Unknown,Transcriptomics,Genomics,Proteomics

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Epigenetic regulation and transcriptional repression by Tet1 in the early post-implantation mouse embryo: ChIP seq

ABSTRACT: The mammalian TET dioxygenases contribute to global waves of DNA demethylation in the zygote and in primordial germ cells, but their involvement during de novo DNA methylation at peri/post-implantation development is unknown. Here, we show novel physiological functions of Tet1 in the pre-primitive streak stage mouse embryo, where it is expressed not only in the primed-state epiblast, but also in the extra-embryonic ectoderm. In the epiblast, Tet1 contributes to DNA methylation patterning, which indirectly results in dominant transcriptional repression involving a Jumonji-family gene Jmjd8. In the extra-embryonic ectoderm, Tet1 suppresses expression of metabolic genes involved in oxidative phosphorylation. These lineage-specific gene repressive functions, involving distinct modes of regulation by DNA methylation, counteract precocious differentiation of the embryo prior to the onset of gastrulation. Such dysregulation in the absence of Tet1 are surprisingly tolerated in an inbred strain but results in full embryonic lethality in non-inbred mice, thus implicating a complex but essential role of Tet1 in normal gestational development.

INSTRUMENT(S): Illumina HiSeq 2500

ORGANISM(S): Mus musculus

SUBMITTER: Bram Boeckx

PROVIDER: E-MTAB-5562 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Lineage-specific functions of TET1 in the postimplantation mouse embryo.

Khoueiry Rita R Sohni Abhishek A Thienpont Bernard B Luo Xinlong X Velde Joris Vande JV Bartoccetti Michela M Boeckx Bram B Zwijsen An A Rao Anjana A Lambrechts Diether D Koh Kian Peng KP

Nature genetics 20170515 7

The mammalian TET enzymes catalyze DNA demethylation. While they have been intensely studied as major epigenetic regulators, little is known about their physiological roles and the extent of functional redundancy following embryo implantation. Here we define non-redundant roles for TET1 at an early postimplantation stage of the mouse embryo, when its paralogs Tet2 and Tet3 are not detectably expressed. TET1 regulates numerous genes defining differentiation programs in the epiblast and extraembry ...[more]

PMID: 28504700

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Project description:The TET dioxygenases erase mediate DNA dedemethylation in pre-implantation embryos and in primordial germ cells, yet limited studies address their contribution to the global gain of DNA methylation following implantation. Here, we show that Tet1 is expressed and non-redundantly contributes to 5-hydroxymethylctyosine (5hmC) non-redundantly in the pre-gastrulation mouse epiblast. Ablation of Tet1 in primed epiblast cells results in widespread loss of 5hmC associated with gain of 5-methylcytosine at CpG islands and promoters. Moreover, Tet1 is expressed, albeit at lower levels, in the extra-embryonic ectoderm. Tet1-deficiency in the pre-streak mouse embryos causes dysregulation of early lineage regulators in the epiblast and increased expression of metabolic genes in the extra-embryonic ectoderm. Our studies reveal a distinct role of Tet1 in regulating the methylome landscape of the post-implantation mammalian epiblast and a hitherto unknown gene repressive effect in the extra-embryonic lineage, providing insights into the early developmental origins of epigenetic-based basis of imprinting and developmental disorders. Lysates of E6.25 epiblast (E) and extra-embryonic (ExE) tissues were pooled, based on retrospective genotyping, from at least 6 embryos (collected from 2-3 litters). Four pooled biological replicates were collected for each tissue compartment and each genotype, i.e. wild type (wt), Tet1gt/wt (Zwt), Tet1gt/gt(ZZ); in 3 of 4 pooled replicates, the E and ExE samples were obtained from the same litters and given the same numbering. One ExE sample of ZZ was lost. RNA was purified using the RNeasy micro Kit (Qiagen) to obtain 1-10 ng of RNA per pool. RNA quality was assessed using a Bioanalyzer 6000 Pico chip and only samples with RNA integrity number (RIN) > 8.0 were processed further. First-strand cDNA synthesis and amplification was performed by using the SMARTer Ultra Low InputÂ RNA amplification kit v3 (Clontech). Libraries were prepared using NEBNext Ultra DNA library prep for Illumina and sequenced on NextSeq 500 in high-output to generate 75-bp single-end reads.Â Â Low quality ends and adapter sequences wereÂ trimmed off from the Illumina reads withÂ FastX 0.0.13 andÂ cutadaptÂ 1.7.1. Using FastX andÂ ShortRead 1.16.3, we filtered subsequently small readsÂ (length < 35 bp), polyA-reads (>90% of the bases equal A),Â ambiguous reads (containing N) and lowÂ quality reads (>50% of theÂ bases < Q25).

Dataset Information

Epigenetic regulation and transcriptional repression by Tet1 in the early post-implantation mouse embryo: ChIP seq

Publications

Lineage-specific functions of TET1 in the postimplantation mouse embryo.

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