Multiscale 3D Genome Rewiring during Mouse Neural Development

Abstract

SummaryChromosome conformation capture technologies have revealed important insights into genome folding. Yet, how spatial genome architecture is related to gene expression and cell fate remains unclear. We comprehensively mapped 3D chromatin organization during mouse neural differentiation in vitro and in vivo, generating the highest-resolution Hi-C maps available to date. We found that transcription is correlated with chromatin insulation and long-range interactions, but dCas9-mediated activation is insufficient for creating TAD boundaries de novo. Additionally, we discovered long-range contacts between gene bodies of exon-rich, active genes in all cell types. During neural differentiation, contacts between active TADs become less pronounced while inactive TADs interact more strongly. An extensive Polycomb network in stem cells is disrupted, while dynamic interactions between neural transcription factors appear in vivo. Finally, cell type-specific enhancer-promoter contacts are established concomitant to gene expression. This work shows that multiple factors influence the dynamics of chromatin interactions in development.

The HoxD cluster is a dynamic and resilient TAD boundary controlling the segregation of antagonistic regulatory landscapes

“…states of configurations in chromatin architecture as reported earlier Sanyal et al 2012;Berlivet et al 2013;Rao et al 2014;Dixon et al 2015;Bonev et al 2017). While some contacts were constitutive, others appeared only when the TAD enhancers were at work.…”

Intrinsic mechanisms of neuronal axon regeneration

“…This lack of success could be because more than one factor is necessary to fully stimulate the growth process; however, another explanation is that the cellular context dictates the competency of the neurons to respond to a given genetic manipulation. Indeed, multiple factors influence the dynamics of chromatin interactions during development 201,226 , and each cell type is likely to have a specific, unique chromatin organization. In the context of cellular reprogramming, the accessibility of the chromatin to a given transcription factor dictates the effectiveness of the conversion 227 .…”

Forces driving the three‐dimensional folding of eukaryotic genomes

“…For instance, upon stem cell differentiation (Dixon et al , ; Fraser et al , ), reprogramming (Beagan et al , ; Krijger et al , ), or cytokine stimulation (Jin et al , ; Le Dily et al , ), TADs exhibit only limited changes (e.g., ~ 11% shifted at least one boundary upon treatment with TNFα). Nevertheless, this limited variation in TAD boundaries can be associated with expression changes in key cell identity genes (Bonev et al , ; Stadhouders et al , ) and in “compartment switching” (Fraser et al , ) illustrating again the importance of TAD‐imposed topological restrictions in gene expression control. Similarly, comparative analysis of Hi‐C data from four mammals revealed that the partitioning of chromosomes into TADs is conserved once syntenic regions are considered.…”

“…On the basis of this new knowledge, whole‐genome conformation studies have been used to decipher how development or developmental disease (Dixon et al , ; Fraser et al , ; Lupiáñez et al , ; Franke et al , ; Bonev et al , ), cancer (Flavahan et al , ; Taberlay et al , ; Hnisz et al , ; Wu et al , ), DNA damage (Aymard et al , ; Canela et al , ), cellular aging (Criscione et al , ), and genetic variation (Javierre et al , ) impact on the structure and function of the genome. Needless to say that the advent of 3C technology (see overview in Denker & de Laat, ) has also provided insights into the higher order genomic organization of bacteria (e.g., Le & Laub, ; Lioy et al , ), fungi (e.g., Mizuguchi et al , ; Kim et al , ; Tanizawa et al , ), nematodes (e.g., Crane et al , ), the Plasmodium falciparum parasite (Ay et al , ), and plants (e.g., Dong et al , ).…”