Our genome consists of 46 DNA polymers and when fully stretched, they can be as long as ~2 meters in total. However, when compacted to ~10𝜇 they form structures called chromosomes required for faithful division of cells. Such a high-density compaction state of chromatin is a well-defined state however the folding pathway to final state is still not well understood. In a relaxed state, chromatin take beads-on-string conformation—the bead is called nucleosome. Almost all nuclear activities are dependent on nucleosome dynamics and the relaxed state of the genome. Nucleosomes are formed by wrapping DNA around histone octamer. Researchers have been trying to explain how nucleosomes organize the genome. The DNA sequence and non-histone factors (NHFs) such as remodeling factors (RFs) and transcription factors (TFs) are some of the key molecular players that can directly interact and regulate genome organization and dynamics (fig. 1). Understanding these molecular components and the mechanisms of genome organization will not only solve questions that concern cellular aging, heterogeneity, differentiation, and evolution but also open new technologies in the field of personal medicine. Here we want to propose some key objectives of our research to understand the physical and sequence origin of nucleosome positioning and chromatin folding.

Physical and genomic determinants of nucleosome positioning

MNase-seq, ODM-seq, long read-seq, and other experiments suggest that nucleosome positioning in the genome is not random, but it is well organized. For instance, in the nearby strongly positioned nucleosome arrays, regulatory elements viz., nucleosome-free regions (NFRs) or nucleosome-depleted regions (NDRs), and nucleosome-inhibitory energy barriers (NIEBs) can be found [1–3] (Fig. 2). Interestingly, these regions correlate well with various vital genome activities viz., transcription, replication, and DNA-repair. Therefore, one of the main goals of my research is to understand what determines nucleosome positioning and how to predict it. To achieve this goal, we use statistical mechanics, computational methods and simulations, and artificial intelligence (AI) or machine learning (ML). The work will explain why some genomic regions are nucleosome-rich and some are not, which will in turn benefit experimental collaborators to design and ask more fundamental questions about how NHFs access DNA.

Chromatin folding pathway and stability

The evidence of 30nm chromatin fibre mostly come from in vitro studies. However, in vivo studies suggest that chromatin fibers are irregular, and the regular fibers are yet to be observed. The question is what determines the folding pathway of the irregular fibers? It has been shown that nucleosome positioning can affect the folding of 3D chromatin fiber by bringing genomic loci to physical contact referred to as “gene looping” [4–6]. However, in the presence of nucleosome breathing and the binding of NHFs the folding cannot be predicted by only the nucleosome positioning. To understand the folding problem, we will start by constructing a simple nucleosome-linker polymer model and study its motion using Brownian Dynamics (BD) simulations (Fig. 3). Next we will introduce nucleosome breathing and in vivo linker DNA distribution and calculate contact frequency and compare with experimental data.