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Series GSE135841 Query DataSets for GSE135841
Status Public on Jun 23, 2020
Title Epigenetic priming by Dppa2/4 in pluripotency facilitates multi-lineage commitment
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
Methylation profiling by high throughput sequencing
Summary Epigenetic priming factors establish a permissive epigenetic landscape which is not required until a later developmental or physiological time point, temporally uncoupling the presence of these factors with their phenotypic effects. One classic example of epigenetic priming is in the context of bivalent chromatin, found in pluripotent stem cells and early embryos at key developmental gene promoters marked by both activating-associated H3K4me3 and repressive-associated H3K27me3 histone modifications. It is currently unknown how these bivalent domains are targeted, or precisely how they impact on lineage commitment. Here we show that the small heterodimerising non-enzymatic DNA binding proteins Developmental Pluripotency Associated 2 (Dppa2) and 4 (Dppa4) act as epigenetic priming factors to establish bivalency at a subset of developmental genes. Dppa2/4 localise to the +1 nucleosome position of bivalent genes and while they are not required for pluripotency in embryonic stem cells (ESCs), double knockout cells fail to exit pluripotency and to differentiate efficiently, with delays in upregulating bivalently marked lineage genes. Proteomics reveal that Dppa2/4 interact on chromatin with members of the COMPASS and Polycomb complexes important for H3K4me3 and H3K27me3 deposition, respectively. Epigenetic profiling reveals a striking loss of H3K4me3, H3K27me3, and their associated enzymatic machinery at a significant subset of bivalent promoters in Dppa2/4 mutants, in addition to loss of H2A.Z and chromatin accessibility. In wild-type ESCs, these “Dppa2/4-dependent” bivalent promoters are characterised by low H3K4me3 enrichment and breadth, near-absent expression levels and initiating but not elongating RNA polymerase. Notably, Dppa2/4-dependent promoters are less evolutionarily conserved suggesting that they lack additional safeguard measures to maintain bivalency at these genes in the absence of Dppa2/4. Concomitantly with the loss of bivalency, Dppa2/4-dependent bivalent promoters gain DNA methylation and consequently are no longer able to be effectively activated upon ESC differentiation, leading to defects in cell fate acquisition. Our findings reveal a targeting principle for bivalency to developmental gene promoters poising them for future lineage specific gene activation.
Overall design Effects of Dppa2/4 loss on the transcriptome (RNAseq) and epigenome (ChIP-seq, NOME-seq) in mouse embryonic stem cells and differentiating cells
Contributor(s) Eckersley-Maslin MA, Reik W
Citation(s) 32572255
Submission date Aug 14, 2019
Last update date Sep 24, 2020
Contact name Steven William Wingett
Organization name MRC Laboratory of Molecular Biology
Department Cell Biology
Street address Francis Crick Avenue, Cambridge Biomedical Campus
City Cambridge
State/province Cambs
ZIP/Postal code CB2 0QH
Country United Kingdom
Platforms (2)
GPL13112 Illumina HiSeq 2000 (Mus musculus)
GPL16417 Illumina MiSeq (Mus musculus)
Samples (189)
GSM4035065 Dppa_DKO_serum_36_A
GSM4035066 Dppa_DKO_serum_36_B
GSM4035067 Dppa_DKO_serum_36_C
BioProject PRJNA560249
SRA SRP218369

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MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE135841_Processed_data_ChIP_and_ATAC.txt.gz 157.9 Mb (ftp)(http) TXT
GSE135841_Processed_data_DNAme.txt.gz 4.1 Mb (ftp)(http) TXT
GSE135841_Processed_data_EB_RNAseq.txt.gz 2.8 Mb (ftp)(http) TXT
GSE135841_Processed_data_ESC_RNAseq_RPM_allgenes.txt.gz 1.4 Mb (ftp)(http) TXT
GSE135841_Processed_data_OE_RNAseq.txt.gz 1.7 Mb (ftp)(http) TXT
GSE135841_Processed_data_Samples_112-129.xlsx 88.9 Kb (ftp)(http) XLSX
GSE135841_Processed_data_Samples_130-171.txt.gz 137.9 Mb (ftp)(http) TXT
GSE135841_Processed_data_Samples_172_189.txt.gz 1.4 Mb (ftp)(http) TXT
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