Decoding STAT1 Isoform-Specific Control of Macrophage Responses Through Multiomics Analysis
While investigating how interferon gamma reshapes macrophage inflammatory responses, researchers at the University of Veterinary Medicine Vienna faced a familiar challenge: integrating transcriptomic and epigenomic data into a coherent biological interpretation required advanced bioinformatics expertise and close scientific dialogue.
Working with Genevia Technologies helped Dr. Birgit Strobl and her team transform a complex multiomics dataset into mechanistic insight, contributing to findings published in BMC Genomics.
Understanding how interferon gamma changes inflammatory signaling
The Birgit Strobl lab at the University of Veterinary Medicine Vienna focuses on immunogenetics and cell signaling, particularly how the JAK-STAT signaling pathway coordinates immune responses during infection and inflammatory disease. Their recent study examined how STAT1 isoforms regulate macrophage responses through coordinated transcriptional and epigenetic mechanisms.
The work formed part of a larger Austrian research initiative, funded by the Austrian Science Fund (FWF; SFB-F61), involving seven groups studying different components of the JAK-STAT pathway. Within this consortium, Dr. Strobl’s team focused on STAT1, a central transcription factor in interferon signaling that exists in two isoforms: the full-length STAT1α and the shorter STAT1β, which lacks part of the C-terminal transactivation domain.
While the group had previously investigated isoform-specific effects at individual genes, this project expanded the question genome-wide: how does interferon gamma preconditioning alter macrophage responses to lipopolysaccharide (LPS), a secondary inflammatory trigger?
Using bulk RNA-seq together with ChIP-seq for the histone marks H3K27ac and H3K4me1, the team compared four genotypes across multiple treatments and time points, generating a dataset that captured both transcriptional and chromatin-level responses.
The results revealed that interferon gamma does not simply enhance inflammatory responses; instead, it selectively suppresses antiviral effector genes normally induced by LPS while simultaneously amplifying or synergizing with other inflammatory programs.
A particularly important finding involved STAT1 isoform-specific repression.
“The suppressive effects of interferon gamma did not work with the STAT1 beta isoform,” Dr. Strobl explains. “Additive and synergistic activities mostly remained intact, but the repressive functions were missing.”
The chromatin data further showed that the missing transactivation domain in STAT1β impaired not only histone acetylation, as previously known, but also deacetylation at regulatory elements.
“The effects on deacetylation were even bigger than the effects on acetylation, which was quite surprising,” she notes.
When bioinformatics becomes the critical bottleneck
Although the experimental side of the project involved extensive work, including standardized consortium-wide protocols and complex sample preparation, Dr. Strobl identifies bioinformatics as the study’s main challenge.
Initial plans to complete the analysis internally became difficult after personnel changes delayed progress, putting pressure on a PhD project built around the study.
“We had to make sure the PhD student could finish in time,” Dr. Strobl says. “The experiments already took a long time, and then bioinformatics became the real bottleneck.”
The team turned to Genevia after hearing positive recommendations from colleagues, and shortly after an introductory call with Genevia’s CEO, Antti Ylipää, the collaboration began.
Early project phases focused on RNA-seq analysis, led by Genevia’s bioinformatician Dr. Maria Liivrand. Later, as the ChIP-seq analysis became more demanding, especially around peak calling and histone mark interpretation, Dr. Grigorios Georgolopoulos took over the most complex analytical work.
From data analysis to scientific interpretation
For Dr. Strobl, the collaboration became especially valuable when Genevia’s role expanded beyond technical data processing into scientific interpretation.
“We got so much more than just a bioinformatics service. Genevia’s bioinformatician did much more than just analyze the data. He suggested what we could do, developed his own ideas about interpretation, and helped us understand which additional analyses would be meaningful.”
— Dr. Birgit Strobl, University of Veterinary Medicine Vienna
Rather than functioning purely as an external analyst, Genevia became an active scientific partner.
“Grigorios was really a collaboration partner, not just a bioinformatician doing what we asked. We could discuss science on a very high level,” Dr. Strobl says.
This dialogue became particularly important when moving from gene-level observations to genome-wide conclusions.
“For my biologist’s brain, I looked at some genes and made conclusions. Grigorios could then extrapolate that to the whole genome and test whether what I saw at a single-gene level was actually true genome-wide.”
A key part of the final analysis involved combining RNA-seq and ChIP-seq through regulatory network modeling.
This multiomics integration identified transcription factor communities that help explain the crosstalk between interferon gamma and TLR4 signaling, clarifying why STAT1β preserved some collaborative functions while failing to mediate enhancer repression.
“The ChIP-seq was much harder to interpret than the RNA-seq,” Dr. Strobl says. “What was amazing was not only the analysis itself, but also the biological understanding behind it.”
Genevia’s contribution also extended to manuscript preparation, figure design, supplementary analyses, and refinement of biological conclusions, ultimately leading to co-authorship on the publication.
Collaboration built on responsiveness and trust
Beyond scientific depth, Dr. Strobl highlights communication as a major strength of the collaboration.
Shared cloud infrastructure ensured continuous file access, and email communication remained fast and responsive throughout the project.
“The data transfer was brilliant. We always had access to everything, and emails were always answered very quickly.”
Responsiveness became especially important when timelines tightened.
“Whenever something needed discussion, there was always someone available. Antti even visited us in Vienna so we could discuss in person.”
Later adjustments to Genevia’s service model, introducing a more predictable monthly allocation of analysis time, further improved continuity and planning.
Looking ahead to single-cell studies
Following this study, Dr. Strobl’s group has moved toward single-cell RNA-seq using newly developed mouse models and in vivo infection systems.
The research increasingly focuses on rare immune cell populations in whole-organism settings, where analytical complexity continues to grow.
As new projects emerge, Dr. Strobl says Genevia remains her first choice whenever funding allows.
“If there is ever any bioinformatics support that we need, I would immediately approach Genevia. I would not even look for other providers.”
For Dr. Strobl, the defining value of the collaboration was not simply technical execution, but the level of scientific engagement it enabled.
“I don’t think many people will have this high level of scientific input. It’s hard to find collaboration partners like this.”
— Dr. Birgit Strobl, University of Veterinary Medicine Vienna
Learn more:
- Akagha MJ, et al. IFNγ shapes macrophage inflammatory responses by STAT1 isoform-specific epigenetic and transcriptional mechanisms. BMC Genomics. 2026.
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