, Kawai, Jun, Nagalakshmi, Ugrappa, Wu, Jiaqian, Lian, Zheng, Lian, Jin, Newburger, Peter, Zhang, Xueqing, Bickel, Peter, Mattick, John S., Carninci, Piero, Hayashizaki, Yoshihide, Weissman, Sherman, Hubbard, Tim, Myers, Richard M., Rogers, Jane, Stadler, Peter F., Lowe, Todd M., Wei, Chia-Lin, Ruan, Yijun, Struhl, Kevin, Gerstein, Mark, Antonarakis, Stylianos E., Fu, Yutao, Green, Eric D., Karaöz, U., Siepel, Adam, Taylor, James, Liefer, Laura A, Wetterstrand, Kris A., Good, Peter J., Feingold, Elise A., Guyer, Mark S., Cooper, Gregory M., Asimenos, George, Dewey, Colin N., Hou, Minmei, Nikolaev, Sergey, Montoya-Burgos, Juan I., Löytynoja, Ari, Whelan, Simon, Pardi, Fabio, Massingham, Tim, Huang, Haiyan, Zhang, Nancy R., Holmes, Ian, Mullikin, James C., Ureta-Vidal, Abel, Paten, Benedict, Seringhaus, Michael, Church, Deanna, Rosenbloom, Kate, Kent, W. James, Stone, Eric A., Batzoglou, Serafim, Goldman, Nick, Hardison, Ross C., Haussler, David, Miller, Webb, Sidow, Arend, Trinklein, Nathan D., Zhang, Zhengdong D., Barrera, Leah, Stuart, Rhona, King, David C., Ameur, Adam, Enroth, Stefan, Bieda, Mark C., Kim, Jonghwan, Bhinge, Akshay A., Jiang, Nan, Liu, Jun, Yao, Fei, Vega, Vinsensius B., Lee, Charlie W., Ng, Patrick, Yang, Annie, Moqtaderi, Zarmik, Zhu, Zhou, Xu, Xiaoqin, Squazzo, Sharon, Oberley, Matthew J., Inman, David, Singer, Michael A., Richmond, Todd A., Munn, Kyle J., Rada-Iglesias, Alvaro, Wallerman, Ola, Komorowski, Jan, Fowler, Joanna C., Couttet, Phillippe, Bruce, Alexander W., Dovey, Oliver M., Ellis, Peter D., Langford, Cordelia F., Nix, David A., Euskirchen, Ghia, Hartman, Stephen, Urban, Alexander E., Kraus, Peter, Van Calcar, Sara, Heintzman, Nate, Kim, Tae Hoon, Wang, Kun, Qu, Chunxu, Hon, Gary, Luna, Rosa, Glass, Christopher K., Rosenfeld, M. Geoff, Aldred, Shelley Force, Cooper, Sara J., Halees, Anason, Lin, Jane M., Shulha, Hennady P., Zhang, Xiaoling, Xu, Mousheng, Haidar, Jaafar N., Yu, Yong, Iyer, Vishwanath R., Green, Roland D., Wadelius, Claes, Farnham, Peggy J., Ren, Bing, Harte, Rachel A., Hinrichs, Angie S., Trumbower, Heather, Clawson, Hiram, Hillman-Jackson, Jennifer, Zweig, Ann S., Smith, Kayla, Thakkapallayil, Archana, Barber, Galt, Kuhn, Robert M., Karolchik, Donna, Armengol, Lluis, Bird, Christine P., de Bakker, Paul I., Kern, Andrew D., Lopez-Bigas, Nuria, Martin, Joel D., Stranger, Barbara E., Woodroffe, Abigail, Davydov, Eugene, Dimas, Antigone, Eyras, Eduardo, Hallgrí­msdóttir, Ingileif B., Huppert, Julian, Zody, Michael C., Abecasis, G. R., Estivill, Xavier, Bouffard, Gerard G., Guan, Xiaobin, Hansen, Nancy F., Idol, Jacquelyn R., Maduro, Valerie V., Maskeri, Baishali, McDowell, Jennifer C., Park, Morgan, Thomas, Pamela J., Young, Alice C., Blakesley, Robert W., Muzny, Donna M., Sodergren, Erica, Wheeler, David A., Worley, Kim C., Jiang, Huaiyang, Weinstock, George M., Gibbs, Richard A., Graves, Tina, Fulton, Robert, Mardis, Elaine R., Wilson, Richard K., Clamp, Michele, Cuff, James, Gnerre, Sante, Jaffe, David B., Chang, Jean L., Lindblad-Toh, Kerstin, Lander, Eric S., Koriabine, Maxim, Nefedov, Mikhail, Osoegawa, Kazutoyo, Yoshinaga, Yuko, Zhu, Baoli, de Jong, Pieter J., Birney, Ewan, Stamatoyannopoulos, John A., Dutta, Anindya, Guigó, Roderic, Gingeras, Thomas R., Margulies, Elliott H., Weng, Zhiping, Snyder, Michael, Dermitzakis, Emmanouil T., Thurman, Robert E., Kuehn, Michael S., Taylor, Christopher M., Neph, Shane, Koch, Christoph M., Asthana, Saurabh, Malhotra, Ankit, Adzhubei, Ivan, Greenbaum, Jason A., Andrews, Robert M., Flicek, Paul, Boyle, Patrick J., Cao, Hua, Carter, Nigel P., Clelland, Gayle K., Davis, Sean, Day, Nathan, Dhami, Pawandeep, Dillon, Shane C., Dorschner, Michael O., Fiegler, Heike, Giresi, Paul G., Goldy, Jeff, Hawrylycz, Michael, Haydock, Andrew, Humbert, Richard, James, Keith D., Johnson, Brett E., Johnson, Ericka M., Frum, Tristan T., Rosenzweig, Elizabeth R., Karnani, Neerja, Lee, Kirsten, Lefebvre, Gregory C., Navas, Patrick A., Neri, Fidencio, Parker, Stephen C., Sabo, Peter J., Sandstrom, Richard, Shafer, Anthony, Vetrie, David, Weaver, Molly, Wilcox, Sarah, Yu, Man, Collins, Francis S., Dekker, Job, Lieb, Jason D., Tullius, Thomas D., Crawford, Gregory E., Sunyaev, Shamil, Noble, William S., Dunham, Ian, Denoeud, France, Reymond, Alexandre, Kapranov, Philipp, Rozowsky, Joel, Zheng, Deyou, Castelo, Robert, Frankish, Adam, Harrow, Jennifer, Ghosh, Srinka, Sandelin, Albin, Hofacker, Ivo L., Baertsch, Robert, Keefe, Damian, Dike, Sujit, Cheng, Jill, Hirsch, Heather A., Sekinger, Edward A., Lagarde, Julien, Abril, Josep F., Shahab, Atif, Flamm, Christoph, Fried, Claudia, Hackermüller, Jörg, Hertel, Jana, Lindemeyer, Manja, Missal, Kristin, Tanzer, Andrea, Washietl, Stefan, Korbel, Jan, Emanuelsson, Olof, Pedersen, Jakob S., Holroyd, Nancy, Taylor, Ruth, Swarbreck, David, Matthews, Nicholas, Dickson, Mark C., Thomas, Daryl J., Weirauch, Matthew T., Gilbert, James, Drenkow, Jorg, Bell, Ian, Zhao, XiaoDong, Srinivasan, K. G., Sung, Wing-Kin, Ooi, Hong Sain, Chiu, Kuo Ping, Foissac, Sylvain, Alioto, Tyler, Brent, Michael, Pachter, Lior, Tress, Michael L., Valencia, Alfonso, Choo, Siew Woh, Choo, Chiou Yu, Ucla, Catherine, Manzano, Caroline, Wyss, Carine, Cheung, Evelyn, Clark, Taane G., Brown, James B., Ganesh, Madhavan, Patel, Sandeep, Tammana, Hari, Chrast, Jacqueline, Henrichsen, Charlotte N., Kai, Chikatoshi, Kawai, Jun, Nagalakshmi, Ugrappa, Wu, Jiaqian, Lian, Zheng, Lian, Jin, Newburger, Peter, Zhang, Xueqing, Bickel, Peter, Mattick, John S., Carninci, Piero, Hayashizaki, Yoshihide, Weissman, Sherman, Hubbard, Tim, Myers, Richard M., Rogers, Jane, Stadler, Peter F., Lowe, Todd M., Wei, Chia-Lin, Ruan, Yijun, Struhl, Kevin, Gerstein, Mark, Antonarakis, Stylianos E., Fu, Yutao, Green, Eric D., Karaöz, U., Siepel, Adam, Taylor, James, Liefer, Laura A, Wetterstrand, Kris A., Good, Peter J., Feingold, Elise A., Guyer, Mark S., Cooper, Gregory M., Asimenos, George, Dewey, Colin N., Hou, Minmei, Nikolaev, Sergey, Montoya-Burgos, Juan I., Löytynoja, Ari, Whelan, Simon, Pardi, Fabio, Massingham, Tim, Huang, Haiyan, Zhang, Nancy R., Holmes, Ian, Mullikin, James C., Ureta-Vidal, Abel, Paten, Benedict, Seringhaus, Michael, Church, Deanna, Rosenbloom, Kate, Kent, W. James, Stone, Eric A., Batzoglou, Serafim, Goldman, Nick, Hardison, Ross C., Haussler, David, Miller, Webb, Sidow, Arend, Trinklein, Nathan D., Zhang, Zhengdong D., Barrera, Leah, Stuart, Rhona, King, David C., Ameur, Adam, Enroth, Stefan, Bieda, Mark C., Kim, Jonghwan, Bhinge, Akshay A., Jiang, Nan, Liu, Jun, Yao, Fei, Vega, Vinsensius B., Lee, Charlie W., Ng, Patrick, Yang, Annie, Moqtaderi, Zarmik, Zhu, Zhou, Xu, Xiaoqin, Squazzo, Sharon, Oberley, Matthew J., Inman, David, Singer, Michael A., Richmond, Todd A., Munn, Kyle J., Rada-Iglesias, Alvaro, Wallerman, Ola, Komorowski, Jan, Fowler, Joanna C., Couttet, Phillippe, Bruce, Alexander W., Dovey, Oliver M., Ellis, Peter D., Langford, Cordelia F., Nix, David A., Euskirchen, Ghia, Hartman, Stephen, Urban, Alexander E., Kraus, Peter, Van Calcar, Sara, Heintzman, Nate, Kim, Tae Hoon, Wang, Kun, Qu, Chunxu, Hon, Gary, Luna, Rosa, Glass, Christopher K., Rosenfeld, M. Geoff, Aldred, Shelley Force, Cooper, Sara J., Halees, Anason, Lin, Jane M., Shulha, Hennady P., Zhang, Xiaoling, Xu, Mousheng, Haidar, Jaafar N., Yu, Yong, Iyer, Vishwanath R., Green, Roland D., Wadelius, Claes, Farnham, Peggy J., Ren, Bing, Harte, Rachel A., Hinrichs, Angie S., Trumbower, Heather, Clawson, Hiram, Hillman-Jackson, Jennifer, Zweig, Ann S., Smith, Kayla, Thakkapallayil, Archana, Barber, Galt, Kuhn, Robert M., Karolchik, Donna, Armengol, Lluis, Bird, Christine P., de Bakker, Paul I., Kern, Andrew D., Lopez-Bigas, Nuria, Martin, Joel D., Stranger, Barbara E., Woodroffe, Abigail, Davydov, Eugene, Dimas, Antigone, Eyras, Eduardo, Hallgrí­msdóttir, Ingileif B., Huppert, Julian, Zody, Michael C., Abecasis, G. R., Estivill, Xavier, Bouffard, Gerard G., Guan, Xiaobin, Hansen, Nancy F., Idol, Jacquelyn R., Maduro, Valerie V., Maskeri, Baishali, McDowell, Jennifer C., Park, Morgan, Thomas, Pamela J., Young, Alice C., Blakesley, Robert W., Muzny, Donna M., Sodergren, Erica, Wheeler, David A., Worley, Kim C., Jiang, Huaiyang, Weinstock, George M., Gibbs, Richard A., Graves, Tina, Fulton, Robert, Mardis, Elaine R., Wilson, Richard K., Clamp, Michele, Cuff, James, Gnerre, Sante, Jaffe, David B., Chang, Jean L., Lindblad-Toh, Kerstin, Lander, Eric S., Koriabine, Maxim, Nefedov, Mikhail, Osoegawa, Kazutoyo, Yoshinaga, Yuko, Zhu, Baoli, and de Jong, Pieter J.

Abstract

We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.

Published
2007
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16. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project

Author

Birney, Ewan, Stamatoyannopoulos, John A, Dutta, Anindya, Guigó, Roderic, Gingeras, Thomas R, Margulies, Elliott H, Weng, Zhiping, Snyder, Michael, Dermitzakis, Emmanouil T, Thurman, Robert E, Kuehn, Michael S, Taylor, Christopher M, Neph, Shane, Koch, Christoph M, Asthana, Saurabh, Malhotra, Ankit, Adzhubei, Ivan, Greenbaum, Jason A, Andrews, Robert M, Flicek, Paul, Boyle, Patrick J, Cao, Hua, Carter, Nigel P, Clelland, Gayle K, Davis, Sean, Day, Nathan, Dhami, Pawandeep, Dillon, Shane C, Dorschner, Michael O, Fiegler, Heike, Giresi, Paul G, Goldy, Jeff, Hawrylycz, Michael, Haydock, Andrew, Humbert, Richard, James, Keith D, Johnson, Brett E, Johnson, Ericka M, Frum, Tristan T, Rosenzweig, Elizabeth R, Karnani, Neerja, Lee, Kirsten, Lefebvre, Gregory C, Navas, Patrick A, Neri, Fidencio, Parker, Stephen C J, Sabo, Peter J, Sandstrom, Richard, Shafer, Anthony, Vetrie, David, Weaver, Molly, Wilcox, Sarah, Yu, Man, Collins, Francis S, Dekker, Job, Lieb, Jason D, Tullius, Thomas D, Crawford, Gregory E, Sunyaev, Shamil, Noble, William S, Dunham, Ian, Denoeud, France, Reymond, Alexandre, Kapranov, Philipp, Rozowsky, Joel, Zheng, Deyou, Castelo, Robert, Frankish, Adam, Harrow, Jennifer, Ghosh, Srinka, Sandelin, Albin, Hofacker, Ivo L, Baertsch, Robert, Keefe, Damian, Dike, Sujit, Cheng, Jill, Hirsch, Heather A, Sekinger, Edward A, Lagarde, Julien, Abril, Josep F, Shahab, Atif, Flamm, Christoph, Fried, Claudia, Hackermüller, Jörg, Hertel, Jana, Lindemeyer, Manja, Missal, Kristin, Tanzer, Andrea, Washietl, Stefan, Korbel, Jan, Emanuelsson, Olof, Pedersen, Jakob S, Holroyd, Nancy, Taylor, Ruth, Swarbreck, David, Matthews, Nicholas, Dickson, Mark C, Thomas, Daryl J, Weirauch, Matthew T, Gilbert, James, Drenkow, Jorg, Bell, Ian, Zhao, XiaoDong, Srinivasan, K G, Sung, Wing-Kin, Ooi, Hong Sain, Chiu, Kuo Ping, Foissac, Sylvain, Alioto, Tyler, Brent, Michael, Pachter, Lior, Tress, Michael L, Valencia, Alfonso, Choo, Siew Woh, Choo, Chiou Yu, Ucla, Catherine, Manzano, Caroline, Wyss, Carine, Cheung, Evelyn, Clark, Taane G, Brown, James B, Ganesh, Madhavan, Patel, Sandeep, Tammana, Hari, Chrast, Jacqueline, Henrichsen, Charlotte N, Kai, Chikatoshi, Kawai, Jun, Nagalakshmi, Ugrappa, Wu, Jiaqian, Lian, Zheng, Lian, Jin, Newburger, Peter, Zhang, Xueqing, Bickel, Peter, Mattick, John S, Carninci, Piero, Hayashizaki, Yoshihide, Weissman, Sherman, Hubbard, Tim, Myers, Richard M, Rogers, Jane, Stadler, Peter F, Lowe, Todd M, Wei, Chia-Lin, Ruan, Yijun, Struhl, Kevin, Gerstein, Mark, Antonarakis, Stylianos E, Fu, Yutao, Green, Eric D, Karaöz, Ulaş, Siepel, Adam, Taylor, James, Liefer, Laura A, Wetterstrand, Kris A, Good, Peter J, Feingold, Elise A, Guyer, Mark S, Cooper, Gregory M, Asimenos, George, Dewey, Colin N, Hou, Minmei, Nikolaev, Sergey, Montoya-Burgos, Juan I, Löytynoja, Ari, Whelan, Simon, Pardi, Fabio, Massingham, Tim, Huang, Haiyan, Zhang, Nancy R, Holmes, Ian, Mullikin, James C, Ureta-Vidal, Abel, Paten, Benedict, Seringhaus, Michael, Church, Deanna, Rosenbloom, Kate, Kent, W James, Stone, Eric A, Batzoglou, Serafim, Goldman, Nick, Hardison, Ross C, Haussler, David, Miller, Webb, Sidow, Arend, Trinklein, Nathan D, Zhang, Zhengdong D, Barrera, Leah, Stuart, Rhona, King, David C, Ameur, Adam, Enroth, Stefan, Bieda, Mark C, Kim, Jonghwan, Bhinge, Akshay A, Jiang, Nan, Liu, Jun, Yao, Fei, Vega, Vinsensius B, Lee, Charlie W H, Ng, Patrick, Yang, Annie, Moqtaderi, Zarmik, Zhu, Zhou, Xu, Xiaoqin, Squazzo, Sharon, Oberley, Matthew J, Inman, David, Singer, Michael A, Richmond, Todd A, Munn, Kyle J, Rada-Iglesias, Alvaro, Wallerman, Ola, Komorowski, Jan, Fowler, Joanna C, Couttet, Phillippe, Bruce, Alexander W, Dovey, Oliver M, Ellis, Peter D, Langford, Cordelia F, Nix, David A, Euskirchen, Ghia, Hartman, Stephen, Urban, Alexander E, Kraus, Peter, Van Calcar, Sara, Heintzman, Nate, Kim, Tae Hoon, Wang, Kun, Qu, Chunxu, Hon, Gary, Luna, Rosa, Glass, Christopher K, Rosenfeld, M Geoff, Aldred, Shelley Force, Cooper, Sara J, Halees, Anason, Lin, Jane M, Shulha, Hennady P, Zhang, Xiaoling, Xu, Mousheng, Haidar, Jaafar N S, Yu, Yong, Iyer, Vishwanath R, Green, Roland D, Wadelius, Claes, Farnham, Peggy J, Ren, Bing, Harte, Rachel A, Hinrichs, Angie S, Trumbower, Heather, Clawson, Hiram, Hillman-Jackson, Jennifer, Zweig, Ann S, Smith, Kayla, Thakkapallayil, Archana, Barber, Galt, Kuhn, Robert M, Karolchik, Donna, Armengol, Lluis, Bird, Christine P, de Bakker, Paul I W, Kern, Andrew D, Lopez-Bigas, Nuria, Martin, Joel D, Stranger, Barbara E, Woodroffe, Abigail, Davydov, Eugene, Dimas, Antigone, Eyras, Eduardo, Hallgrímsdóttir, Ingileif B, Huppert, Julian, Zody, Michael C, Abecasis, Gonçalo R, Estivill, Xavier, Bouffard, Gerard G, Guan, Xiaobin, Hansen, Nancy F, Idol, Jacquelyn R, Maduro, Valerie V B, Maskeri, Baishali, McDowell, Jennifer C, Park, Morgan, Thomas, Pamela J, Young, Alice C, Blakesley, Robert W, Muzny, Donna M, Sodergren, Erica, Wheeler, David A, Worley, Kim C, Jiang, Huaiyang, Weinstock, George M, Gibbs, Richard A, Graves, Tina, Fulton, Robert, Mardis, Elaine R, Wilson, Richard K, Clamp, Michele, Cuff, James, Gnerre, Sante, Jaffe, David B, Chang, Jean L, Lindblad-Toh, Kerstin, Lander, Eric S, Koriabine, Maxim, Nefedov, Mikhail, Osoegawa, Kazutoyo, Yoshinaga, Yuko, Zhu, Baoli, de Jong, Pieter J, Birney, Ewan, Stamatoyannopoulos, John A, Dutta, Anindya, Guigó, Roderic, Gingeras, Thomas R, Margulies, Elliott H, Weng, Zhiping, Snyder, Michael, Dermitzakis, Emmanouil T, Thurman, Robert E, Kuehn, Michael S, Taylor, Christopher M, Neph, Shane, Koch, Christoph M, Asthana, Saurabh, Malhotra, Ankit, Adzhubei, Ivan, Greenbaum, Jason A, Andrews, Robert M, Flicek, Paul, Boyle, Patrick J, Cao, Hua, Carter, Nigel P, Clelland, Gayle K, Davis, Sean, Day, Nathan, Dhami, Pawandeep, Dillon, Shane C, Dorschner, Michael O, Fiegler, Heike, Giresi, Paul G, Goldy, Jeff, Hawrylycz, Michael, Haydock, Andrew, Humbert, Richard, James, Keith D, Johnson, Brett E, Johnson, Ericka M, Frum, Tristan T, Rosenzweig, Elizabeth R, Karnani, Neerja, Lee, Kirsten, Lefebvre, Gregory C, Navas, Patrick A, Neri, Fidencio, Parker, Stephen C J, Sabo, Peter J, Sandstrom, Richard, Shafer, Anthony, Vetrie, David, Weaver, Molly, Wilcox, Sarah, Yu, Man, Collins, Francis S, Dekker, Job, Lieb, Jason D, Tullius, Thomas D, Crawford, Gregory E, Sunyaev, Shamil, Noble, William S, Dunham, Ian, Denoeud, France, Reymond, Alexandre, Kapranov, Philipp, Rozowsky, Joel, Zheng, Deyou, Castelo, Robert, Frankish, Adam, Harrow, Jennifer, Ghosh, Srinka, Sandelin, Albin, Hofacker, Ivo L, Baertsch, Robert, Keefe, Damian, Dike, Sujit, Cheng, Jill, Hirsch, Heather A, Sekinger, Edward A, Lagarde, Julien, Abril, Josep F, Shahab, Atif, Flamm, Christoph, Fried, Claudia, Hackermüller, Jörg, Hertel, Jana, Lindemeyer, Manja, Missal, Kristin, Tanzer, Andrea, Washietl, Stefan, Korbel, Jan, Emanuelsson, Olof, Pedersen, Jakob S, Holroyd, Nancy, Taylor, Ruth, Swarbreck, David, Matthews, Nicholas, Dickson, Mark C, Thomas, Daryl J, Weirauch, Matthew T, Gilbert, James, Drenkow, Jorg, Bell, Ian, Zhao, XiaoDong, Srinivasan, K G, Sung, Wing-Kin, Ooi, Hong Sain, Chiu, Kuo Ping, Foissac, Sylvain, Alioto, Tyler, Brent, Michael, Pachter, Lior, Tress, Michael L, Valencia, Alfonso, Choo, Siew Woh, Choo, Chiou Yu, Ucla, Catherine, Manzano, Caroline, Wyss, Carine, Cheung, Evelyn, Clark, Taane G, Brown, James B, Ganesh, Madhavan, Patel, Sandeep, Tammana, Hari, Chrast, Jacqueline, Henrichsen, Charlotte N, Kai, Chikatoshi, Kawai, Jun, Nagalakshmi, Ugrappa, Wu, Jiaqian, Lian, Zheng, Lian, Jin, Newburger, Peter, Zhang, Xueqing, Bickel, Peter, Mattick, John S, Carninci, Piero, Hayashizaki, Yoshihide, Weissman, Sherman, Hubbard, Tim, Myers, Richard M, Rogers, Jane, Stadler, Peter F, Lowe, Todd M, Wei, Chia-Lin, Ruan, Yijun, Struhl, Kevin, Gerstein, Mark, Antonarakis, Stylianos E, Fu, Yutao, Green, Eric D, Karaöz, Ulaş, Siepel, Adam, Taylor, James, Liefer, Laura A, Wetterstrand, Kris A, Good, Peter J, Feingold, Elise A, Guyer, Mark S, Cooper, Gregory M, Asimenos, George, Dewey, Colin N, Hou, Minmei, Nikolaev, Sergey, Montoya-Burgos, Juan I, Löytynoja, Ari, Whelan, Simon, Pardi, Fabio, Massingham, Tim, Huang, Haiyan, Zhang, Nancy R, Holmes, Ian, Mullikin, James C, Ureta-Vidal, Abel, Paten, Benedict, Seringhaus, Michael, Church, Deanna, Rosenbloom, Kate, Kent, W James, Stone, Eric A, Batzoglou, Serafim, Goldman, Nick, Hardison, Ross C, Haussler, David, Miller, Webb, Sidow, Arend, Trinklein, Nathan D, Zhang, Zhengdong D, Barrera, Leah, Stuart, Rhona, King, David C, Ameur, Adam, Enroth, Stefan, Bieda, Mark C, Kim, Jonghwan, Bhinge, Akshay A, Jiang, Nan, Liu, Jun, Yao, Fei, Vega, Vinsensius B, Lee, Charlie W H, Ng, Patrick, Yang, Annie, Moqtaderi, Zarmik, Zhu, Zhou, Xu, Xiaoqin, Squazzo, Sharon, Oberley, Matthew J, Inman, David, Singer, Michael A, Richmond, Todd A, Munn, Kyle J, Rada-Iglesias, Alvaro, Wallerman, Ola, Komorowski, Jan, Fowler, Joanna C, Couttet, Phillippe, Bruce, Alexander W, Dovey, Oliver M, Ellis, Peter D, Langford, Cordelia F, Nix, David A, Euskirchen, Ghia, Hartman, Stephen, Urban, Alexander E, Kraus, Peter, Van Calcar, Sara, Heintzman, Nate, Kim, Tae Hoon, Wang, Kun, Qu, Chunxu, Hon, Gary, Luna, Rosa, Glass, Christopher K, Rosenfeld, M Geoff, Aldred, Shelley Force, Cooper, Sara J, Halees, Anason, Lin, Jane M, Shulha, Hennady P, Zhang, Xiaoling, Xu, Mousheng, Haidar, Jaafar N S, Yu, Yong, Iyer, Vishwanath R, Green, Roland D, Wadelius, Claes, Farnham, Peggy J, Ren, Bing, Harte, Rachel A, Hinrichs, Angie S, Trumbower, Heather, Clawson, Hiram, Hillman-Jackson, Jennifer, Zweig, Ann S, Smith, Kayla, Thakkapallayil, Archana, Barber, Galt, Kuhn, Robert M, Karolchik, Donna, Armengol, Lluis, Bird, Christine P, de Bakker, Paul I W, Kern, Andrew D, Lopez-Bigas, Nuria, Martin, Joel D, Stranger, Barbara E, Woodroffe, Abigail, Davydov, Eugene, Dimas, Antigone, Eyras, Eduardo, Hallgrímsdóttir, Ingileif B, Huppert, Julian, Zody, Michael C, Abecasis, Gonçalo R, Estivill, Xavier, Bouffard, Gerard G, Guan, Xiaobin, Hansen, Nancy F, Idol, Jacquelyn R, Maduro, Valerie V B, Maskeri, Baishali, McDowell, Jennifer C, Park, Morgan, Thomas, Pamela J, Young, Alice C, Blakesley, Robert W, Muzny, Donna M, Sodergren, Erica, Wheeler, David A, Worley, Kim C, Jiang, Huaiyang, Weinstock, George M, Gibbs, Richard A, Graves, Tina, Fulton, Robert, Mardis, Elaine R, Wilson, Richard K, Clamp, Michele, Cuff, James, Gnerre, Sante, Jaffe, David B, Chang, Jean L, Lindblad-Toh, Kerstin, Lander, Eric S, Koriabine, Maxim, Nefedov, Mikhail, Osoegawa, Kazutoyo, Yoshinaga, Yuko, Zhu, Baoli, and de Jong, Pieter J

Abstract

We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function., QC 20111222

Published
2007
Full Text
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17. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project.

Author

Birney, Ewan, Stamatoyannopoulos, John A, Dutta, Anindya, Guigó, Roderic, Gingeras, Thomas R, Margulies, Elliott H, Weng, Zhiping, Snyder, Michael, Dermitzakis, Emmanouil T, Thurman, Robert E, Kuehn, Michael S, Taylor, Christopher M, Neph, Shane, Koch, Christoph M, Asthana, Saurabh, Malhotra, Ankit, Adzhubei, Ivan, Greenbaum, Jason A, Andrews, Robert M, Flicek, Paul, Boyle, Patrick J, Cao, Hua, Carter, Nigel P, Clelland, Gayle K, Davis, Sean, Day, Nathan, Dhami, Pawandeep, Dillon, Shane C, Dorschner, Michael O, Fiegler, Heike, Giresi, Paul G, Goldy, Jeff, Hawrylycz, Michael, Haydock, Andrew, Humbert, Richard, James, Keith D, Johnson, Brett E, Johnson, Ericka M, Frum, Tristan T, Rosenzweig, Elizabeth R, Karnani, Neerja, Lee, Kirsten, Lefebvre, Gregory C, Navas, Patrick A, Neri, Fidencio, Parker, Stephen C J, Sabo, Peter J, Sandstrom, Richard, Sandelin, Albin, Pedersen, Jakob Skou, Birney, Ewan, Stamatoyannopoulos, John A, Dutta, Anindya, Guigó, Roderic, Gingeras, Thomas R, Margulies, Elliott H, Weng, Zhiping, Snyder, Michael, Dermitzakis, Emmanouil T, Thurman, Robert E, Kuehn, Michael S, Taylor, Christopher M, Neph, Shane, Koch, Christoph M, Asthana, Saurabh, Malhotra, Ankit, Adzhubei, Ivan, Greenbaum, Jason A, Andrews, Robert M, Flicek, Paul, Boyle, Patrick J, Cao, Hua, Carter, Nigel P, Clelland, Gayle K, Davis, Sean, Day, Nathan, Dhami, Pawandeep, Dillon, Shane C, Dorschner, Michael O, Fiegler, Heike, Giresi, Paul G, Goldy, Jeff, Hawrylycz, Michael, Haydock, Andrew, Humbert, Richard, James, Keith D, Johnson, Brett E, Johnson, Ericka M, Frum, Tristan T, Rosenzweig, Elizabeth R, Karnani, Neerja, Lee, Kirsten, Lefebvre, Gregory C, Navas, Patrick A, Neri, Fidencio, Parker, Stephen C J, Sabo, Peter J, Sandstrom, Richard, Sandelin, Albin, and Pedersen, Jakob Skou

Abstract

Udgivelsesdato: 2007-Jun-14, We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.

Published
2007

18. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project.

Author

Birney, Ewan, Stamatoyannopoulos, John A, Dutta, Anindya, Guigó, Roderic, Gingeras, Thomas R, Margulies, Elliott H, Weng, Zhiping, Snyder, Michael, Dermitzakis, Emmanouil T, Thurman, Robert E, Kuehn, Michael S, Taylor, Christopher M, Neph, Shane, Koch, Christoph M, Asthana, Saurabh, Malhotra, Ankit, Adzhubei, Ivan, Greenbaum, Jason A, Andrews, Robert M, Flicek, Paul, Boyle, Patrick J, Cao, Hua, Carter, Nigel P, Clelland, Gayle K, Davis, Sean, Day, Nathan, Dhami, Pawandeep, Dillon, Shane C, Dorschner, Michael O, Fiegler, Heike, Giresi, Paul G, Goldy, Jeff, Hawrylycz, Michael, Haydock, Andrew, Humbert, Richard, James, Keith D, Johnson, Brett E, Johnson, Ericka M, Frum, Tristan T, Rosenzweig, Elizabeth R, Karnani, Neerja, Lee, Kirsten, Lefebvre, Gregory C, Navas, Patrick A, Neri, Fidencio, Parker, Stephen C J, Sabo, Peter J, Sandstrom, Richard, Sandelin, Albin, Pedersen, Jakob Skou, Birney, Ewan, Stamatoyannopoulos, John A, Dutta, Anindya, Guigó, Roderic, Gingeras, Thomas R, Margulies, Elliott H, Weng, Zhiping, Snyder, Michael, Dermitzakis, Emmanouil T, Thurman, Robert E, Kuehn, Michael S, Taylor, Christopher M, Neph, Shane, Koch, Christoph M, Asthana, Saurabh, Malhotra, Ankit, Adzhubei, Ivan, Greenbaum, Jason A, Andrews, Robert M, Flicek, Paul, Boyle, Patrick J, Cao, Hua, Carter, Nigel P, Clelland, Gayle K, Davis, Sean, Day, Nathan, Dhami, Pawandeep, Dillon, Shane C, Dorschner, Michael O, Fiegler, Heike, Giresi, Paul G, Goldy, Jeff, Hawrylycz, Michael, Haydock, Andrew, Humbert, Richard, James, Keith D, Johnson, Brett E, Johnson, Ericka M, Frum, Tristan T, Rosenzweig, Elizabeth R, Karnani, Neerja, Lee, Kirsten, Lefebvre, Gregory C, Navas, Patrick A, Neri, Fidencio, Parker, Stephen C J, Sabo, Peter J, Sandstrom, Richard, Sandelin, Albin, and Pedersen, Jakob Skou

Abstract

Udgivelsesdato: 2007-Jun-14, We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.

Published
2007

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