Co-transcriptional genome surveillance by HUSH is coupled to termination machinery

Andrew L Spencley; Shiran Bar; Tomek Swigut; Ryan A Flynn; Cameron H Lee; Liang-Fu Chen; Michael C Bassik; Joanna Wysocka

doi:10.1016/j.molcel.2023.04.014

Co-transcriptional genome surveillance by HUSH is coupled to termination machinery

Mol Cell. 2023 May 18;83(10):1623-1639.e8. doi: 10.1016/j.molcel.2023.04.014. Epub 2023 May 9.

Authors

Andrew L Spencley¹, Shiran Bar², Tomek Swigut², Ryan A Flynn³, Cameron H Lee⁴, Liang-Fu Chen², Michael C Bassik⁴, Joanna Wysocka⁵

Affiliations

¹ Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA; Cancer Biology Program, Stanford University School of Medicine, Stanford, CA, USA.
² Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA.
³ Stem Cell Program, Boston Children's Hospital, Boston, MA, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
⁴ Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
⁵ Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA; Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA; Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: [email protected].

Abstract

The HUSH complex recognizes and silences foreign DNA such as viruses, transposons, and transgenes without prior exposure to its targets. Here, we show that endogenous targets of the HUSH complex fall into two distinct classes based on the presence or absence of H3K9me3. These classes are further distinguished by their transposon content and differential response to the loss of HUSH. A de novo genomic rearrangement at the Sox2 locus induces a switch from H3K9me3-independent to H3K9me3-associated HUSH targeting, resulting in silencing. We further demonstrate that HUSH interacts with the termination factor WDR82 and-via its component MPP8-with nascent RNA. HUSH accumulates at sites of high RNAPII occupancy including long exons and transcription termination sites in a manner dependent on WDR82 and CPSF. Together, our results uncover the functional diversity of HUSH targets and show that this vertebrate-specific complex exploits evolutionarily ancient transcription termination machinery for co-transcriptional chromatin targeting and genome surveillance.

Keywords: CPSF; HUSH complex; MPP8; SETDB1; TASOR; WDR82; gene silencing; heterochromatin; transcription termination; transposable elements.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Gene Silencing*
Genome / genetics
RNA
Transcription Factors* / metabolism
Transcription, Genetic

Substances

Transcription Factors
RNA

Abstract

Publication types

MeSH terms

Substances

Grants and funding