CTCF-mediated topological boundaries during development foster appropriate gene regulation

Abstract

The genome is organized into repeating topologically associated domains (TADs), each of which is spatially isolated from its neighbor by poorly understood boundary elements thought to be conserved across cell types. Here, we show that deletion of CTCF (CCCTC-binding factor)-binding sites at TAD and sub-TAD topological boundaries that form within the HoxA and HoxC clusters during differentiation not only disturbs local chromatin domain organization and regulatory interactions but also results in homeotic transformations typical of Hox gene misregulation. Moreover, our data suggest that CTCF-dependent boundary function can be modulated by competing forces, such as the self-assembly of polycomb domains within the nucleus. Therefore, CTCF boundaries are not merely static structural components of the genome but instead are locally dynamic regulatory structures that control gene expression during development.

CTCF binding landscape in jawless fish with reference to Hox cluster evolution

“…In mice, the outward CTCF binding motif located between HoxA5 and HoxA6 functions as an anchor point for long range interaction 12 . Studies on cyclostomes should thus help pinpoint the timing of its establishment.…”

Embryonic timing, axial stem cells, chromatin dynamics, and the Hox clock

“…The various subgroups of contiguous Hox genes showing either sustained transcription or subsequent reactivation could be defined by the distribution of bound CTCF proteins, as the deletion of specific CTCF-binding sites within the HoxA and HoxC clusters was found recently to locally disturb the organization of chromatin domains and cause Hox gene misregulation, leading to patterning defects and motoneuron misspecification in mice (Narendra et al 2015(Narendra et al , 2016. As active versus inactive domains of Hox clusters are labeled by the absence or presence of Polycomb complexes, an interplay between these complexes and CTCF to establish these domains may occur (Narendra et al 2015).…”

Static and Dynamic DNA Loops form AP-1-Bound Activation Hubs during Macrophage Development

“…Loop-based transcriptional regulation plays a part in many biological contexts but is critically important for human development and cellular differentiation (Krijger and de Laat, 2016). Alteration of DNA loops has been implicated in a variety of developmental abnormalities and human diseases (Hnisz et al, 2016; Montavon et al, 2011; Narendra et al, 2016). …”