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Big thanks are again in order to @damonrunyon.org and the Bernard Levine Fellowship at NYU for their support! 12/

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The big takeaway: DCs orchestrate tolerance in the steady state by supporting Treg function and ETV3 is central to this process by controlling the fidelity of the DC tolerogenic program. 11/

As a repressor, ETV3 prevented upregulation of a suite of T cell activation factors, including costimulatory molecule OX40L that is typically expressed on DCs during inflammation-induced maturation. Blocking OX40L in ETV3-deficient mice partially rescued the Treg phenotypes. 10/

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Mechanistically, ETV3 regulated multiple tolerogenic pathways in migDCs, including cholesterol efflux and promoting NF-κB footprint on chromatin. 9/

Furthermore, ETV3 deficiency exacerbated TLR7-driven lupus-like disease, consistent with the genetic association of human ETV3 with lupus. We validated that the effect allele of the lupus-associated ETV3 SNP led to lower ETV3 expression in monocyte-derived DCs. 8/

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These same phenotypes were observed in mice with DC-specific deletion of ETV3, supporting a role for ETV3 in maintaining T cell tolerance via the DC compartment. 7/

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ETV3-deficient mice displayed expansion of dysfunctional regulatory T cells and spontaneous conventional T cell activation, precipitating multiorgan T cell infiltration. 6/

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ETV3 facilitated CCR7 expression, migration and homeostatic maturation of DCs in the steady state. 5/

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We found that ETV3 is induced upon DC maturation, and in the steady state is expressed preferentially in migDCs. 4/

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However, transcription factors that control homeostatic DC maturation and promote the tolerogenic function of these migratory DCs (migDCs) were unknown. 3/

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In the steady state, DCs in tissues undergo “homeostatic maturation”, upregulating MHC-II and migrating to the draining LN. This maturation process overlaps with, but is distinct from, inflammation-induced maturation, eliciting T cell tolerance rather than activation. 2/

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Again big thanks to @damonrunyon.org and the Bernard Levine Fellowship at NYU for supporting me and this research over the course of my postdoc!

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Notably, these chromatin changes occurred during pDC development, preceding active transcription of IFN-I genes, suggesting an anticipatory mechanism preparing pDCs for their eventual activation. 7/

Intranuclear translocation and promoter opening were mediated by the pDC-enriched transcription factor IRF8, likely representing one of many mechanisms whereby IRF8 facilitates pDC development and function. 6/

Finally, the promoters of most IFN-I genes showed baseline accessibility specifically in pDCs. 5/

Furthermore, the IFN-I locus underwent changes to its 3D chromatin structure during pDC differentiation, becoming organized into a distinct TAD and preemptively partitioned into A-compartments. It followed that the pDC IFN-I response was critically dependent on cohesin. 4/

During pDC differentiation, the IFN-I locus translocated into the transcriptionally permissive nuclear interior. Irina Solovei and Simon Ullrich @lmu.de helped us generate these beautiful DNA-FISH images. 3/

Previous work has focused on endosomal signaling in pDCs, yet we were inspired by the fact that all IFN-I genes are clustered together within a single locus. We hypothesized the IFN-I locus is uniquely organized at the chromatin level in pDCs. 2/

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A special thank you to @damonrunyon.org and for the Bernard Levine Fellowship at NYU for supporting me and this research during my postdoc!

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As Sasha eloquently put it, cohesin isn’t just about genome structure-it’s an essential regulator of immune function, influencing how DCs develop and fight pathogens and tumors. 7/

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On the flip-side, TAD boundaries surrounding the Irf8 locus were required for optimal Irf8 expression, supporting a bidirectional interplay between cohesin and IRF8 in driving chromatin architecture and differentiation of cDCs. 6/

The key DC TF IRF8 orchestrated the genome organization of differentiating DCs both by facilitating cohesin-mediated features, and by enforcing cohesin-independent compartmentalization. 5/

In mice with genetic deletion of cohesin subunit Smc3 in DCs, we show that cohesin controls the terminal differentiation and function of conventional DCs, including cross-presentation, IL-12 secretion and DC-dependent response to checkpoint blockade. 4/

We tackled these questions in dendritic cells of the immune system, using a combination of high-throughput chromatin and transcriptional profiling assays in orthogonal genetic models. 3/

It is well established that cohesin extrudes chromatin into TADs, yet its biological implications for cell differentiation and function, and the crosstalk between lineage-specifying TFs and cohesin in shaping chromatin architecture are unclear. 2/