Global Genome Conformational Programming during Neuronal Development Is Associated with CTCF and Nuclear FGFR1-The Genome Archipelago Model.

Brandon Decker,Hussam Abdellatif,Josep M Jornet,Michal Liput,Yongho Bae,Michal K Stachowiak,Donald Yergeau,Ewa K Stachowiak

doi:10.3390/ijms22010347

Abstract

During the development of mouse embryonic stem cells (ESC) to neuronal committed cells (NCC), coordinated changes in the expression of 2851 genes take place, mediated by the nuclear form of FGFR1. In this paper, widespread differences are demonstrated in the ESC and NCC inter- and intra-chromosomal interactions, chromatin looping, the formation of CTCF- and nFGFR1-linked Topologically Associating Domains (TADs) on a genome-wide scale and in exemplary HoxA-D loci. The analysis centered on HoxA cluster shows that blocking FGFR1 disrupts the loop formation. FGFR1 binding and genome locales are predictive of the genome interactions; likewise, chromatin interactions along with nFGFR1 binding are predictive of the genome function and correlate with genome regulatory attributes and gene expression. This study advances a topologically integrated genome archipelago model that undergoes structural transformations through the formation of nFGFR1-associated TADs. The makeover of the TAD islands serves to recruit distinct ontogenic programs during the development of the ESC to NCC.

Highlights

The ontogenic process begins with the pluripotent Embryonic Stem Cells (ESCs) of the blastocyst giving rise to all cell types in the body [1]
The study explored the fundamental phase of neuronal development, differentiation of the ESCs to neuronal committed cells (NCC) and the roles of two proteins, the pan-ontogenic genome programmer nFGFR1 and the architectural protein CTCF in chromatin structural organization and remodeling
At the level of 4.5 mb genomic spans, visible differences were observed between ESC and NCC interactomes, including within the HoxA-D gene clusters

Summary

Introduction

The ontogenic process begins with the pluripotent Embryonic Stem Cells (ESCs) of the blastocyst giving rise to all cell types in the body [1] This development potential gradually becomes restricted as the cells proceed to their terminal tissue phenotypes. Differentiation of human NCC from the neural stem cells alters the expression of 4704 genes [3], the majority of which bind nFGFR1 [4]. This development of NCCs is accompanied by (1) the deconstruction of coordinated gene activity networks that underwrite phenotypes of non-differentiated cells and (2) the construction of new coordinated networks underwriting cell differentiation and neuronal development. Our overall question is how can thousands of diverse genes at different genomic locations be coordinately expressed and regulated?

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Conclusion