title: High-resolution profiling of the LEDGF/p75 chromatin interaction in the ENCODE region.
abstract: Lens epithelium-derived growth factor/p75 (LEDGF/p75) is a transcriptional coactivator involved in stress response, autoimmune disease, cancer and HIV replication. A fusion between the nuclear pore protein NUP98 and LEDGF/p75 has been found in human acute and chronic myeloid leukemia and association of LEDGF/p75 with mixed-lineage leukemia (MLL)/menin is critical for leukemic transformation. During lentiviral replication, LEDGF/p75 tethers the pre-integration complex to the host chromatin resulting in a bias of integration into active transcription units (TUs). The consensus function of LEDGF/p75 is tethering of cargos to chromatin. In this regard, we determined the LEDGF/p75 chromatin binding profile. To this purpose, we used DamID technology and focused on the highly annotated ENCODE (Encyclopedia of DNA Elements) regions. LEDGF/p75 primarily binds downstream of the transcription start site of active TUs in agreement with the enrichment of HIV-1 integration sites at these locations. We show that LEDGF/p75 binding is not restricted to stress response elements in the genome, and correlation analysis with more than 200 genomic features revealed an association with active chromatin markers, such as H3 and H4 acetylation, H3K4 monomethylation and RNA polymerase II binding. Interestingly, some associations did not correlate with HIV-1 integration indicating that not all LEDGF/p75 complexes on the chromosome are amenable to HIV-1 integration.
authors.affiliation: Laboratory for Molecular Virology and Gene Therapy, KULeuven and IRC KULAK, Kapucijnenvoer 33, B-3000 Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: De Rijck
authors.forename: Koen
authors.initials: K
authors.lastname: Bartholomeeusen
authors.forename: Hugo
authors.initials: H
authors.lastname: Ceulemans
authors.forename: Zeger
authors.initials: Z
authors.lastname: Debyser
authors.forename: Rik
authors.initials: R
authors.lastname: Gijsbers
mesh_terms: D001665:Binding Sites; D002460:Cell Line; D002843:Chromatin / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000737:chemistry; D015497:HIV-1 / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D024363:Transcription Initiation Site; D014158:Transcription, Genetic; D016662:Virus Integration
chemical_list: D002843:Chromatin; D036341:Intercellular Signaling Peptides and Proteins; D011993:Recombinant Fusion Proteins; C119380:lens epithelium-derived growth factor; D004247:DNA