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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
2005 Mar;37(3):300-4. Epub 2005 Feb 6.
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.
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.
Inherent Nuclear Reprogramming in Mammalian Embryos
Lim AK, Kai T, Knowles BB, Messerschmidt DM.
Nuclear Reprogramming and Stem Cells, Humana Press.
Wnt Signalling in Development
Rudloff S, Messerschmidt DM, Kemler R.
Handbook of Cell Signalling, Academic Press.