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Genome 3D structure regulation of Immune cell development and activation


Each type of cell in the immune system performs critical function to protect the body and maintain health. In the past few decades, the development and activation of T, B and NK cells have been thoroughly studied. However, it’s only until recently that we developed high throughput technology to study how genome folding structure is regulated in the immune cell development process. Here, I exploited the new techniques to study the development of B cell, T cell, and the activation process of neutrophils.

In B cell activation, the transition from the follicular B to the plasma cell stage is orchestrated by an ensemble of transcriptional regulators. We examined how changes in expression patterns of key developmental regulators relate to alterations in nuclear positioning and found that gene activation at the onset of plasma cell development was concomitant with a gain in euchromatic character for an ensemble of genomic regions that dictate plasma cell fate, including the Prdm1 and Atf4 loci. We found that to permit the onset of plasma cell development the Ebf1 locus repositioned to peri-centromeric heterochromatin. Plasma cell differentiation was also associated with increased inter-chromosomal associations concurrent with alterations in gene expression and co-localization of Prdm1, Xbp1 and Atf4 transcripts in nuclear bodies. These data indicate that Ebf1 enforces the follicular B cell fate and that the onset of plasma cell fate is orchestrated by elaborate changes in compartmentalization and inter-chromosomal associations.

In T cell differentiation, it is well known that Bcl11b specifies T cell fate. Here, we show that in developing T cells, the Bcl11b enhancer repositioned from the lamina to the nuclear interior. Our identified a non-coding RNA named ThymoD (thymocyte differentiation factor) controls the re-localization of Bcl11b enhancers. ThymoD transcription promoted demethylation at CTCF bound sites and activated cohesin-dependent looping to reposition the Bcl11b enhancer from the lamina to the nuclear interior and to juxtapose the Bcl11b enhancer and promoter into a single-loop domain. These large-scale changes in nuclear architecture were associated with the deposition of activating epigenetic marks across the loop domain, plausibly facilitating phase separation. These finding indicate how noncoding transcription orchestrates chromatin folding and compartmentalization to direct with high precision enhancer-promoter communication.

During neutrophil activation, the cell undergoes large-scale changes in nuclear morphology. We found that neutrophils rapidly (<3 hours) repositioned the ensemble of pro-inflammatory genes towards the transcriptionally permissive compartment upon microbial exposure. The repositioning of genes was closely lined with recruitment of cohesin, which permits immediate enhancer-promoter interaction and activation of genes. In the meantime, the activated enhancers were highly associated with cistromic elements occupied by PU.1, CEBPB, TFE3, JUN and FOSL2. The study revealed, upon microbial challenge, how the cohesin machinery is recruited to an activated enhancer repertoire to activate an inflammatory gene program through regulating 3D genome structure.

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