RNA interference knockdown of DNA methyltransferase 3 affects gene alternative splicing in the honey bee

Hongmei Li-Byarlay, Yang Li, Hume Stroud, Suhua Feng, Thomas C. Newman, Megan Kaneda, Kirk K. Hou, Kim C. Worley, Christine G. Elsik, Samuel A. Wickline, Steven E. Jacobsen, Jian Ma, Gene E. Robinson

Research output: Contribution to journalArticlepeer-review

187 Scopus citations


Studies of DNA methylation from fungi, plants, and animals indicate that gene body methylation is ancient and highly conserved in eukaryotic genomes, but its role has not been clearly defined. It has been postulated that regulation of alternative splicing of transcripts was an original function of DNA methylation, but a direct experimental test of the effect of methylation on alternative slicing at the whole genome level has never been performed. To do this, we developed a unique method to administer RNA interference (RNAi) in a high-throughput and noninvasive manner and then used it to knock down the expression of DNA methyltransferase 3 (dnmt3), which is required for de novo DNA methylation. We chose the honey bee (Apis mellifera) for this test because it has recently emerged as an important model organism for studying the effects of DNA methylation on development and social behavior, and DNA methylation in honey bees is predominantly on gene bodies. Here we show that dnmt3 RNAi decreased global genomic methylation level as expected and in addition caused widespread and diverse changes in alternative splicing in fat tissue. Four different types of splicing events were affected by dnmt3 gene knockdown, and change in two types, exon skipping and intron retention, was directly related to decreased methylation. These results demonstrate that one function of gene body DNA methylation is to regulate alternative splicing.

Original languageEnglish (US)
Pages (from-to)12750-12755
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number31
StatePublished - Jul 30 2013
Externally publishedYes


  • Epigenetics
  • Gene regulation
  • Gene silencing
  • Insect

ASJC Scopus subject areas

  • General


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