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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Jul 23, 2024 |
| Title |
Two-factor authentication underpins the precision of piRNA-directed LINE1 DNA methylatio |
| Organism |
Mus musculus |
| Experiment type |
Other
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| Summary |
The PIWI-interacting RNA (piRNA) pathway guides the DNA methylation of young active transposons during male mouse germline development. piRNAs tether the PIWI protein MIWI2 (PIWIL4) to the nascent transposon transcript that results in DNA methylation through SPOCD1. Transposon methylation requires exacting precision: all copies need to be methylated yet, at the same time, off-target methylation must be avoided. However, the underlying mechanisms that ensure this precision remain unknown. Here, we show that SPOCD1 directly interacts with SPIN1 (SPINDLIN1), a chromatin reader that primarily binds H3K4me3 K9me3. The prevailing assumption is that all molecular events required for piRNA-directed DNA methylation occur after the engagement of MIWI2. Interestingly, we find that SPIN1 expression precedes that of both SPOCD1 and MIWI2. Furthermore, we demonstrate that young LINE1s, but not old copies are marked by H3K4me3, H3K9me3 and SPIN1 prior to the initiation of piRNA-directed DNA methylation. We generated a Spocd1 separation-of-function allele in the mouse that encodes a SPOCD1 variant that no longer interacts with SPIN1. We found that the SPOCD1-SPIN1 interaction is essential for spermatogenesis and piRNA-directed DNA methylation of young LINE1 elements. We propose that young LINE1 elements require a two-factor authentication process for DNA methylation, the first being the recruitment of SPIN1-SPOCD1 to licence the locus and the second is MIWI2 engagement with the nascent transcript, which is also the trigger for methylation. In summary, independent events that licence, and trigger methylation underpin the basis of precision.
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| Overall design |
CUT&TAG sequencing of histone modifications H3K4me3 and H3K9me3 as well as the protein SPIN1 in E14.5 foetal germ cells with corresponding IgG controls.
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| Web link |
https://pubmed.ncbi.nlm.nih.gov/39294378/
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| Contributor(s) |
Heep M, Zoch A, Leismann J, Webb S, Berrens RV, Valsakumar D, Kabayama Y, Schito M, Chowdhury T, MacLeod D, Xiang X, Zou J, Rappsilber J, Allshire RC, Voigt P, Cook AG, Barau J, O’Carroll D |
| Citation(s) |
39294378 |
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| Submission date |
Jun 07, 2024 |
| Last update date |
Oct 24, 2024 |
| Contact name |
Shaun Michael Webb |
| E-mail(s) |
shaun.webb@ed.ac.uk
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| Organization name |
University of Edinburgh
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| Department |
Wellcome Trust Centre for Cell Biology
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| Lab |
Bioinformatics Core Facility
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| Street address |
2.21 Swann Building, Kings Buildings
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| City |
Edinburgh |
| ZIP/Postal code |
EH9 3JR |
| Country |
United Kingdom |
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| Platforms (1) |
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| Samples (13)
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| Relations |
| BioProject |
PRJNA1121247 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE269344_RAW.tar |
295.8 Mb |
(http)(custom) |
TAR (of BW) |
SRA Run Selector |
| Raw data are available in SRA |
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