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MIWI2 and MILI Have Differential Effects on piRNA Biogenesis and DNA Methylation

Manakov, Sergei A. and Pezic, Dubravka and Marinov, Georgi K. and Pastor, William A. and Sachidanandam, Ravi and Aravin, Alexei A. (2015) MIWI2 and MILI Have Differential Effects on piRNA Biogenesis and DNA Methylation. Cell Reports, 12 (8). pp. 1234-1243. ISSN 2211-1247. PMCID PMC4554733.

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In developing male germ cells, prospermatogonia, two Piwi proteins, MILI and MIWI2, use Piwi-interacting RNA (piRNA) guides to repress transposable element (TE) expression and ensure genome stability and proper gametogenesis. In addition to their roles in post-transcriptional TE repression, both proteins are required for DNA methylation of TE sequences. Here, we analyzed the effect of Miwi2 deficiency on piRNA biogenesis and transposon repression. Miwi2 deficiency had only a minor impact on piRNA biogenesis; however, the piRNA profile of Miwi2-knockout mice indicated overexpression of several LINE1 TE families that led to activation of the ping-pong piRNA cycle. Furthermore, we found that MILI and MIWI2 have distinct functions in TE repression in the nucleus. MILI is responsible for DNA methylation of a larger subset of TE families than MIWI2 is, suggesting that the proteins have independent roles in establishing DNA methylation patterns.

Item Type:Article
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URLURL TypeDescription CentralArticle
Marinov, Georgi K.0000-0003-1822-7273
Additional Information:© 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license ( Received: May 14, 2015; revised: July 2, 2015; accepted: July 16, 2015; published: August 13, 2015. We thank Katalin Fejes Tóth and members of the Aravin lab for helpful discussion and comments on the manuscript. We thank Alyssa Maskell (Caltech) for assistance with mouse work. We thank Igor Antoshechkin (Caltech) for help with RNA-seq and Maria Ninova for help with genome annotation. This work was supported by grants from the NIH (R00 HD057233 and DP2 OD007371A) and by the Searle Scholar Award and Packard Fellowship (to A.A.A.). Author Contributions: S.A.M., D.P., and A.A.A. designed the experiments. D.P. performed the experiments, S.A.M. performed computational analysis of all deep-sequencing data, and G.K.M. performed ping-pong analysis. R.S. created bioinformatics tools for small RNA analysis. W.A.P. cloned and sequenced RNA-seq libraries from Mili mutant. S.A.M., D.P., and A.A.A. interpreted the data and wrote the manuscript.
Funding AgencyGrant Number
NIHR00 HD057233
NIHDP2 OD007371A
Searle Scholars ProgramUNSPECIFIED
David and Lucile Packard FoundationUNSPECIFIED
Issue or Number:8
PubMed Central ID:PMC4554733
Record Number:CaltechAUTHORS:20150821-154811940
Persistent URL:
Official Citation:Sergei A. Manakov, Dubravka Pezic, Georgi K. Marinov, William A. Pastor, Ravi Sachidanandam, Alexei A. Aravin, MIWI2 and MILI Have Differential Effects on piRNA Biogenesis and DNA Methylation, Cell Reports, Volume 12, Issue 8, 25 August 2015, Pages 1234-1243, ISSN 2211-1247, (
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:59819
Deposited By: Jason Perez
Deposited On:21 Aug 2015 23:39
Last Modified:29 Oct 2019 23:20

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