TY  - JOUR
A1  - Schneider, Eberhard
A1  - Dittrich, Marcus
A1  - Böck, Julia
A1  - Nanda, Indrajit
A1  - Müller, Tobias
A1  - Seidmann, Larissa
A1  - Tralau, Tim
A1  - Galetzka, Danuta
A1  - El Hajj, Nady
A1  - Haaf, Thomas
T1  - CpG sites with continuously increasing or decreasing methylation from early to late human fetal brain development
JF  - Gene
N2  - Normal human brain development is dependent on highly dynamic epigenetic processes for spatial and temporal gene regulation. Recent work identified wide-spread changes in DNA methylation during fetal brain development. We profiled CpG methylation in frontal cortex of 27 fetuses from gestational weeks 12-42, using Illumina 450K methylation arrays. Sites showing genome-wide significant correlation with gestational age were compared to a publicly available data set from gestational weeks 3-26. Altogether, we identified 2016 matching developmentally regulated differentially methylated positions (m-dDMPs): 1767 m-dDMPs were hypermethylated and 1149 hypomethylated during fetal development. M-dDMPs are underrepresented in CpG islands and gene promoters, and enriched in gene bodies. They appear to cluster in certain chromosome regions. M-dDMPs are significantly enriched in autism-associated genes and CpGs. Our results promote the idea that reduced methylation dynamics during fetal brain development may predispose to autism. In addition, m-dDMPs are enriched in genes with human-specific brain expression patterns and/or histone modifications. Collectively, we defined a subset of dDMPs exhibiting constant methylation changes from early to late pregnancy. The same epigenetic mechanisms involving methylation changes in cis-regulatory regions may have been adopted for human brain evolution and ontogeny.
KW  - Autism spectrum disorders
KW  - DNA methylation
KW  - Genome
KW  - Autism
KW  - Frontal cortex
KW  - Human prefrontal cortex
KW  - Gene-expression
KW  - Schizophrenia
KW  - Patterns
KW  - Transcription
KW  - Epigenetics
KW  - Environment
KW  - Fetal brain development
KW  - DNA methylation dynamics
KW  - Methylome
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186936
VL  - 592
IS  - 1
ER  - 
TY  - JOUR
A1  - Ceteci, Fatih
A1  - Xu, Jiajia
A1  - Ceteci, Semra
A1  - Zanucco, Emanuele
A1  - Thakur, Chitra
A1  - Rapp, Ulf R.
T1  - Conditional Expression of Oncogenic C-RAF in Mouse Pulmonary Epithelial Cells Reveals Differential Tumorigenesis and Induction of Autophagy Leading to Tumor Regression
JF  - Neoplasia
N2  - Here we describe a novel conditional mouse lung tumor model for investigation of the pathogenesis of human lung cancer. On the basis of the frequent involvement of the Ras-RAF-MEK-ERK signaling pathway in human non-small cell lung carcinoma (NSCLC), we have explored the target cell availability, reversibility, and cell type specificity of transformation by oncogenic C-RAF. Targeting expression to alveolar type II cells or to Clara cells, the two likely precursors of human NSCLC, revealed differential tumorigenicity between these cells. Whereas expression of oncogenic C-RAF in alveolar type II cells readily induced multifocal macroscopic lung tumors independent of the developmental state, few tumors with type II pneumocytes features and incomplete penetrance were found when targeted to Clara cells. Induced tumors did not progress and were strictly dependent on the initiating oncogene. Deinduction of mice resulted in tumor regression due to autophagy rather than apoptosis. Induction of autophagic cell death in regressing lung tumors suggests the use of autophagy enhancers as a treatment choice for patients with NSCLC.
KW  - Human lung-cancer
KW  - K-RAS
KW  - Induced senescence
KW  - Gene-expression
KW  - In-vivo
KW  - Kinase pathway
KW  - P53
KW  - Activation
KW  - Model
KW  - Adenocarcinomas
Y1  - 2011
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134347
VL  - 13
IS  - 11
ER  -