The role of CTCF in the organization of the centromeric 11p15 imprinted domain interactome

Abstract

DNA methylation, chromatin-binding proteins, and DNA looping are common components regulating genomic imprinting which leads to parent-specific monoallelic gene expression. Loss of methylation (LOM) at the human imprinting center 2 (IC2) on chromosome 11p15 is the most common cause of the imprinting overgrowth disorder Beckwith-Wiedemann Syndrome (BWS). Here, we report a familial transmission of a 7.6 kB deletion that ablates the core promoter of KCNQ1. This structural alteration leads to IC2 LOM and causes recurrent BWS. We find that occupancy of the chromatin organizer CTCF is disrupted proximal to the deletion, which causes chromatin architecture changes both in cis and in trans. We also profile the chromatin architecture of IC2 in patients with sporadic BWS caused by isolated LOM to identify conserved features of IC2 regulatory disruption. A strong interaction between CTCF sites around KCNQ1 and CDKN1C likely drive their expression on the maternal allele, while a weaker interaction involving the imprinting control region element may impede this connection and mediate gene silencing on the paternal allele. We present an imprinting model in which KCNQ1 transcription is necessary for appropriate CTCF binding and a novel chromatin conformation to drive allele-specific gene expression.

Allele-specific aberration of imprinted domain chromosome architecture associates with large offspring syndrome

“…We showed this to be the case for expression of IGF2R and DNA methylation at KvDMR1 in this study. Further, using fibroblast cells will allow comparison of findings with the human counterpart syndrome BWS, since skin fibroblasts is one of the frequently obtained tissue samples from these patients and is being used to characterize the syndrome ( Brioude et al., 2018 ; Naveh et al., 2021 ).…”

Exploring chromatin structural roles of non-coding RNAs at imprinted domains

“…Finally, it is timely to determine the importance of lncRNAs and chromatin architecture in human imprinting disorders (IDs) [ 4 , 69 ]. Initial studies have reported altered chromatin structural interactions within the KCNQ1 and IGF2-H19 domains in the growth disorders Beckwith-Wiedemann Syndrome (BWS) and Silver-Russell Syndrome (SRS) [ 102 , 128 , 129 ].…”

Widespread allele-specific topological domains in the human genome are not confined to imprinted gene clusters

“…The viewpoint interaction traces mostly show weak biallelic interaction traces for the KvDMR associations. The CTCF site highlighted with an * is “region 3”, previously been shown to be important for allele-specific (maternal) expression of KCNQ1 (Naveh et al ., 2021).…”

“…In contrast, the adjacent imprinted gene cluster, clearly shows that the ICR (Kv-DMR) regulating imprinting at the KCNQ1 locus, has weak if any effects on 3D chromatin structure. If there is allele-specific loop extrusion, this occurs at a CTCF site previously identified as “region 3” and shown to be required for setting up a maternal allele-specific loop to facilitate KCNQ1 expression (Naveh et al ., 2021). The paternally expressed KCNQ1OT1 lncRNA transcript is regulated by the Kv-DMR, and its transcription may disrupt CTCF binding at region 3 on the paternal allele to prevent this loop.…”