Impact of epigenetic reprogramming on neutrophil function

PROJECT OVERVIEW

Neutrophils are the most abundant circulating leukocytes and form a first line of defence against infection. They rapidly migrate to sites of tissue injury, kill microbes through phagocytosis, degranulation, reactive oxygen species, and neutrophil extracellular trap (NET) formation, and help orchestrate the inflammatory response[1].

Neutrophils undergo one of the most dramatic nuclear transformations in mammalian cells: a round progenitor nucleus becomes highly segmented while its chromatin landscape is extensively reorganised[2]. Defects in neutrophil shape and nuclear segmentation are often associated with disease, including congenital neutrophil disorders, inflammatory syndromes, and impaired host defence.

The transition between round and segmented nuclear shape coincides with depletion of lamin A/C and redistribution of peripheral heterochromatin, but the exact molecular mechanisms and functional consequences for neutrophil transcriptional responses and NET formation are yet unknown.

Builds on our preliminary evidence that neutrophils show altered peripheral heterochromatin and lamin composition during differentiation, we hypothesise that the loss of lamin A/C in mature neutrophils replaces canonical Lamin A/C-dependent anchoring with an alternate protein complex, involving novel lamina-associated proteins and histone-modifying enzymes. This switch may selectively weaken repressive histone modifications in lamina-associated domains, facilitate nuclear segmentation, and prime chromatin for rapid inflammatory responses and NET formation.
Overall, this study will elucidate how nuclear lamins coordinate chromatin dynamics, nuclear architecture, and immune function in neutrophils, offering insight into dysregulated granulopoiesis in disease contexts and identifying points for selective modulation of pathogenic neutrophil responses. It also extends previous work demonstrating stage-specific chromatin remodelling and transcription-factor control during neutrophil maturation and inflammation[3,4].

Objectives

Objective 1: to examine the impact of genetically altered lamin on neutrophil nuclear morphology levels using high-resolution imaging and state-of-the-art microscopy.

Objective 2: to define how lamins influence neutrophil chromatin accessibility using genomic approaches

Objective 3: to identify lamin-associated proteins in neutrophils by mass-spectrometry proteomics

Objective 4: to assess the biological relevance of nuclear structural changes and chromatin remodeling by single cell transcriptomics and functional assays.

KEYWORDS

Neutrophils; lamins; heterochromatin; epigenetics; granulopoiesis

TRAINING OPPORTUNITIES

The Kennedy Institute is a world-renowned research centre and is housed in a state-of-the-art research facility. Training will be provided in a wide range of functional genomics approaches (e.g. RNA-Seq, ATAC-Seq, ChIP-Seq etc), immunological (cell isolation, tissue culture, FACS), and imaging (immunofluorescence on tissue sections) approaches, as well as cutting edge single cell platforms (10x, Nanostring GeoMx, Nanostring CosMx) and computational pipelines.

The project will combine in-vitro neutrophil model culture, directed granulopoiesis, and primary mouse myeloid-cell isolation by flow cytometry with CRISPR/Cas9 knockout, knockdown, and rescue approaches. It will integrate chromatin profiling by CUT&RUN/ChIP-seq, ATAC-seq, and RNA-seq,-together with quantitative confocal imaging, nuclear morphometry, and spatial analysis of peripheral heterochromatin. Protein interaction networks will be examined by co-immunoprecipitation, proximity assays, and targeted mass-spectrometry proteomics. Functional consequences in neutrophils will be assessed using established assays.

A core curriculum of lectures will be taken in the first term to provide a strong foundation across a broad range of subjects, including musculoskeletal biology, inflammation, epigenetics, translational immunology and data analysis. The student will attend weekly seminars within the department and those relevant in the wider University. They will present their research regularly to the department and the Genomics of Inflammation group, and at the Computational Genomics Forum. They will also attend external conferences at which they will present their research to a global audience.

KEY PUBLICATIONS

1. Ng, L.G. et al. From complexity to consensus: A roadmap for neutrophil classification. Immunity. 2025 Aug 12;58(8):1890-1903
2. van Grinsven, E., Mukherjee, A.K. & Udalova, I.A. (2026). Shaping neutrophil morphology and function: the importance of a segmented nucleus. Nature Reviews Immunology 26, 269-283. doi:10.1038/s41577-025-01237-3.
3. Khoyratty, T.E., Ai, Z., Ballesteros, I. et al. (2021). Distinct transcription factor networks control neutrophil-driven inflammation. Nature Immunology 22, 1093-1106. doi:10.1038/s41590-021-00968-4.
4. Devaprasad, A., Ai, Z., Mukherjee, A.K. et al. (2024). Zfp263 is a transcriptional checkpoint of neutrophil development. bioRxiv. doi:10.1101/2024.08.22.609132.

THEMES

• Inflammation biology and innate immunity
• Epigenetics and 3D genome organisation
• Cell differentiation, plasticity and nuclear architecture
• Advanced imaging, genomics and proteomics

CONTACT INFORMATION OF ALL SUPERVISORS

Professor Irina A. Udalova (Lead supervisor) 

Professor Benedikt M. Kessler (Proteomics co-supervisor)

Dr Ananda Kishore Mukherjee (Postdoctoral supervisor)