'Organisation for Economic Co-Operation and Development (OECD)'
Doi
Abstract
BACKGROUND: CTCF binding to DNA helps partition the mammalian genome into discrete structural and regulatory domains. Complete removal of CTCF from mammalian cells causes catastrophic genome dysregulation, likely due to widespread collapse of 3D chromatin looping and alterations to inter- and intra-TAD interactions within the nucleus. In contrast, Ctcf hemizygous mice with lifelong reduction of CTCF expression are viable, albeit with increased cancer incidence. Here, we exploit chronic Ctcf hemizygosity to reveal its homeostatic roles in maintaining genome function and integrity. RESULTS: We find that Ctcf hemizygous cells show modest but robust changes in almost a thousand sites of genomic CTCF occupancy; these are enriched for lower affinity binding events with weaker evolutionary conservation across the mouse lineage. Furthermore, we observe dysregulation of the expression of several hundred genes, which are concentrated in cancer-related pathways, and are caused by changes in transcriptional regulation. Chromatin structure is preserved but some loop interactions are destabilized; these are often found around differentially expressed genes and their enhancers. Importantly, the transcriptional alterations identified in vitro are recapitulated in mouse tumors and also in human cancers. CONCLUSIONS: This multi-dimensional genomic and epigenomic profiling of a Ctcf hemizygous mouse model system shows that chronic depletion of CTCF dysregulates steady-state gene expression by subtly altering transcriptional regulation, changes which can also be observed in primary tumors.This work was supported by Cancer Research UK (SJA, XIS, CF, JCM, DTO: 20412), the Wellcome Trust (SJA: 106563/Z/14; XIS: 108438/Z/15 to JCM; SJA, XIS, CF, DTO: 202878/A/16/Z; 108749/Z/15/Z and 202878/B/16/Z to PF), Pathological Society of Great Britain & Ireland (SJA: SGS 2015/04/04), the European Research Council (CF, DTO: 615584) and the European Molecular Biology Laboratory (EK, PF, JCM)
