Program Director

Principal Investigator

Awardee Organization

University Of Pittsburgh At Pittsburgh
United States

Fiscal Year
Activity Code
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

Imaging nanoscale chromatin folding in early carcinogenesis

This application is to evaluate the potential of a super-resolution microscopy system to image disrupted nanoscale chromatin folding as an early event in carcinogenesis and explore its potential to improve cancer risk stratification. Abnormal chromatin structure is among the most universal characteristics of tumor cells and has been used for clinical cancer diagnosis for two centuries. However, due to the diffraction-limited resolution of conventional light microscopy, only microscale structural abnormalities can be observed. As a result, cells undergoing early stages of malignant transformation often appear normal. Such limitation in image resolution has compromised our ability to accurately risk-stratify precursor lesions or distinguish aggressive from indolent forms. Recent advances in super-resolution fluorescence nanoscopy now enable us to image molecular-level chromatin structure down to a resolution of ~20-30 nm. Our group recently improved the throughput and robustness in stochastic optical reconstruction microscopy (STORM)-based super-resolution microscopy and enabled robust imaging of chromatin folding on the most widely used clinical samples. Built upon our preliminary studies that revealed a significant and gradual disruption of nanoscale chromatin folding in early carcinogenesis, this project will first further confirm the disrupted chromatin folding that accompanies carcinogenesis and identify their molecular characteristics and functional consequences. Second, we will optimize the workflow of super-resolution imaging system, sample preparation and image analysis to enable efficient and reproducible analysis of nanoscale chromatin folding in clinical tissue samples. We will also validate our finding of disrupted chromatin folding in patients with various colorectal precursor lesions and cancer. Third, we will evaluate the potential of imaging nanoscale chromatin folding to in patients with colorectal adenomatous polyps. This study will establish the scientific basis and underlying molecular profile of disrupted nanoscale chromatin folding in early carcinogenesis, opening a new avenue for risk stratification, facilitating the development and evaluation of new preventive strategies.


  • Mela CA, Liu Y. Application of convolutional neural networks towards nuclei segmentation in localization-based super-resolution fluorescence microscopy images. BMC bioinformatics. 2021 Jun 15;22(1):325. PMID: 34130628
  • Ma H, Liu Y. Robust emitter localization with enhanced harmonic analysis. Optics letters. 2021 Dec 1;46(23):5798-5801. PMID: 34851893
  • Xu J, Sun X, Kim K, Brand RM, Hartman D, Ma H, Brand RE, Bai M, Liu Y. Ultrastructural visualization of chromatin in cancer pathogenesis using a simple small-molecule fluorescent probe. Science advances. 2022 Mar 4;8(9):eabm8293. Epub 2022 Mar 4. PMID: 35245126
  • Ma H, Jiang W, Xu J, Liu Y. Enhanced super-resolution microscopy by extreme value based emitter recovery. Scientific reports. 2021 Oct 14;11(1):20417. PMID: 34650088
  • Ma F, Akolkar H, Xu J, Liu Y, Popova D, Xie J, Youssef MM, Benosman R, Hart RP, Herrup K. The Amyloid Precursor Protein Modulates the Position and Length of the Axon Initial Segment. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2023 Mar 8;43(10):1830-1844. Epub 2023 Jan 30. PMID: 36717226
  • Ma H, Liu Y. Embedded nanometer position tracking based on enhanced phasor analysis. Optics letters. 2021 Aug 15;46(16):3825-3828. PMID: 34388751