Chromatin is a DNA–protein complex that is densely packed in the cell nucleus. The nanoscale chromatin compaction plays critical roles in the modulation of cell nuclear processes. However, little is known about the spatiotemporal dynamics of chromatin compaction states because it remains difficult to quantitatively measure the chromatin compaction level in live cells. Here, we demonstrate a strategy, referenced as DYNAMICS imaging, for mapping chromatin organization in live cell nuclei by analyzing the dynamic scattering signal of molecular fluctuations. Highly sensitive optical interference microscopy, coherent brightfield (COBRI) microscopy, is implemented to detect the linear scattering of unlabeled chromatin at a high speed. A theoretical model is established to determine the local chromatin density from the statistical fluctuation of the measured scattering signal. DYNAMICS imaging allows us to reconstruct a speckle-free nucleus map that is highly correlated to the fluorescence chromatin image. Moreover, together with calibration based on nanoparticle colloids, we show that the DYNAMICS signal is sensitive to the chromatin compaction level at the nanoscale. We confirm the effectiveness of DYNAMICS imaging in detecting the condensation and decondensation of chromatin induced by chemical drug treatments. Importantly, the stable scattering signal supports a continuous observation of the chromatin condensation and decondensation processes for more than 1 h. Using this technique, we detect transient and nanoscopic chromatin condensation events occurring on a time scale of a few seconds. Label-free DYNAMICS imaging offers the opportunity to investigate chromatin conformational dynamics and to explore their significance in various gene activities.

Optical interference microscopy is a powerful bioimaging technique by measuring the complex light fields associated with the specimen. Nowadays, the state-of-the-art interference microscopy makes it possible to directly visualize very small single biological nanoparticles and unlabeled macromolecules. The stable and indefinite linear scattering signal allows for continuous observation of the sample at a high speed, offering the opportunities to investigate single-molecule biophysics with the unprecedented details. Meanwhile, using interference microscopy to explore complex biological samples, such as a biological cell, emerges as an exciting research field. In this Perspective, we share our views on the impacts of optical interference microscopy on live cell imaging. Strategies for discriminating the scattering signals from different cell organelles and biological macromolecules are presented. In particular, the dynamic optical signal of live cells contains rich temporal information that is useful for enhancing the molecular specificity and functional information in label-free cell imaging. Finally, the challenges in three-dimensional imaging and turbidity suppression are discussed.

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We demonstrate a computational method to map the nuclear organization of live cells based on a deep-learning approach where the time-varying scattering signal is used to estimate the density of chromatin in the fluorescence image.

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