Kanazawa University NanoLSI Podcast: Chromatin Accessibility: A new avenue for gene editing

Chromatin Accessibility: A new avenue for gene editing

Hello and welcome to the NanoLSI podcast. Thank you for joining us today. In this episode we feature the latest research by researchers from Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, led by Yusuke Miyanari.

The research described in this podcast was published in Nature Genetics in February 2024

Kanazawa University NanoLSI website

https://nanolsi.kanazawa-u.ac.jp/en/

Chromatin Accessibility: A new avenue for gene editing

In a study recently published in Nature Genetics, researchers from Nano Life Science Institute (WPI-NanoLSI) at Kanazawa University explore chromatin accessibility, that is, endogenous access pathways to the genomic DNA, and its use as a tool for gene editing.

Our DNA is protected from unwanted external modifications by forming structures called nucleosomes that consist of threads of DNA wound around chunks of special proteins known as histones. This unique coiled shape prevents the access of undesirable molecules to a cell’s DNA. However, for vital genetic functions—such as DNA repair—the right set of proteins require access to these DNA fragments. This phenomenon known as ‘chromatin accessibility’ involves a privileged set of protein molecules, many of which are still unknown.

Now, researchers from Nano Life Science Institute (WPI-NanoLSI) at Kanazawa University, led by Yusuke Miyanari, have used advanced genetic screening methods to unravel chromatin accessibility and its pathways.

So how did they go about it?

For the investigation the team used a combination of two technologies—CRISPR screening and ATAC-see. While the former is a method to suppress the function of a desired set of genes, the latter is a means to identify which ones are essential for chromatin accessibility. Thus, using this method all genes playing a crucial role in chromatin accessibility could be pinned down.

With the help of these assays, novel pathways and individual players involved in chromatin accessibility were uncovered—some playing a positive role and some negative. Of these, one particular protein, TFDP1, showed a negative effect on chromatin accessibility. When it was suppressed, a significant increase in chromatin accessibility was observed, accompanied by nucleosome reduction. A deeper dive into the mechanism of TFDP1 revealed that it functions by regulating the genes responsible for production of certain histone proteins.

The team then focused their study towards exploring biotechnological applications of their findings. After suppressing TFDP1, two different approaches were tried. The first approach involved gene editing using the CRISPR/Cas9 tool. This revealed that deletion of TFDP1 made the gene editing process easier. Now, most chromatin accessibility occurs in nucleosome-depleted regions or NDRs. However, by suppressing TFDP1 chromatin accessibility occurred not only in NDRs but across other regions as well. Secondly, the depletion of TFDP1 aided the process of converting regular cells into stem cells, a massive step forward in cellular transformation.

This study identified new chromatin accessibility pathways and channels for exploring its potential even further. “Our study shows the significant potential to manipulate chromatin accessibility as a novel strategy to enhance DNA-templated biological applications, including genome editing and cellular reprogramming,” conclude the researchers.

Reference

Satoko Ishii, Taishi Kakizuka, Sung-Joon Park, Ayako Tagawa, Chiaki Sanbo, Hideyuki Tanabe, Yasuyuki Ohkawa, Mahito Nakanishi, Kenta Nakai, Yusuke Miyanari. Genome-wide ATAC-see screening identifies TFDP1 as a modulator of global chromatin accessibility. Nature Genetics, Feb

NanoLSI Podcast website