Tumor suppressor genes (TSGs) are essential for normal cellular function in multicellular organisms, but many TSGs and tumor-suppressing mechanisms remain unknown. Planarian flatworms exhibit particularly robust tumor suppression, yet the specific mechanisms underlying this trait remain unclear. Here, we analyze histone H3 lysine 4 trimethylation (H3K4me3) signal across the planarian genome to determine if the broad H3K4me3 chromatin signature that marks essential cell identity genes and TSGs in mammalian cells is conserved in this valuable model of in vivo stem cell function. We find that this signature is indeed conserved on the planarian genome and that the lysine methyltransferase Set1 is largely responsible for creating it at both cell identity and putative TSG loci. In addition, we show that depletion of set1 in planarians induces stem cell phenotypes that suggest loss of TSG function, including hyperproliferation and an abnormal DNA damage response (DDR). Importantly, this work establishes that Set1 targets specific gene loci in planarian stem cells and marks them with a conserved chromatin signature. Moreover, our data strongly suggest that Set1 activity at these genes has important functional consequences both during normal homeostasis and in response to genotoxic stress.

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Published in Genes, v. 12, issue 8, 1182.

© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

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This research was funded by a Pilot grant from the Elsa U. Pardee Foundation and an NIH/ NIGMS grant (P20 GM121327).

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Genomic data from this study are available from the Gene Expression Omnibus (GEO) database with accession numbers GSE73027 (RNA-seq from WT planarian stem cells), GSE74054 (all X-linked H3K4me3 ChIP-seq), and GSE180591 (Mnase H3K4me3 ChIP-seq).

The following are available online at https://www.mdpi.com/article/10.3390/genes12081182/s1, Figure S1: The H3K4me3 peak width distribution is highly similar between different methods of chromatin solubilization for ChIP-seq. Figure S2: Varying the diffReps window size parameter affects its ability to detect significant changes in H3K4me3 after set1 depletion at some gene loci. Figure S3: A 2 Gy radiation treatment causes abnormal effects in set1(RNAi) stem cells. Table S1: Set1 target gene list. These materials are also available for download as the additional file listed at the end of this record.

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