Yuen

Monday, June 13, 2011, 9:00 am. Room 203, Graduate Student Centre

“Epigenetics of Human Fetal and Placental Development”

 

EXAMINING COMMITTEE:

Chair: Dr. Dan Rurak (Obstetrics and Gynaecology)
Supervisory Committee: Dr. Wendy Robinson, Research Supervisor (Medical Genetics) & Dr. Louis Lefebvre (Medical Genetics)
University Examiners: Dr. Diana Juriloff (Medical Genetics) & Dr. Wan Lam (Pathology)
External Examiner: Dr. Benjamin Tycko. Institute for Cancer Genetics. Columbia University. New York, New York. United States

SUPERVISORY COMMITTEE:
Dr. Wendy Robinson (Medical Genetics)
Dr. Peter von Dadelszen (Obstetrics & Gynecology)
Dr. Michael Kobor (Medical Genetics)
Dr. Louis Lefebvre (Medical Genetics)



ABSTRACT:
Dysregulation of placental and fetal epigenetics can affect gene expression patterns, including the parent-of-origin dependent expression in imprinted genes. While defects of imprinted genes have been implicated in some adverse pregnancy outcomes, little is currently known about the role of epigenetics in regulating normal or pathological human pregnancy and development. The objective of this thesis is to provide fundamental DNA methylation profiles of human fetal and placental development so as to offer insights into the etiology of human disease and adverse pregnancy outcomes.
Taking advantage of the unbalanced parental genomic constitutions in triploidies, 45 novel imprinted genes were identified by comparing the genome-wide DNA methylation profiles between 10 diandries (extra paternal haploid set) and 10 digynies (extra maternal haploid set). A comparison of DNA methylation profiles between placentas of different gestations and other somatic tissues showed tissue-specific and gestational age-specific DNA methylation changes in many imprinted genes. To gain insight into the genomic pattern of tissue-specific methylation, DNA methylation profile was evaluated in 5 somatic tissues (brain, kidney, lung, muscle and skin) from eight normal second-trimester fetuses. Tissue-specific differentially methylated regions (tDMRs) were identified in 195 loci, suggesting that tissue-specific methylation is established early in the second trimester. Importantly, only 17% of the identified fetal tDMRs were found to maintain this same tissue-specific methylation in adult tissues, implicating an extensive epigenetic reprogramming between fetus and adult. Besides intra-individual differences, there is also substantial DNA methylation variation between individuals. While many sites show a continuous pattern of DNA methylation variation between different placentas, WNT2, TUSC3 and EPHB4 were identified to have epipolymorphisms at their promoter region. The methylation status at the TUSC3 promoter showed an association with preeclampsia, suggesting a role of DNA methylation change in adverse pregnancy outcomes. A further investigation of DNA methylation profiles in 26 placentas from preeclampsia, IUGR and control subjects showed 34 loci were hypomethylated in the early-onset preeclamptic (EOPET) placentas. These results provided comprehensive DNA methylation profiles for both normal and abnormal fetal and placental tissues, which contribute to the biological and clinical aspects of the pathogenesis of fetal and placental disorders.

 

SELECTED PUBLICATIONS:

Yuen RKC, Jiang R, Peñaherrera MS, McFadden DE, Robinson WP. (2011) Genome-wide mapping of imprinted differentially methylated regions (DMRs) by DNA methylation profiling of human placentas from triploidies. Submitted.

Yuen RKC, Neumann SMA, Fok AK, Peñaherrera MS, McFadden DE, Robinson WP, Kobor MS. (2011) Extensive epigenetic reprogramming in human somatic tissues between fetus and adult. Epigenetics Chromatin. 4(1):7.

Yuen RKC and Robinson WP. (2011) Review: A high capacity of the human placenta for genetic and epigenetic variation: implications for assessing pregnancy outcome. Placenta. 32(Suppl2): S136-41.

Bourque DK, Peñaherrera MS, Yuen RKC, McFadden DE, Robinson WP. (2011) The utility of quantitative methylation assays at imprinted genes for the diagnosis of fetal and placental disorders. Clinical Genetics. 79(2):169-75.

Avila L, Yuen RKC, Diego-Alvarez D, Peñaherrera MS, Robinson WP. (2010) Evaluating methylation and expression variability in the human term placenta. Placenta. 31(12):1070-77.

Yuen RKC, Peñaherrera MS, von Dadelszen P, McFadden DE, Robinson WP. (2010) DNA methylation profiling of human placentas reveals promoter hypomethylation of multiple genes in early-onset preeclampsia. Eur J Hum Genet. 18(9):1006-12.

Yuen RKC, Avila L, Peñaherrera MS, von Dadelszen P, Lefebvre L, Kobor MS, Robinson WP. (2009) Human placental-specific epipolymorphism and its association with adverse pregnancy outcomes. PLoS One. 4(10):e7389.


SELECTED PRESENTATIONS:
Yuen RKC, Jiang R, Peñaherrera MS, McFadden DE, Robinson WP. (2011) Genome-wide mapping of imprinted genes by DNA methylation profiling of human placentas from triploidies. ACMG Annual Clinical Genetics Meeting 2011. Vancouver, BC, Canada. March 16-20, 2011. (Poster).

Yuen RKC, Jiang R, Peñaherrera MS, McFadden DE, Robinson WP. (2010) Genome-wide mapping of imprinted genes by DNA methylation profiling of human placentas from triploidies. International Federation of Placenta Associations Meeting 2010. Santiago, Chile. October 19-22, 2010. (Talk).

Yuen RKC, Peñaherrera MS, von Dadelszen P, McFadden DE, Robinson WP. (2010) DNA methylation profiling of human placentas with preeclampsia and intra-uterine growth restriction. International Federation of Placenta Associations Meeting 2010. Santiago, Chile. October 19-22, 2010. (Poster).

Yuen RKC, Peñaherrera MS, von Dadelszen P, McFadden DE, Robinson WP. (2010) Identification of Potential Biomarkers for Hypertension in Pregnancy through Epigenetic Profiling of Human Placentas. The 23rd Scientific Meeting of the International Society of Hypertension. Vancouver, BC, Canada. September 26-30, 2010. (Talk).

Yuen RKC, Peñaherrera MS, von Dadelszen P, Robinson WP. (2010) DNA methylation profiling of human placentas with preeclampsia and intra-uterine growth restriction. Keystone Symposia “Developmental Origins and Epigenesis in Human Health and Disease”. Swissotel The Stamford, Singapore. April 26-30, 2010. (Poster).

Yuen RKC, Peñaherrera MS, von Dadelszen P, Lefebvre L, Kobor MS, Robinson WP. (2009) Identification of epipolymorphisms in the human placenta. 59th American Society of Human Genetics (ASHG) Annual Meeting. Honolulu, Hawaii, USA. Oct 20-24, 2009. (Poster).

Yuen RKC, Peñaherrera MS, von Dadelszen P, Kobor MS, Robinson WP. (2009) A genome-wide search of epigenetic fetal DNA markers for non-invasive prenatal diagnosis of aneuploidies. The 7th European Cytogenetics Conference. Stockholm, Sweden. July 4-7, 2009. (Talk)



BIOGRAPHICAL NOTES:
Born: January 28, 1982, Hong Kong
Academic Studies: B. Sc. Hong Kong University of Science and Technology, 2005. M. Phil. Chinese University of Hong Kong, 2007


GRADUATE STUDIES:
Field of Study: Epigenetics
Courses:
MEDG 419: Human Cytogenetics. Dr. Carolyn Brown
MEDG 520: Advanced Human Molecular Genetics. Dr. Matthew Lorincz
MEDG 530: Human Genetics. Dr. Lorne Clarke
MEDG 545: Current Topics in Medical Genetics. Dr. Carolyn Brown
MEDG 548A: Directed Studies. Dr. Wendy Robinson
MEDG 649: Doctoral Dissertation. Dr. Wendy Robinson


AWARDS:
2010-2011: Child & Family Research Institute Graduate Studentship
2010: International Society of Hypertension 2010 International Forum Poster Prize
2010: YW (Charlie) Loke New Investigator Award
2010: British Columbia Clinical Genomics Network (BCCGN) Training Award
2010: Keystone Symposia Scholarship
2009: BCCGN Travel Award
2007-2009: Interdisciplinary Women’s Reproductive Health Trainee Award