DNA Methylation Landscapes of Human Fetal Development.
Remodelling the methylome is a hallmark of mammalian development and cell differentiation. However, current knowledge of DNA methylation dynamics in human tissue specification and organ development largely stems from the extrapolation of studies in vitro and animal models. Here, we report on the DNA methylation landscape using the 450k array of four human tissues (amnion, muscle, adrenal and pancreas) during the first and second trimester of gestation (9,18 and 22 weeks). We show that a tissue-specific signature, constituted by tissue-specific hypomethylated CpG sites, was already present at 9 weeks of gestation (W9). Furthermore, we report large-scale remodelling of DNA methylation from W9 to W22. Gain of DNA methylation preferentially occurred near genes involved in general developmental processes, whereas loss of DNA methylation mapped to genes with tissue-specific functions. Dynamic DNA methylation was associated with enhancers, but not promoters. Comparison of our data with external fetal adrenal, brain and liver revealed striking similarities in the trajectory of DNA methylation during fetal development. The analysis of gene expression data indicated that dynamic DNA methylation was associated with the progressive repression of developmental programs and the activation of genes involved in tissue-specific processes. The DNA methylation landscape of human fetal development provides insight into regulatory elements that guide tissue specification and lead to organ functionality.
Molecular Epidemiology Section, Leiden University Medical Center, Leiden, The Netherlands.
Roderick C
RC
Slieker
Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands.
Matthias S
MS
Roost
Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands.
Liesbeth
L
van Iperen
Molecular Epidemiology Section, Leiden University Medical Center, Leiden, The Netherlands.
H Eka D
HE
Suchiman
Molecular Epidemiology Section, Leiden University Medical Center, Leiden, The Netherlands.
Elmar W
EW
Tobi
Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands.
Françoise
F
Carlotti
Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands; Hubrecht Institute, Utrecht, The Netherlands.
Eelco J P
EJ
de Koning
Molecular Epidemiology Section, Leiden University Medical Center, Leiden, The Netherlands.
P Eline
PE
Slagboom
Molecular Epidemiology Section, Leiden University Medical Center, Leiden, The Netherlands.
Bastiaan T
BT
Heijmans
Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands; Department for Reproductive Medicine, Ghent University Hospital, Ghent, Belgium.
Susana M
SM
Chuva de Sousa Lopes
D000311:Adrenal Glands / Q000254:growth & development / Q000378:metabolism; D000650:Amnion / Q000254:growth & development / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic; D005260:Female; D047109:Fetal Development / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D015894:Genome, Human; D006801:Humans; D018482:Muscle, Skeletal / Q000254:growth & development / Q000378:metabolism; D009928:Organ Specificity / Q000235:genetics; D010179:Pancreas / Q000254:growth & development / Q000378:metabolism; D011247:Pregnancy; D011261:Pregnancy Trimester, First / Q000235:genetics; D011262:Pregnancy Trimester, Second / Q000235:genetics; D011401:Promoter Regions, Genetic; D012045:Regulatory Sequences, Nucleic Acid