Cellular functions of the transposon-derived domesticated SETMAR gene in human cells
Final Report Abstract
SETMAR is a primate specific protein in apes and humans with a not yet fully understood cellular function. With our ongoing studies we are aiming at characterizing the function of SETMAR in humans. It has been shown that the ability of SETMAR to bind transposon derived genomic loci represented by the Hsmar1 IRs is under strong evolutionary constraints. In line with these observations we found that some of the Hsmar1 binding sites are conserved in anthropoid primates. After obtaining experimental indications that the SETMAR protein is under selection in primates for reasons other than its potential to initiate chromosomal recombination we proposed a hypothesis, which assumes that the physiological function of SETMAR is associated with its ability to bind specific genomic loci represented by the Hsmar1 IRs. In this scenario the SETMAR protein and its binding sites would constitute a primatespecific regulatory network, in which the SETMAR functions as a sequence specific chromatin modifier protein. The proposed hypothesis was addressed by studying the binding of SETMAR to human chromosomes in vivo with ChlP-PCR and ChlP-Seq methodology. We determined that SETMAR binds a subset of its putative binding sites and Hsmar1 derived has-mir-548 family of primate-specific miRNAs, but also tethers to chromosomal loci, which are not transposon derived. With a parallel line of experiments we showed that has-mir-548 miRNAs have the potential to regulate gene expression post transcriptionally in primates. Our continuing efforts focus on deducing the proposed primate specific evolutionary network by combining high throughput approaches. Expression profiles obtained from massively parallel sequencing of the entire short and long RNA repertoire of the established human cell lines and conditions are being associated to SETMAR DNA-binding and chromatin modification landscape obtained by ChlP sequencing. Our findings will expectantly shed light on how a primate-specific transposon-mediated gene regulatory innovation was coopted during human evolution to rewire a pre-existing network of histone modification mechanism.
