Daniel M MESSERSCHMIDT 
                       
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  Daniel M Messerschmidt  
  Lab Location: #3-12B

email:
danielm@imcb.a-star.edu.sg
tel:65869868
 
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  Key Publications  
 

Loss of maternal Trim28 causes male-predominant early-embryonic lethality
Sampath A, Seah M, Ling KY, Wang Y, Tan J, Nitsch S, Lim SL, Lorthongpanich C, Wollmann H, Low D, Guccione E, Messerschmidt DM
Genes & Development, In press

A twist in zygotic reprogramming.
Messerschmidt DM.
Nature Cell Biology, 2016

Multiplexed locus-specific analysis of DNA methylation in single cells.
Cheow LF, Quake SR, Burkholder WF, Messerschmidt DM.
Nature Protocols, 2015

DNA-methylation dynamics and functions during mammalian development
Messerschmidt DM, Knowles BB, Solter D
Genes & Development, 2014

Single-Cell DNA-Methylation Analysis Reveals Epigenetic Chimerism in Preimplantation Embryos
Lorthongpanich C, Cheow LF, Balu S, Quake SR, Knowles BB, Burkholder WF, Solter D, Messerschmidt DM
Science, 2013

A genetic and developmental pathway from STAT3 to the OCT4–NANOG circuit is essential for maintenance of ICM lineages in vivo
Do DV, Ueda J, Messerschmidt, DM, Lorthongpanich C, Zhou Y, Feng B, Guo G, Lin PJ, Hossain MZ, Zhang W, Moh A, Wu Q, Robson P, Ng HH, Poellinger L, Knowles BB, Solter , Fu XY
Genes & Development, 2013

Trim28 is required for epigenetic stability during oocyte to embryo transition
Messerschmidt DM, deVries W, Ito M, Solter D, Ferguson-Smith A, Knowles BB
Science, 2012

 

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  Daniel M MESSERSCHMIDT


Daniel M. Messerschmidt obtained his master in biochemistry at the Max Planck Institute for Developmental Biology and the University of Tuebingen (Germany) where he studied organ formation and protein interactions in nematodes.
He then embarked on his doctoral work at the Max Planck Institute for Immunobiology (Freiburg, Germany) studying differentiation events in mouse preimplantation embryos. His work on lineage segregation and differentiation in the blastocyst and embryonic stem cells ultimately showed a non-cell autonomous requirement of the pluripotency transcription factor NANOG for primitive endoderm formation in vivo.
In 2009 he joined the laboratory of Barbara Knowles and Davor Solter at the A*STAR Institute of Medical Biology (Singapore) to follow his interests in epigenetic aspects of differentiation and early embryonic development. He addresses epigenetic reprogramming during oocyte-to-embryo transition, an essential measure to ensure totipotency in the mammalian zygote and early embryo.
In 2013, he was awarded an IMCB Junior Investigator (IJI) position to conduct independent research at the Institute of Molecular and Cell Biology where he continued to pursue is investigation on the early epigenetic reprogramming events in mouse embryos.
In 2014 he was awarded the prestigious Fellowship by the National Research Foundation (NRF) and is Principal Investigator at IMCB since. He is further Adjunct Assistant Professor at the Department of Biochemistry, Yong Loo Lin School of Medicine, National University, Singapore since 2015.

     
  Developmental Epigenetics & Disease
 


Functional specialization of cells during development is the outcome of their differential transcriptional programs. These programs are driven by the transcription/translation machinery, which in turn is guided and controlled by epigenetic modifications of both DNA and chromatin. This epigenome, which does not affect the genetic code itself, is robust and heritable at each mitotic cell division, yet remarkably adaptable under circumstances of differentiation and cell fate commitment. Unquestionably, the epigenome is most flexible during germ cell formation, the oocyte-to-embryo transition (OET) and very early embryonic development, when epigenetic reprogramming must take place to create the unique environment producing the totipotent state.

During this transition, nuclear reprogramming resets the epigenome of both parental pronuclei to a ground state. Radical, global DNA demethylation, occurring actively in the paternal and passively in the maternal genome is a prominent feature of nuclear reprogramming, yet this process poses a danger to a subset of methylated sequences that must be preserved for their germ-line to soma inheritance. Prominently, imprinted loci, gene clusters with parent-of-origin specific gene expression patterns, must retain their differential methylation status acquired during gametogenesis throughout embryogenesis and in adult tissues.

We have identified a complex, formed by maternal TRIM28/KAP1 and its binding partners ZFP57 and SETDB1, playing an essential role preventing detrimental demethylation of imprinted genes during reprogramming. The loss of maternal TRIM28 leads to severe phenotypic and epigenetic variability ultimately resulting in embryonic lethality. Though usually attributed to genetic background variations or environmental influence, we show the phenotypic variability to be derived from early and minute epigenetic variations in single blastomeres. The, at best, partial rescue by paternally expressed TRIM28 is owed to the methylation-dependent DNA binding of the complex. A full rescue of all developmental defects can however be achieved by mere pronuclear transfer of maternal mutant pronuclei into normal enucleated zygotes, thus timing the requirement of maternal TRIM28 protein to the zygote shortly after fertilization, proving it expendable for oocyte growth and maturation. Our results not only shed light on the long elusive players protecting imprinting marks in the shifting epigenetic environment of the early preimplantation embryo, but also reveal the long-ranging effects of a maternal gene deletion on epigenetic memory and illustrate the delicate timing and equilibrium of maternal and zygotic factors during nuclear reprogramming.