TY - JOUR T1 - Genetic control of KRAB-ZFP genes explains distal CpG-site methylation which associates with human disease phenotypes JF - bioRxiv DO - 10.1101/2022.01.18.476742 SP - 2022.01.18.476742 AU - Andrew D. Bretherick AU - Yanni Zeng AU - Rosie M. Walker AU - Caroline Hayward AU - David J. Porteous AU - Kathryn L. Evans AU - Andrew M. McIntosh AU - J. Kenneth Baillie AU - Chris Haley AU - Chris P. Ponting Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/01/20/2022.01.18.476742.abstract N2 - Krüppel-associated box zinc finger proteins (KRAB-ZFPs) are the largest gene family of transcriptional regulators in higher vertebrates. We have developed a method for inferring these factors’ DNA binding-sites in vivo. We achieved this by combining the genome-wide association of methylation at 573,027 CpG-sites (meQTL) in blood and KRAB-ZFP RNA expression changes (eQTL). This method’s efficacy is clearly demonstrated by showing that the CpG-sites whose methylation is affected by KRAB-ZFP expression changes occur preferentially near KRAB-ZFP binding-sites in the HEK293T cell line. We found such an enrichment to be significant for 31% of factors tested. In addition, we found that binding-sites of many KRAB-ZFPs are significantly enriched (or sometimes depleted) in disease-associated CpG-sites. In total, 9% (11 of 125) of the traits tested, and 14% (32 of 222) of the factors (KRAB-ZFPs and TIF1-beta) tested, were enriched or depleted in one or more trait-factor pairing. Rheumatoid arthritis and human immunodeficiency virus (HIV) infection were associated with the largest number of KRAB-ZFP enrichments. There have been variable reports on the effects on HIV infection dynamics of transcription intermediary factor 1-beta (TIF1-beta, also known as KAP1 or TRIM28), a nuclear corepressor for KRAB-ZFPs. We provide evidence that KRAB-ZFP-independent effects of TIF1-beta are responsible for the decreased methylation of CpG-sites within its binding-sites that is observed in HIV infection. In conclusion, KRAB-ZFPs often affect CpG-site methylation within the proximity of their binding-sites, and CpG-sites within the binding-sites of KRAB-ZFPs are enriched for association with many traits, including rheumatoid arthritis and HIV infection.Competing Interest StatementAMM has received research support from The Sackler Trust and speaker fees from Illumina and Janssen. All other authors declare no conflicts of interest. ER -