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

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/

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/

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/

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

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

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

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

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/

Transcription factor Etv3 controls the tolerogenic function of dendritic cells Dendritic cells (DCs) facilitate the maintenance of immunological tolerance in the steady state. We report that transcription factor Etv3 is preferentially expressed in mature DCs, including tissue-de...

Very happy to share the final chapter of my postdoc work with Boris Reizis @NYU @uchicagocoi.bsky.social published today in @science.org! We identify and define the role of transcription factor ETV3 in the tolerogenic function of dendritic cells (DCs). 1/

www.science.org/doi/10.1126/...

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!

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/

Chromatin-mediated anticipatory control of type I interferon production in plasmacytoid dendritic cells Powerful interferon (IFN)-I-producing capacity distinguishes plasmacytoid dendritic cells (pDCs) from related innate cells. Adams et al. find that, during pDC development, the locus encoding IFN-I gen...

Why are pDCs so good at producing type I interferons? We set out to address this long unanswered question in our @cp-immunity.bsky.social study. A great collaboration between the Reizis Lab @NYU @uchicagocoi.bsky.social and @agalicina.bsky.social & Leonid Mirny @MIT 1/
www.cell.com/immunity/ful...

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

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/

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/

Excited to share our work published yesterday (and featured on the cover!) of #ScienceImmunology. This was a true team effort between the Reizis lab at NYU @uchicagocoi.bsky.social and Sasha Galitsyna & Leonid Mirny at MIT 1/
www.science.org/doi/10.1126/...