It remains unclear why acute depletion of CTCF (CCCTC-binding factor) and cohesin only marginally affects expression of most genes despite substantially perturbing three-dimensional (3D) genome folding at the level of domains and structural loops. To address this conundrum, we used high-resolution Micro-C and nascent transcript profiling in mouse embryonic stem cells. We find that enhancer-promoter (E-P) interactions are largely insensitive to acute (3-h) depletion of CTCF, cohesin or WAPL. YY1 has been proposed as a structural regulator of E-P loops, but acute YY1 depletion also had minimal effects on E-P loops, transcription and 3D genome folding. Strikingly, live-cell, single-molecule imaging revealed that cohesin depletion reduced transcription factor (TF) binding to chromatin. Thus, although CTCF, cohesin, WAPL or YY1 is not required for the short-term maintenance of most E-P interactions and gene expression, our results suggest that cohesin may facilitate TFs to search for and bind their targets more efficiently. 

/pdf/enhancer-promoter-interactions-and-transcription-are-largely-1nvhxgj5.pdf

Enhancer–promoter interactions and transcription are largely maintained upon acute loss of CTCF, cohesin, WAPL or YY1

Conserved ATP-dependent chromatin remodelers establish and maintain genome-wide chromatin architectures of regulatory DNA during cellular lifespan, but the temporal interactions between remodelers and chromatin targets have been obscure. We performed live-cell single-molecule tracking for RSC, SWI/SNF, CHD1, ISW1, ISW2, and INO80 remodeling complexes in budding yeast and detected hyperkinetic behaviors for chromatin-bound molecules that frequently transition to the free state for all complexes. Chromatin-bound remodelers display notably higher diffusion than nucleosomal histones, and strikingly fast dissociation kinetics with 4-7 s mean residence times. These enhanced dynamics require ATP binding or hydrolysis by the catalytic ATPase, uncovering an additional function to its established role in nucleosome remodeling. Kinetic simulations show that multiple remodelers can repeatedly occupy the same promoter region on a timescale of minutes, implicating an unending 'tug-of-war' that controls a temporally shifting window of accessibility for the transcription initiation machinery.

Single-molecule imaging of chromatin remodelers reveals role of ATPase in promoting fast kinetics of target search and dissociation from chromatin.

Single-molecule tracking of transcription protein dynamics in living cells: seeing is believing, but what are we seeing?

In this article we propose a novel approach for comparing the persistent homology representations of two spaces (filtrations). Commonly used methods are based on numerical summaries such as persistence diagrams and persistence landscapes, along with suitable metrics (e.g. Wasserstein). These summaries are useful for computational purposes, but they are merely a marginal of the actual topological information that persistent homology can provide. Instead, our approach compares between two topological representations directly in the data space. We do so by defining a correspondence relation between individual persistent cycles of two different spaces, and devising a method for computing this correspondence. Our matching of cycles is based on both the persistence intervals and the spatial placement of each feature. We demonstrate our new framework in the context of topological inference, where we use statistical bootstrap methods in order to differentiate between real features and noise in point cloud data.

Cycle Registration in Persistent Homology with Applications in Topological Bootstrap

Super-resolution imaging can generate thousands of single-particle trajectories. These data can potentially reconstruct subcellular organization and dynamics, as well as measure disease-linked changes. However, computational methods that can derive quantitative information from such massive datasets are currently lacking. We present data analysis and algorithms that are broadly applicable to reveal local binding and trafficking interactions and organization of dynamic subcellular sites. We applied this analysis to the endoplasmic reticulum and neuronal membrane. The method is based on spatiotemporal segmentation that explores data at multiple levels and detects the architecture and boundaries of high-density regions in areas measuring hundreds of nanometers. By connecting dense regions, we reconstructed the network topology of the endoplasmic reticulum (ER), as well as molecular flow redistribution and the local space explored by trajectories. The presented methods are available as an ImageJ plugin that can be applied to large datasets of overlapping trajectories offering a standard of single-particle trajectory (SPT) metrics. 

https://doi.org/10.1016/j.crmeth.2022.100277

High-throughput super-resolution single-particle trajectory analysis reconstructs organelle dynamics and membrane reorganization

Enhancer-promoter dynamics are crucial for the spatiotemporal control of gene expression, but it remains unclear whether these dynamics are controlled by chromatin regulators, such as the nucleosome remodelling and deacetylase (NuRD) complex. The NuRD complex binds to all active enhancers to modulate transcription and here we use Hi-C experiments to show that it blurs TAD boundaries and increases the proximity of intermediate-range (~1 Mb) genomic sequences and enhancer-promoter interactions. To understand whether NuRD alters the dynamics of 3D genome structure, we developed an approach to segment and extract key biophysical parameters from 3D single-molecule trajectories of the NuRD complex determined using live-cell imaging. Unexpectedly, this revealed that the intact NuRD complex decompacts chromatin structure and makes NuRD-bound enhancers move faster, increasing the overall volume of the nucleus that these key regulatory regions explore. Interestingly, we also uncovered a rare fast-diffusing state of NuRD bound enhancers that exhibits directed motion. The NuRD complex reduces the amount of time that enhancers remain in this fast-diffusing state, which we propose might otherwise re-organise enhancer-promoter proximity. Thus, we uncover an intimate connection between a chromatin remodeller and the spatial dynamics of the local regions of the genome to which it binds.

/pdf/live-cell-3d-single-molecule-tracking-reveals-how-nurd-lqfm3yp7c1.pdf

Live-cell 3D single-molecule tracking reveals how NuRD modulates enhancer dynamics

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Live-cell 3D single-molecule tracking reveals how NuRD modulates enhancer dynamics