Daniela Meilinger

Ludwig-Maximilians-Universität München

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Trends

Author Order

Document Type

Co-Authors

Fabio Spada

Guy's and St Thomas' NHS Foundation Trust

Sebastian Bultmann

Ludwig-Maximilians-Universität München

Heinrich Leonhardt

Ludwig-Maximilians-Universität München

Dietmar E. Martin

Ludwig-Maximilians-Universität München

Kerstin C. Maier

Max Planck Institute for Multidisciplinary Sciences

Andrea Rottach

Ludwig-Maximilians-Universität München

Weihua Qin

North University of China

Stefan Hasenöder

Helmholtz Zentrum München

Christine S. Schmidt

DKFZ-ZMBH Alliance

Christian Peter

Technical University of Munich

Cooperative Institutions

Ludwig-Maximilians-Universität München

Center for Integrated Protein Science Munich

Max Planck Institute for Plant Breeding Research

University of Cologne

Helmholtz Zentrum München

Heidelberg University

Max Planck Institute for Multidisciplinary Sciences

Max Planck Institute for Biophysical Chemistry

Max Planck Society

LMU Klinikum

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Field

Global DNA Hypomethylation Prevents Consolidation of Differentiation Programs and Allows Reversion to the Embryonic Stem Cell State

PLoS ONE (2012)

Christine S. Schmidt Sebastian Bultmann Daniela Meilinger Benedikt Zacher Achim Tresch

DNA methylation patterns change dynamically during mammalian development and lineage specification, yet scarce information is available about how DNA methylation affects gene expression profiles upon differentiation. Here we determine genome-wide transcription profiles during undirected differentiation of severely hypomethylated (Dnmt1−/−) embryonic stem cells (ESCs) as well as ESCs completely devoid of DNA methylation (Dnmt1−/−;Dnmt3a−/−;Dnmt3b−/− or TKO) and assay their potential to transit in and out of the ESC state. We find that the expression of only few genes mainly associated with germ line function and the X chromosome is affected in undifferentiated TKO ESCs. Upon initial differentiation as embryoid bodies (EBs) wild type, Dnmt1−/− and TKO cells downregulate pluripotency associated genes and upregulate lineage specific genes, but their transcription profiles progressively diverge upon prolonged EB culture. While Oct4 protein levels are completely and homogeneously suppressed, transcription of Oct4 and Nanog is not completely silenced even at late stages in both Dnmt1−/− and TKO EBs. Despite late wild type and Dnmt1−/− EBs showing a much higher degree of concordant expression, after EB dissociation and replating under pluripotency promoting conditions both Dnmt1−/− and TKO cells, but not wild type cells rapidly revert to expression profiles typical of undifferentiated ESCs. Thus, while DNA methylation seems not to be critical for initial activation of differentiation programs, it is crucial for permanent restriction of developmental fate during differentiation.

Homeobox protein NANOG

Embryoid body

DNMT1

10.1371/journal.pone.0052629

Cite

Citations (42)

Different Binding Properties and Function of CXXC Zinc Finger Domains in Dnmt1 and Tet1

PLoS ONE (2011)

Carina Frauer Andrea Rottach Daniela Meilinger Sebastian Bultmann Karin Fellinger

Several mammalian proteins involved in chromatin and DNA modification contain CXXC zinc finger domains. We compared the structure and function of the CXXC domains in the DNA methyltransferase Dnmt1 and the methylcytosine dioxygenase Tet1. Sequence alignment showed that both CXXC domains have a very similar framework but differ in the central tip region. Based on the known structure of a similar MLL1 domain we developed homology models and designed expression constructs for the isolated CXXC domains of Dnmt1 and Tet1 accordingly. We show that the CXXC domain of Tet1 has no DNA binding activity and is dispensable for catalytic activity in vivo. In contrast, the CXXC domain of Dnmt1 selectively binds DNA substrates containing unmethylated CpG sites. Surprisingly, a Dnmt1 mutant construct lacking the CXXC domain formed covalent complexes with cytosine bases both in vitro and in vivo and rescued DNA methylation patterns in dnmt1−/− embryonic stem cells (ESCs) just as efficiently as wild type Dnmt1. Interestingly, neither wild type nor ΔCXXC Dnmt1 re-methylated imprinted CpG sites of the H19a promoter in dnmt1−/− ESCs, arguing against a role of the CXXC domain in restraining Dnmt1 methyltransferase activity on unmethylated CpG sites.

DNMT1

CpG site

DNA methyltransferase

10.1371/journal.pone.0016627

Cite

Citations (95)