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Series GSE81222 Query DataSets for GSE81222
Status Public on Oct 10, 2017
Title Erasure of Tet-oxidized 5-methylcytosine by a SRAP nuclease
Organism Mus musculus
Experiment type Genome binding/occupancy profiling by high throughput sequencing
Methylation profiling by high throughput sequencing
Expression profiling by high throughput sequencing
Summary Enzymatic oxidation of 5-methylcytosine (5mC) in DNA by the Tet (Ten-eleven translocation) family of dioxygenases reprograms genome function during pre-implantation development and in primordial germ cells. Tet-oxidized derivatives of 5mC such as 5-hydroxymethylcytosine (5hmC) act as transient intermediates in DNA demethylation or serve as stable epigenetic marks, yet how these alternate fates are specified at individual CpGs is not understood. Here, we report that the Sos-response associated peptidase (SRAP) domain-containing protein Srap1, the mammalian orthologue of an ancient protein superfamily operonically associated with the DNA damage response in bacteria and bacteriophage, binds directly and selectively to Tet-oxidized forms of 5mC in DNA and catalyses turnover of these bases to unmodified cytosine by an autopeptidase cleavage-coupled endonuclease. Biallelic inactivation of Srap1 in mouse embryonic stem (ES) cells results in the global accumulation of Tet-oxidized 5mC derivatives, with ectopic 5hmC in promoters of highly expressed genes, across gene bodies and within enhancer elements. Srap1 deficiency causes partially penetrant lethality in late blastocysts prior to uterine implantation, while surviving midgestation embryos exhibit aberrant patterns of DNA methylation associated with altered gene expression, including hypermethylation in regions closely linked to ectopic 5hmC detected earlier in development. Thus, highly specific removal of 5hmC and its oxidized derivatives by Srap1 sustains genome-wide DNA methylation homeostasis. These findings establish a function for a previously unknown structural class of DNA base modification-specific eraser enzymes that combine the catalytic properties of an autopeptidase with endonuclease activation, and position Srap1 as a key determinant of 5mC demethylation trajectories during mammalian embryonic development.
Overall design Analysis of Srap1 distribution by ChIP-seq and 5mC/5hmC/5fC/5caC distribution by DIP-seq in wild-type and Srap1 knockout (KO) mouse ES cells. RNA-seq profiling in wild-type and Srap1 KO mouse ES cells. RRBS analysis of E9.5 wild-type and Srap1 KO embryos.
Contributor(s) Kweon S, Zhu B, Chen Y, Aravind L, Xu S, Feldman DE
Citation(s) 29020633
Submission date May 08, 2016
Last update date Jul 25, 2021
Contact name Douglas Edmund Feldman
Organization name USC Keck School of Medicine
Department Pathology
Lab HMR 212
Street address 2011 Zonal Avenue
City Los Angeles
State/province CA
ZIP/Postal code 90033
Country USA
Platforms (2)
GPL13112 Illumina HiSeq 2000 (Mus musculus)
GPL19057 Illumina NextSeq 500 (Mus musculus)
Samples (31)
GSM2146807 FHA-Srap1 ChIP-Seq
GSM2176993 input_WT MeDIP-seq
GSM2176994 input_KO MeDIP-seq
BioProject PRJNA320954
SRA SRP074594

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Supplementary file Size Download File type/resource
GSE81222_RAW.tar 924.2 Mb (http)(custom) TAR (of BED, BEDGRAPH, BIGWIG, TXT, WIG)
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Raw data are available in SRA
Processed data provided as supplementary file

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