Abstract
All life forms defend their genome against DNA invasion. Eukaryotic cells recognize incoming DNA and limit its transcription through repressive chromatin modifications. The human silencing hub (HUSH) complex transcriptionally represses long interspersed element-1 retrotransposons (L1s) and retroviruses through histone H3 lysine 9 trimethylation (H3K9me3)1–3. How HUSH recognizes and initiates silencing of these invading genetic elements is unknown. Here we show that HUSH is able to recognize and transcriptionally repress a broad range of long, intronless transgenes. Intron insertion into HUSH-repressed transgenes counteracts repression, even in the absence of intron splicing. HUSH binds transcripts from the target locus, prior to and independent of H3K9me3 deposition, and target transcription is essential for both initiation and propagation of HUSH-mediated H3K9me3. Genomic data reveal how HUSH binds and represses a subset of endogenous intronless genes generated through retrotransposition of cellular mRNAs. Thus intronless cDNA—the hallmark of reverse transcription—provides a versatile way to distinguish invading retroelements from host genes and enables HUSH to protect the genome from ‘non-self’ DNA, despite there being no previous exposure to the invading element. Our findings reveal the existence of a transcription-dependent genome-surveillance system and explain how it provides immediate protection against newly acquired elements while avoiding inappropriate repression of host genes.
Highlights
To silence mobile elements, the human silencing hub (HUSH) complex of TASOR, MPP8 and periphilin, recruits two effectors: MORC2—an ATP-dependent chromatin remodeller—enables chromatin compaction[13,14], and SETDB1 deposits H3K9me[31]
Since HUSH-repressed long interspersed element-1 retrotransposons (L1s) are found in diverse genomic integration sites[2,3,15], the signal for HUSH recognition must be intrinsic to the L1
L1 expression was monitored by flow cytometry with iRFP fluorescence reflecting L1 mRNA abundance (Extended Data Fig. 1a)
Summary
Our study reveals how the HUSH epigenetic repressor complex provides a versatile defence system against genome invasion. Similar to S. pombe, transcription-induced recruitment of HUSH to replicated chromatin may ensure inheritance of the repressed state following DNA replication[26,27]. Most mammalian genes are organized such that exons comprise small islands within a sea of intronic sequences, whereas the cDNA products of reverse transcription are RNA-derived and intronless. Intronless cDNA, the product of reverse transcription, is the molecular pattern recognized by HUSH, which provides a means to distinguish invading retroelements from host genes. To avoid HUSH recognition, retroelements would need to maintain long, non-coding intron sequences, but are constrained by selective pressure for a compact genome. By rapidly repressing transcription of novel retroelements without the need for genetic memory, HUSH buffers any potentially deleterious effects on cellular fitness. A. et al Epigenetic silencing by the HUSH complex mediates position-effect variegation in human cells. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
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