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Review
. 2021 Mar 29:12:633825.
doi: 10.3389/fimmu.2021.633825. eCollection 2021.

Spatial Organization of Chromatin: Transcriptional Control of Adaptive Immune Cell Development

Jagan M R Pongubala  1 , Cornelis Murre  2
Affiliations
Review

Spatial Organization of Chromatin: Transcriptional Control of Adaptive Immune Cell Development

Jagan M R Pongubala et al. Front Immunol. .

Abstract

Higher-order spatial organization of the genome into chromatin compartments (permissive and repressive), self-associating domains (TADs), and regulatory loops provides structural integrity and offers diverse gene regulatory controls. In particular, chromatin regulatory loops, which bring enhancer and associated transcription factors in close spatial proximity to target gene promoters, play essential roles in regulating gene expression. The establishment and maintenance of such chromatin loops are predominantly mediated involving CTCF and the cohesin machinery. In recent years, significant progress has been made in revealing how loops are assembled and how they modulate patterns of gene expression. Here we will discuss the mechanistic principles that underpin the establishment of three-dimensional (3D) chromatin structure and how changes in chromatin structure relate to alterations in gene programs that establish immune cell fate.

Keywords: B and T cell development; chromatin organization; cis-regulatory interactions; gene regulatory networks; phase-separation.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The hierarchical organization of the 3D chromatin. Inside the interphase nucleus, chromosomes occupy distinct territories (highlighted by different colors). Within each chromosome territory the chromatin is folded into multiple loops and segregated into two distinct compartments: compartment A clustered around nucleolus and nuclear bodies (permissive region, red lines), and compartment B (repressive region, blue lines) associated with LADs at the nuclear periphery. Chromatin interactions occur predominantly between the compartments with similar biochemical or functional properties. Majority of the chromatin interactions are intra-chromosomal. The permissive chromatin regions tend to position away from the nuclear lamina or from pericentromeric heterochromatin. Preferential self-interactions within the heterochromatin and euchromatin (A and B compartments) regions result in the formation of topologically associating domains (TADs), demarcated by boundary elements enriched with CTCF/Cohesin. Within TADs chromatin undergo multiple folds to form ‘regulatory loops’ that facilitate close proximity interactions between gene promoters and their cognate enhancers.
Figure 2
Figure 2
Chromatin dynamics in B cell progenitors. Hi-C analysis revealed that the mammalian genome is organized into topologically associated domains (TADs), generated by aggregation of self-interaction chromatin regions that feature similar properties, permissive or repressive, respectively. TADs are separated from each other by boundary elements that restrain interactions with adjacent TADs. The boundary elements are enriched with insulator proteins cohesin and CTCF. (A) The cartoon illustrates the Hi-C interactome of the mouse chromosome 12 for a genomic region that is partitioned into multiple TADs at the pre-pro-B cell stage. The frequency of intra-chromosomal interactions is indicated by the color gradient. (B) Schematic representation of the extended TAD of the same genomic region observed in committed B cells (57). During differentiation transcribing regions establish strong ectopic-TAD chromatin interactions leading to the merging of multiple adjacent TADs into a single de novo TAD. The increased cis-regulatory interactions within and between the TADs may be accomplished by loss of insulator proteins at the boundary regions accompanied by binding of TFs to their cognate regulatory elements thereby promoting alterations in genome confirmations. Dotted arrow lines represent possible ectopic-TAD interactions, blue rectangles represent genome scale high-frequency Hi-C interactions, and black arrowheads represent boundary elements.
Figure 3
Figure 3
Mechanism of chromatin loop formation. TADs contain varying number of chromatin loops generated through loop extrusion by CTCF/cohesin complexes. Chromatin loop formation facilitates interactions between promoter and enhancer elements. (Right panel) In the presence of NIPBL and MAU2, the cohesin complex loaded on to the DNA. Then, cohesin extrudes chromatin until a pair of convergent CTCF binding sites is reached. (Right panel) The N-terminus of CTCF and convergent positioning of the CTCF-DNA complex stabilizes cohesin binding and stall chromatin extrusion leading to the establishment higher-order chromatin organization. The intervening DNA between two convergent CTCF sites leads to the formation of a loop domain, which adopts variety of complex shapes comprised of multiple regulatory loops. The internal structure of loop domain is likely determined by polymer chromatin-chromatin self-interactions, which may be further stabilized by phase separation. The contacts within the loop domains facilitate the targeting of enhancers to specific genes (104). The black arrow depicts the direction of loop extrusion.
Figure 4
Figure 4
Role of EBF1 in orchestrating phase separated condensates. Repositioning of Ebf1 locus is illustrated during the developmental transition from pre-pro-B to pro-B stage. (A) Genomic locus of Ebf1 is localized in close spatial proximity to the repressive compartment of the nuclear periphery at the pre-pro-B cell stage. In the absence of Ebf1, B lineage genes are transcriptionally silent due to inaccessibility of the TF to their target sites or lack of TF that are necessary for their activation. (B) The Ebf1 locus repositions from the transcriptionally repressive compartment to the nuclear interior. The Ebf1 locus becomes transcriptionally active in response to PU.1 and E2A binding as well as IL-7R mediated signaling. It has recently been proposed that following activation of Ebf1 at pro-B cell stage and beyond, Ebf1 coordinates the establishment of multivalent interactions involving transcription factors, co-activators and transcription initiation proteins containing unstructured flexible regions to form a phase separation body (143).
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