About Our Research

The Section of Genetics and Physiology explores how cytokines control genetic programs, with an emphasis on the mammary gland and immune regulation. We use genomic technologies to identify complex regulatory elements and investigate their structure and function through advanced genome-editing. With the emergence of COVID-19, we used our expertise in a quest to understand the cytokine storm and immune response in patients infected with SARS-CoV-2, and the newly emerging highly infective variants of concern (VOC). As part of this, we also conduct studies to identify and understand the genetic programs in mammary tissue, kidney and lung following cytokine storms seen in COVID-19 patients.  

Current Research

COVID-19

The emergence of COVID-19 called for an unprecedented effort to understand the overreacting and uncontrolled immune system in patients infected with SARS-CoV-2. The immune system is controlled by cytokines, their cellular receptors, tyrosine kinases and transcription factors from the STAT family. Our extensive experience in cytokine signaling and genomic technologies placed us in a prime position to contribute to the global efforts to understand and combat COVID-19. We also had access to patients from the Ischgl community, which had gone through a superspreading event at the dawn of the pandemic, in February 2020. This permitted us to investigate specific immune responses in a cohort of highly exposed asymptomatic and symptomatic patients. 

SARS-CoV-2 infection ranges from asymptomatic to severe with lingering symptomatology and sequelae in some. We investigated the immune activation in individuals from the Ischgl community following a superspreading event through a comparative transcriptome analysis and showed that asymptomatic infection was not associated with enduring immunological activation (1). We are currently expanding our investigation to patients infected with more infectious variants, such as B.1.351 and B.1.1.7, and to patients with underlying conditions, such as cystic fibrosis. This will aid our understanding of specific immune responses triggered by the new variants of concern (VOC).

The cytokine storm following SARS-CoV-2 infection activates genetic programs in different tissues, including airway epithelium and kidney, which are critical for the disease progression. We have characterized and defined the responses of primary human kidney (2) and bronchial cells (3) to interferons that trigger the cytokine storm through genomic technologies. 

Genetic programs in the mammary gland

Although COVID-19 resulted in a major shift of our research, we continue to address fundamental problems related to the activation of genetic programs in mammary tissue during pregnancy and lactation. Current research is aimed towards an understanding the genetic logic behind mammary-specific programs. Our scientists have discovered that JAK-STAT signaling pathways are essential for the establishment of the mammary gland and the activation of specific genetic programs during pregnancy. Using large-scale genomic approaches (ChIP-seq, Hi-C, RNA-seq), we continue to explore the chromatin landscape of differentiating mammary cells as a means to identify putative key regulatory elements. Super-enhancers and other regulatory elements have been identified and their structures and functions are being investigated using tools of experimental genetics,(4-8). Our scientists continue to investigate the fidelity of the fast-evolving CRISPR/Cas9 genome editing technologies, including deaminase base editing (4,8-11).

1. Lee, H.K., Knabl, L., Pipperger, L., Volland, A., Furth, P.A., Kang, K., Smith, H.E., Knabl, L., Sr., Bellmann, R., Bernhard, C. et al. (2021) Immune transcriptomes of highly exposed SARS-CoV-2 asymptomatic seropositive versus seronegative individuals from the Ischgl community. Sci Rep, 11, 4243.
2. Jankowski, J., Lee, H.K., Wilflingseder, J. and Hennighausen, L. (2021) Interferon-regulated genetic programs and JAK/STAT pathway activate the intronic promoter of the short ACE2 isoform in renal proximal tubules. bioRxiv.
3. Lee, H.K., Jung, O. and Hennighausen, L. (2020) Activation of ACE2 and interferon-stimulated transcriptomes in human airway epithelium is curbed by Janus Kinase inhibitors. bioRxiv.
4. Lee, H.K., Willi, M., Miller, S.M., Kim, S., Liu, C., Liu, D.R. and Hennighausen, L. (2018) Targeting fidelity of adenine and cytosine base editors in mouse embryos. Nat Commun, 9, 4804.
5. Lee, H.K., Willi, M., Shin, H.Y., Liu, C. and Hennighausen, L. (2018) Progressing super-enhancer landscape during mammary differentiation controls tissue-specific gene regulation. Nucleic Acids Res, 46, 10796-10809.
6. Lee, H.K., Willi, M., Smith, H.E., Miller, S.M., Liu, D.R., Liu, C. and Hennighausen, L. (2019) Simultaneous targeting of linked loci in mouse embryos using base editing. Sci Rep, 9, 1662.
7. Lee, H.K., Willi, M., Wang, C., Yang, C.M., Smith, H.E., Liu, C. and Hennighausen, L. (2017) Functional assessment of CTCF sites at cytokine-sensing mammary enhancers using CRISPR/Cas9 gene editing in mice. Nucleic Acids Res, 45, 4606-4618.
8. Shin, H.Y., Willi, M., HyunYoo, K., Zeng, X., Wang, C., Metser, G. and Hennighausen, L. (2016) Hierarchy within the mammary STAT5-driven Wap super-enhancer. Nat Genet, 48, 904-911.
9. Lee, H.K., Smith, H.E., Liu, C., Willi, M. and Hennighausen, L. (2020) Cytosine base editor 4 but not adenine base editor generates off-target mutations in mouse embryos. Commun Biol, 3, 19.
10. Willi, M., Smith, H.E., Wang, C., Liu, C. and Hennighausen, L. (2018) Mutation frequency is not increased in CRISPR-Cas9-edited mice. Nat Methods, 15, 756-758.
11. Shin, H.Y., Wang, C., Lee, H.K., Yoo, K.H., Zeng, X., Kuhns, T., Yang, C.M., Mohr, T., Liu, C. and Hennighausen, L. (2017) CRISPR/Cas9 targeting events cause complex deletions and insertions at 17 sites in the mouse genome. Nat Commun, 8, 15464. 

Current Collaborators

• Kyun Bae Bae (Gwangju, South Korea)
• So-young Bang (Hanyang University, Seoul, South Korea)
• Simon Choi (Gwangju, South Korea)
• Jason Kim (Gwangju, South Korea)
• Ludwig Knabl (Tyrol, Austria)
• Markus List (Munich, Germany)
• Chengyu Liu (NHLBI, NIH)
• John O’Shea (NIAMS, NIH)
• Kyung Hyun Yoo (Seoul, South Korea)
• Dorothee von Laer (Innsbruck, Austria) 
• Bing Mei Zhu (Chengdu, China)

Our Section in the News

• NIH Catalyst: Creating a “Spellchecker” for Genes
• NIH I Am IRP Blog: Cutting-Edge Technique Simultaneously Edits Multiple Genetic Targets
• NIH Record: NIDDK Scientist Pedals His Way to 'Ancien' Status