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Femtosecond Laser Cross-Linking and Integrated Analytical Workflows for Decoding the Dynamic DNA–Protein Interactome

Objective

FEMTOMICS is redefining analytical chemistry by introducing the first femtosecond-based platform for proteome-wide decoding of dynamic DNA–protein interactions in cells. Capturing weak and transient interactions in intact cells remains a key challenge in measurement science. Chemical cross-linking is slow, perturbs cellular equilibrium, and has limited specificity, while UV irradiation is inefficient, damaging, and fails to stabilise fleeting contacts. Current methods detect abundant interactions, such as histones, but cannot resolve many transcription factors or other DNA-binding proteins whose short-lived bindings are essential for gene regulation. Moreover, genomic, proteomic, and structural layers are typically studied in isolation, overlooking integration.

FEMTOMICS closes these gaps with a paradigm-shifting platform that integrates femtosecond laser cross-linking (fliX) with high-resolution mass spectrometry (fliX–MS) and nanopore sequencing (fliX–NPS). With sub-ps, fliX enables zero-length cross-linking of DNA–protein interactions while preserving DNA integrity. fliX–MS provides proteome-wide detection of DNA-bound proteins at atomic resolution, and fliX–NPS pinpoints binding sites at single-nucleotide resolution with matched transcriptome and methylation profiles; all datasets are integrated through advanced bioinformatics for structural and functional analysis. These modules yield time-resolved, multimodal maps of transient DNA–protein complexes in situ.

By benchmarking against established methods, FEMTOMICS will demonstrate measurable gains in temporal resolution, specificity, and coverage, expanding detection from histones to rare transcription factors. The resulting datasets will reconstruct networks, generate hypotheses, and resolve regulatory states. As proof of concept, the platform will be validated in breast cancer cell models, demonstrating how photonics, sequencing, and data science set new standards in chemistry and medicine.

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HORIZON-ERC - HORIZON ERC Grants

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Call for proposal

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(opens in new window) ERC-2025-ADG

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Host institution

HAWK HOCHSCHULE FUR ANGEWANDTE WISSENSCHAFT UND KUNST FACHHOCHSCHULE HILDESHEIM/HOLZMINDEN/GOTTINGEN
Net EU contribution

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€ 2 106 735,00
Address
HOHNSEN 4
31134 Hildesheim
Germany

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Region
Niedersachsen Hannover Hildesheim
Activity type
Higher or Secondary Education Establishments
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Total cost

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Beneficiaries (2)