Biology subjects

Katko, A.

Publications and source records attributed to Katko, A..

4 recordsLinked to original sources

bioRxiv2026

Gene regulatory networks define human airway epithelial cell types and their distinct responses to type I interferon

The human airway epithelium (HAE) is composed of diverse cell types that coordinate essential functions and host defenses. Among these defenses, interferons (IFNs) are central to antiviral programs. However, the gene regulatory networks (GRNs) governing HAE cellular identities and their IFN responses are incompletely defined. At single-cell resolution, we characterized the transcriptomes and accessible chromatin landscapes of HAE cell types, at steady state and following IFN{beta} stimulation. The resulting scRNA-seq and snATAC-seq data informed genome-scale GRN construction and inference of transcriptional circuits underlying cell identities. In response to IFN, we identified a shared transcriptional program across HAE cell types, and an expanded set of interferon-responsive genes exhibiting cell type-associated expression patterns. Cell type-associated transcription factors and chromatin accessibility contribute to distinct IFN-responsive gene expression programs. Together, these data provide a blueprint for molecular regulation of complex HAE responses and a foundation for therapeutic strategies to enhance host antiviral defense.

systems biology↗

bioRxiv2025

Gene regulatory network determinants of rapid recall in human memory CD4+ T cells

Rapid recall is the hallmark of memory T cells. While naive cells require days to mount effector responses to new threats, antigen-experienced memory cells produce cytokines within hours of repeat encounter. Memory establishment and the control of rapid recall across lifespan is poorly understood. Epigenetic poising is a likely mechanism. Compared to naive, memory cells exhibit enhanced chromatin accessibility proximal to rapid recall genes, but the transcription factors (TFs) that establish, maintain and utilize these putative regulatory elements are unknown. We leverage single-nuclei (sn)multiome-seq (snRNA-seq and snATAC-seq) to characterize the dynamic activation responses of CD4+ T cell subsets and (2) reconstruct the underlying gene regulatory networks. Memory-associated TFs (MAF, PRDM1, RUNX2, SMAD3, KLF6) were predicted to orchestrate rapid recall. KLF6 binding to its predicted target genes was confirmed by ChIP-seq, while the memory-associated activities of all five factors replicated in independent scRNA-seq studies. Integrating GWAS data, we nominate CD4+ T cell populations and gene regulatory mechanisms that might underly genetic risk to immune-mediated diseases.

systems biology↗

bioRxiv2023

An atlas of gene regulatory networks for T memory cells in youth and old age

Aging profoundly affects immune-system function, promoting susceptibility to pathogens, cancers and chronic inflammation. We previously identified a population of IL-10-producing, T follicular helper-like cells ("Tfh10"), linked to suppressed vaccine responses in aged mice. Here, we integrate single-cell (sc)RNA-seq, scATAC-seq and genome-scale modeling to characterize Tfh10 - and the full CD4+ memory T cell (CD4+TM) compartment - in young and old mice. We identified 13 CD4+TM populations, which we validated through cross-comparison to prior scRNA-seq studies. We built gene regulatory networks (GRNs) that predict transcription-factor control of gene expression in each T-cell population and how these circuits change with age. Through integration with pan-cell aging atlases, we identified intercellular-signaling networks driving age-dependent changes in CD4+TM. Our atlas of finely resolved CD4+TM subsets, GRNs and cell-cell communication networks is a comprehensive resource of predicted regulatory mechanisms operative in memory T cells, presenting new opportunities to improve immune responses in the elderly.

immunology↗

bioRxiv2018

A non-canonical metal center drives activity of the Sediminispirochaeta smaragdinae metallo-β- lactamase SPS-1

In an effort to evaluate whether a recently reported putative metallo-{beta}-lactamase (M{beta}L) contains a novel M{beta}L active site, SPS-1 from Sediminispirochaeta smaragdinae was over-expressed, purified, and characterized using spectroscopic and crystallographic studies. Metal analyses demonstrate that recombinant SPS-1 binds nearly 2 equivalents of Zn (II), and steady-state kinetic studies show that the enzyme hydrolyzes carbapenems and certain cephalosporins but not {beta}-lactam substrates with bulky substituents in the 6-7 position. Spectroscopic studies on Co (II)-substituted SPS-1 suggest a novel metal center in SPS-1, with reduced spin coupling between the metal ions and a novel Zn1 metal binding site. This site was confirmed with a crystal structure of the enzyme. The structure shows a Zn2 site that is similar that that in NDM-1 and other subclass B1 M{beta}Ls; however, the Zn1 metal ion is coordinated by 2 histidine residues and a water molecule, which is held in position by a hydrogen bond network. The Zn1 metal is displaced nearly 1 [A] from the position reported in other M{beta}Ls. The structure also shows extended helices above the active site, which create a binding pocket that precludes the binding of substrates with large, bulky substituents in the 6/7 position of {beta}-lactam antibiotics. This study reveals a novel metal binding site in M{beta}Ls, and suggests that the targeting of metal binding sites in M{beta}Ls with inhibitors is now more challenging with the identification of this new M{beta}L.

biochemistry↗