Regulation of endogenous retroelements by the Human Silencing Hub (HUSH) complex

The HUSH complex creates repressive chromatin in two ways (reviewed in Seczynska and Lehner 2023). Firstly, HUSH can cause spreading of existing heterochromatin by binding existing trimethylated H3K9 and recruiting SETDB1 to trimethylate H3K9 of adjacent nucleosomes. Secondly, HUSH can initiate heterochromatin by binding nascent transcripts via its PHPLN1 subunit and recruiting SETDB1 to trimethylate lysine-9 of histone H3 (H3K9) at the locus being transcribed.

By an uncharacterized mechanism, the HUSH complex targets long intronless cDNAs, such as those produced by retroelements, as well as unusually long exons of normal cellular genes. Introns somehow protect against silencing by HUSH, though actual splicing is not required. In mice, ZNF638 (NP220, Znf638 gene) recruits the HUSH complex to unintegrated murine leukemia virus (MLV) and in human cells ZNF638 (NP220) and HUSH silence recombinant adeno-associated viruses. The potential recruitment of HUSH by ZNF638 to human retroelements is not yet demonstrated.