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.

Light absorption is a common phenomenon in nature, but accurate and quantitative absorption measurement at the nanoscale remains challenging especially in the application of widefield imaging. Here, we demonstrated optical widefield interferometric photothermal microscopy that allowed us to visualize and quantify the heat generation of single nanoparticles. The working principle was to measure the scattering signal due to the refractive index change of the surrounding media induced by the dissipated heat (known as the thermal lens effect). The sensitivity of our local heat measurement was a few nanowattsthe high sensitivity made it possible to detect single gold nanoparticles, as small as 5 nm. By changing the particle sizes, we found that, for small metallic nanoparticles (gold and silver nanoparticles < 40 nm), the photothermal signal was determined by the amount of the dissipated heat, independent of the particle size. A model was established to explain our experimental results, indicating that the photothermal signal was essentially contributed by the interferometric detection of the scattered field of the thermal lens. Importantly, on the basis of this model, we further investigated the photothermal signal of large nanoparticles (40–100 nm for our setup) where the scattered light of the particle was considerable relative to the probe light. In this regime, the strong scattered field of the particle effectively served as the main reference beam that interfered with the scattered field of the thermal lens, resulting in an enhanced photothermal signal. Our work illustrates an important fact that the measured photothermal signal is fundamentally affected by the scattering property of the sample. This finding paves the way to accurate and sensitive absorption-based imaging in complex biological samples where the scattering is often spatially heterogeneous.

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