SETMAR regulates gene expression and modulates higher order chromatin structure [II]
The human genome contains thousands of sequences of unknown function, many derived from transposable elements. One such element, the DNA transposon Hsmar1, entered the primate lineage approximately 50 million years ago leaving behind terminal inverted repeat (TIR) sequences and a single intact copy of the MAR transposase fused with a SET domain in the chimeric SETMAR gene. Although no longer capable of catalyzing transposition, SETMAR retains its ancestral sequence-specific TIR-DNA binding activity. Here, we provide a structural basis for SETMAR-TIR interactions and identify ~5000 TIR sequences in the human genome that are recognized by SETMAR and conserved in simian primate genomes. Surprisingly, 95% of these TIRs are located outside of promoter regions. We demonstrate that loss of SETMAR in human cells results in differential expression of ~2400 genes and alters higher order chromatin structure. Thus, we suggest that through its interactions with TIR sequences, SETMAR functions as a chromatin-organizing factor, a distinct role for a transposon-derived protein and one that is present only in simian primates. Overall design: HEK293T parental cells were compared to 1F9 SETMAR knockout cells (which were derived by using CRISPR/Cas9 gene editing to silence SETMAR in HEK293T cells). 8 total samples were analyzed,  4 replicates of each cell line. HEK293T cells are the parental control.