Cohesin Distribution Alone Predicts Chromatin Organization in Yeast via Conserved-Current Loop Extrusion Model

Core Concepts

The conserved-current loop extrusion (CCLE) model can accurately predict the topologically associating domain (TAD) scale chromatin organization in yeast based solely on cohesin ChIP-seq data, without requiring additional information about CTCF or other boundary elements.

Abstract

The article presents the conserved-current loop extrusion (CCLE) model, which extends the loop extrusion factor (LEF) model to interpret loop-extruding cohesin as a nearly-conserved probability current across the genome. The key insights are: The CCLE model can accurately predict the TAD-scale chromatin organization in interphase Schizosaccharomyces pombe and both meiotic and mitotic Saccharomyces cerevisiae, even though their Hi-C maps appear quite different. This suggests that loop extrusion by cohesin is the primary mechanism underlying TADs in these yeast systems, without the need for specific boundary elements like CTCF found in vertebrates. The model provides new estimates for loop extrusion parameters like LEF density and processivity, which align well with independent experimental observations. The CCLE model represents a modified paradigm for loop extrusion that goes beyond solely discrete, localized barriers to also include more continuous variation in loop extrusion rates across the genome. The ability to predict chromatin organization from cohesin distribution alone, without requiring additional information about specific boundary elements, extends the applicability of the LEF model to a broader range of organisms.

Stats

"TADs have led to the loop extrusion factor (LEF) model, where TADs arise from loop extrusion by cohesin complexes." "From cohesin ChIP-seq data alone, we thus derive a position-dependent loop extrusion rate, allowing for a modified paradigm for loop extrusion." "The model also gives new values for loop extrusion parameters such as the LEF density and processivity, which compare well to independent estimates."

Quotes

"To extend the LEF model across the tree of life, here, we propose the conserved-current loop extrusion (CCLE) model that interprets loop-extruding cohesin as a nearly-conserved probability current." "It follows that loop extrusion by cohesin is indeed the primary mechanism underlying TADs in these systems."

Key Insights Distilled From

Cohesin distribution alone predicts chromatin organization in yeast via conserved-current loop extrusion.

by Yuan,T., Yan... at www.biorxiv.org 10-06-2023

https://www.biorxiv.org/content/10.1101/2023.10.05.560890v3

Deeper Inquiries

How does the CCLE model's ability to predict chromatin organization from cohesin distribution alone compare to other approaches that incorporate additional genomic features or boundary elements?

The CCLE model's ability to predict chromatin organization solely from cohesin distribution presents a significant advancement compared to approaches that rely on additional genomic features or boundary elements. While other models often incorporate specific DNA sequences or binding proteins like CTCF to define TAD boundaries, the CCLE model takes a more universal approach by interpreting loop-extruding cohesin as a nearly-conserved probability current. This allows for a position-dependent loop extrusion rate derived from cohesin ChIP-seq data alone, enabling a more comprehensive and generalized understanding of chromatin organization. By not being reliant on specific genomic features, the CCLE model provides a more versatile framework that can be applied across different organisms, including those lacking known boundary elements like CTCF.

What are the potential limitations or caveats of the CCLE model, and how might it be further refined or extended to capture more complex aspects of chromatin organization?

Despite its strengths, the CCLE model does have potential limitations and caveats that should be considered. One limitation is that the model assumes a uniform loop extrusion rate across the genome, which may not fully capture the intricacies of chromatin organization where varying loop extrusion rates could play a role. Additionally, the model's reliance on cohesin ChIP-seq data alone may overlook other factors influencing chromatin structure. To address these limitations, the CCLE model could be refined by incorporating additional factors that influence loop extrusion dynamics, such as chromatin accessibility, histone modifications, or other chromatin-binding proteins. By integrating these factors into the model, it could better capture the complexity of chromatin organization and provide a more comprehensive understanding of the mechanisms driving TAD formation.

Given the insights into loop extrusion parameters provided by the CCLE model, what new experimental or computational investigations could be pursued to better understand the in vivo composition and dynamics of loop extrusion factors in yeast and other organisms?

The insights into loop extrusion parameters offered by the CCLE model open up new avenues for experimental and computational investigations to further understand the in vivo composition and dynamics of loop extrusion factors in various organisms. Experimental studies could focus on validating the predicted loop extrusion rates and processivity by directly measuring cohesin dynamics in live cells using advanced imaging techniques. Additionally, investigating the interplay between cohesin and other chromatin regulators through genetic perturbations or proteomic analyses could shed light on the composition of loop extrusion complexes in different cellular contexts. On the computational front, simulations could be used to explore how variations in loop extrusion parameters impact chromatin organization and gene regulation, providing insights into the functional consequences of altered loop extrusion dynamics. By combining experimental and computational approaches, a more comprehensive understanding of loop extrusion factors and their role in chromatin organization can be achieved.