Daniel MESSERSCHMIDT

Developmental Epigenetics & Disease

Profile

Daniel M MESSERSCHMIDT
Lab Location: #5-02B   Email: danielm@imcb.a-star.edu.sg   Tel: 65869868

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 cell fates and organ formation in nematodes.

 

In 2005 he embarked on his doctoral work at the Max Planck Institute for Immunobiology (Freiburg, Germany) studying differentiation events in mouse preimplantation embryos. The work on lineage segregation and differentiation in the mouse blastocyst ultimately elucidated 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 addressed 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 (IMCB) where he continued to pursue is investigation on the early epigenetic reprogramming events in mouse embryos.

 

In 2015 he was awarded the prestigious Fellowship by the National Research Foundation (NRF) and is Principal Investigator at IMCB since.

In 2018 Daniel was selected to become an EMBO Young Investigator.

Research

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.

Our Team

Staff

Department: Daniel MESSERSCHMIDT

Name: Yaju WANG

Designation: Senior Research Officer

Email: yjwang@imcb.a-star.edu.sg


Name: Ka Yi LING

Designation: Research Fellow

Email: kyling@imcb.a-star.edu.sg


Name: Brenda Yuyuan HAN

Designation: Research Fellow

Email: yyhan@imcb.a-star.edu.sg


Name: Wen Jun PEH

Designation: Research Officer

Email: pehwj@imcb.a-star.edu.sg


Name: Joel Heng Loong TAN

Designation: Research Fellow

Email: tanhl@imcb.a-star.edu.sg


Name: Hui Mun LOH

Designation: Research Officer

Email: hmloh@imcb.a-star.edu.sg


Name: Michelle Kay Yi SEAH

Designation: Research Fellow

Email: kymseah@imcb.a-star.edu.sg


Publications

Recent Publications

Peer reviewed:

PRDM15 safeguards naive pluripotency by transcriptionally regulating WNT and MAPK-ERK signaling.
Mzoughi S, Zhang J, Hequet D, Teo SX, Fang H, Xing QR, Bezzi M, Seah MKY, Ong SLM, Shin EM, Wollmann H, Wong ESM, Al-Haddawi M, Stewart CL, Tergaonkar V, Loh YH, Dunn NR, Messerschmidt DM, Guccione E.
Nat Genet. 2017 Jul 24. doi: 10.1038/ng.3922.

ELABELA deficiency promotes preeclampsia and cardiovascular malformations in mice.
Ho L, Van Dijk M, Chye STJ, Messerschmidt DM, Chng SC, Ong S, Yi LK, Boussata S, Goh GH, Afink GB, Lim CY, Dunn NR, Solter D, Knowles BB, Reversade B.
Science. 2017 Jun 29. pii: eaam6607. doi: 10.1126/science.aam6607.

*** Personal highlight 1 ***

Loss of maternal Trim28 causes male-predominant early embryonic lethality.
Sampath Kumar A, Seah MK, Ling KY, Wang Y, Tan JH, Nitsch S, Lim SL, Lorthongpanich C, Wollmann H, Low DH, Guccione E, Messerschmidt DM.
Genes Dev. 2017 Jan 1;31(1):12-17. doi: 10.1101/gad.291195.116.

We hypothesized that TRIM28 maintains epigenetic stability beyond safeguarding imprints and endogenous retroviruses. Here we describe an extraordinary male-specific, early embryonic lethality phenotype in Trim28 maternal mutant embryos. The defect originates from the Y-chromosome, from which Rbmy1a1 is ectopically expressed. This ordinarily testis-specific splice factor triggers substantial missplicing when active in the embryo causing the developmental arrest. Remarkably, the requirement of TRIM28 to maintain hypermethylation at the Rbmy1a1 promoter is restricted to the zygote and 2-cell stage embryo.
This paper expands the concept of genomic imprinting maintenance in the early embryo to non-imprinted genes and thus establishes a paradigm for an early epigenetic reprogramming defect -at a single gene- causing developmental abnormalities at later stages.

β-Catenin-mediated adhesion is required for successful preimplantation mouse embryo development.
Messerschmidt DM, de Vries WN, Lorthongpanich C, Balu S, Solter D, Knowles BB.
Development. 2016 Jun 1;143(11):1993-9. doi: 10.1242/dev.133439.

Multiplexed locus-specific analysis of DNA methylation in single cells.
Cheow LF, Quake SR, Burkholder WF, Messerschmidt DM.
Nat Protoc. 2015 Apr;10(4):619-31. doi: 10.1038/nprot.2015.041.

DNA methylation dynamics during epigenetic reprogramming in the germline and preimplantation embryos.
Messerschmidt DM*, Knowles BB, Solter D.
Genes Dev. 2014 Apr 15;28(8):812-28. doi: 10.1101/gad.234294.113. Review. (*corresponding author)

*** Personal highlight 2 ***

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 Sep 6;341(6150):1110-2. doi: 10.1126/science.1240617.

This paper shows the mosaicism of epimutations in maternal mutant Trim28 embryos explaining the variable phenotypes. Oocytes are unaffected and imprints are aberrantly demethylated post-fertilization. Yet, hypomethylation is incomplete and variable amongst cells in individuals, resulting in unpredictable patterns of defects in the embryo proper. We prove this mosaicism by a single cell methylation analysis method established for this very purpose. The SCRAM assay is robust, versatile and was widely publicized. Last, transfer of mutant pronuclei into enucleated wildtype zygotes and vice versa rescues/mimics the maternal Trim28 knock-out effects. Thus, imprint demethylation can be prevented by reestablishing a normal maternal proteome. This implies that any maternal defect affecting embryonic integrity could potentially be cured by a ‘three parent approach’.
I chose this paper for its detailed insights into a complex epigenetic problem impacting on the very core of mammalian development.

The nuage mediates retrotransposon silencing in mouse primordial ovarian follicles.
Lim AK, Lorthongpanich C, Chew TG, Tan CW, Shue YT, Balu S, Gounko N, Kuramochi-Miyagawa S, Matzuk MM, Chuma S, Messerschmidt DM, Solter D, Knowles BB.
Development. 2013 Sep;140(18):3819-25. doi: 10.1242/dev.099184.

Temporal reduction of LATS kinases in the early preimplantation embryo prevents ICM lineage differentiation.
Lorthongpanich C, Messerschmidt DM, Chan SW, Hong W, Knowles BB, Solter D.
Genes Dev. 2013 Jul 1;27(13):1441-6. doi: 10.1101/gad.219618.113.

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 D, Fu XY.
Genes Dev. 2013 Jun 15;27(12):1378-90. doi: 10.1101/gad.221176.113.

*** Personal highlight 3 ***

Trim28 is required for epigenetic stability during mouse oocyte to embryo transition.
Messerschmidt DM*, de Vries W, Ito M, Solter D, Ferguson-Smith A, Knowles BB.
Science. 2012 Mar 23;335(6075):1499-502. doi: 10.1126/science.1216154. (*corresponding author)

Mammalian imprinting was described by Solter and Surani three decades ago. Followed by a colossal effort to understand the mechanisms behind this epigenetic phenomenon two fundamental questions remained unanswered: How are imprints established in germ cells? And, how do imprints resist reprogramming in embryos to ensure vital inheritance from germline to soma? Our work answered the latter. We found that TRIM28, through interaction with its binding partners ZFP57 and SETDB1, marks imprinted alleles with H3K9me3. Even more importantly, we showed that through targeted recruitment of DNMT1, the maintenance DNA methyltransferase, TRIM28, makes these sites impervious to the innate demethylating activity of the early embryo. We established the concept of non-canonical DNMT1-targeting through sequence-specific mechanisms to counteract DNA demethylation, thus uncoupling DNMT1 from its DNA-replication dependent function.
This paper is a milestone in epigenetic and developmental biology.

Nanog is required for primitive endoderm formation through a non-cell autonomous mechanism.
Messerschmidt DM*, Kemler R.
Dev Biol. 2010 Aug 1;344(1):129-37. doi: 10.1016/j.ydbio.2010.04.020. Epub 2010 May 12. (*corresponding author)

Zebrafish Pou5f1-dependent transcriptional networks in temporal control of early development.
Onichtchouk D, Geier F, Polok B, Messerschmidt DM, Mössner R, Wendik B, Song S, Taylor V, Timmer J, Driever W.
Mol Syst Biol. 2010;6:354. doi: 10.1038/msb.2010.9. Epub 2010 Mar 9.

Conservation and diversification of Wnt signaling function during the evolution of nematode vulva development.
Zheng M, Messerschmidt DM, Jungblut B, Sommer RJ.
Nat Genet. 2005 Mar;37(3):300-4. Epub 2005 Feb 6.


Other publications:

From Germline to Soma: Epigenetic Dynamics in the Mouse Preimplantation Embryo.
Seah MKY, Messerschmidt DM.
Curr Top Dev Biol. 2018;128:203-235. doi: 10.1016/bs.ctdb.2017.10.011.

Single Cell Restriction Enzyme-Based Analysis of Methylation at Genomic Imprinted Regions in Preimplantation Mouse Embryos.
Ling KY, Cheow LF, Quake SR, Burkholder WF, Messerschmidt DM.
Methods Mol Biol. 2017;1605:171-189. doi: 10.1007/978-1-4939-6988-3_12.

A twist in zygotic reprogramming.
Messerschmidt DM.
Nat Cell Biol. 2016 Feb;18(2):139-40. doi: 10.1038/ncb3304.

Epigenetic Control of Early Mouse Development.
Lim CY, Knowles BB, Solter D, Messerschmidt DM.
Curr Top Dev Biol. 2016;120:311-60. doi: 10.1016/bs.ctdb.2016.05.002.

Erase-Maintain-Establish: Natural Reprogramming of the Mammalian Epigenome.
Leseva M, Knowles BB, Messerschmidt DM, Solter D.
Cold Spring Harb Symp Quant Biol. 2015;80:155-63. doi: 10.1101/sqb.2015.80.027441. Review.

Should I stay or should I go: protection and maintenance of DNA methylation at imprinted genes.
Messerschmidt DM.
Epigenetics. 2012 Sep;7(9):969-75.

Inherent Nuclear Reprogramming in Mammalian Embryos
Lim AK, Kai T, Knowles BB, Messerschmidt DM.
Nuclear Reprogramming and Stem Cells, Humana Press. (2011)

Wnt Signalling in Development
Rudloff S, Messerschmidt DM, Kemler R.
Handbook of Cell Signalling, Academic Press. (2009)